Diphenylethylene compounds and compositions thereof

Abstract

The present application relates to uses of diphenylethylene compounds or pharmaceutically acceptable salts, prodmgs and / or solvates thereof and / or pterostilbene or pharmaceutically acceptable salts, prodrugs and / or solvates thereof, and to compositions comprising them and further combination with a curcuminoid and a catechin in the treatment of papillomavirus infections, and diseases, disorders or conditions arising from a papillomavirus infections such as cancer.

Description

DIPHENYLETHYLENE COMPOUNDS AND COMPOSITIONS THEREOFFIELD OF THE INVENTION

[0001] The present application relates to uses of diphenylethylene compounds and compositions thereof in therapy. In certain embodiments, the present application relates to uses of diphenylethylene compounds and compositions thereof in the treatment of papillomavirus infections, and diseases, disorders or conditions arising from a papillomavirus infections such as cancer.

[0002] All publications, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes and to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be constmed as an admission that such is prior art to the present invention.CROSS REFERENCE TO RELATED APPLICATIONSThis application claims priority from U.S. Provisional Patent Application No. 63 / 526,122 filed on July 11, 2023, the contents of which are hereby expressly incorporated by reference herein.BACKGROUND

[0003] Diphenylethylene compounds have aromatic groups bonded to each end of a carbon-carbon double bond, are versatile in scope, and participate in various biochemical, photochemical, and photochromatic reactions. Plants produce incredibly diverse and bioactive forms, characterized by the presence of a 1,2-diphenylethylene nucleus, with (E)-stilbenes being the most biologically relevant stereoisomer.

[0004] There are more than 400 natural stilbenes, many of which are phytoalexins produced by plants in response to injury by pathogenic bacteria, fungi, and viruses. These rich, bioactive compounds have been the basis for using many medicinal plants to treat human diseases and are a source of drug discovery for antiviral and antimicrobial therapeutics.

[0005] Human papillomavirus (HPV) consists of a group of viruses that infect cutaneous and mucosal surfaces to cause a spectrum of epithelial lesions, ranging from benign growths (e.g., warts) to cancers. There are more than 400 types of HPV that are classified into five different genera, named Alpha,Beta, Gamma, Mu, and Nupapillomaviruses. About 80% of men and women acquire HPV at some point in their lifetime.

[0006] Papillomaviridae is a family of small non-enveloped DNA viruses. They infect various species, such as birds, reptiles, and mammals, such as dogs, cats, rabbits, mice, and humans. Collectively, these viruses are known as papillomaviruses. They are host-specific and do not cross species. Thus, human papillomavirus (HPV) is only transmitted between people and infects cutaneous or mucous membranes. HPV can cause papillomas (warts) on the skin, larynx, or urogenital area, while some genotypes induce malignant transformation to cause overt cancer. There are more than 400 types of HPV, and many are classified as either low or high-risk HPVs depending on their cancer-causing potential.

[0007] While most HPV infections are transient, 10-15% become chronic, and these persistent infections lead to malignancies. HPV is the main cause of cervical cancer. In the US, 1.8 million women have chronic cervical HPV, leading to 200,000 cervical precancer cases each year. Globally, over 28 million women with persistent cervical HPV infection and are at risk of developing cervical carcinoma These patients have no specific treatment options. HPV vaccines can prevent HPV and cervical cancer. However, they are ineffective in treating those with established infections.

[0008] Furthermore, only 15% of eligible females worldwide have received the full HPV vaccine series. In the absence of a cure for HPV, physicians' standard practice is to offer a "watch and wait" approach whereby patients infected with a high-risk HPV are just followed for the development of precancers. Surgical and ablative interventions are the only options to treat precancerous lesions once they develop. This makes HPV infection one of the most problematic viral infections in women, with cervical cancer remaining the 4thmost common malignancy in females worldwide.

[0009] HPV infection also causes a spectrum of diseases in men and women, leading to additional morbidity and mortality. Twenty-five percent of men in the US carry genital oncogenic HPV infections that, at present, cannot be treated and are a major source of continued viral spread. HPV infection also induces other malignancies such as oral, anal, vaginal, and penile carcinoma. Low-risk HPV genotypes cause a variety of difficult-to-treat and painful papillary growths (warts) on the skin and external genitals, as well as laryngeal papillomas and lesions on body surfaces. The CDC estimates that each year there are 14 million new cases of HPV infection. The US healthcare system's annual cost just for cervical HPV diagnosis and treatment reaches the billions, making it the second-costliest sexually transmitted infection. Currently, there are no known antivirals, and this infection remains incurable.

[0010] Resveratrol (trans-3,5,4' trihydroxystilbene) is a polyphenolic phytoalexin that was first isolated and identified from the roots of Veratrum grandiflorum O.Loes and possesses anticancer and antiviral properties. In preclinical studies, resveratrol modulates a large number of cell-signaling and regulatory proteins, including Wnt, nuclear factor -KB (NF-KB), cytokines, caspases, Notch, matrix metalloproteinases (MMPs), 5 ’ -AMP-activated protein kinase (AMPK), sirtuin type 1 (SIRT1), and tumor necrosis factor a (TNF-a). These promising studies have led to clinical trials using resveratrol to treat varied diseases or disorders. However, the successes seen in laboratory studies have not translated into the clinical setting. Most clinical trials have had poor or minimal positive results. This is due to resveratrol's low solubility, rapid degradation in an aqueous environment, and overall poor target tissue concentration to achieve biological effects. Even more problematic is the observation that cancer cells acquire resveratrol resistance (Colin D.J. et al., Cell Death Dis. 2014 Nov 20;5(l l):el533 Aires V, et al. Nutrients. 2019 Sep 4; l l(9):2098; Park D, et al. Sci Rep. 2016 Feb 23;6:21772; Nie JH, et al. Int J Mol Sci. 2019 Jan 7;20(l): 191; Amintas S, et al Journal of Functional Foods, Volume 99, December 2022, 105345 doi.org / 10.1016 / j .jff.2022. 105345). Though promising in preclinical studies, resveratrol has not been effective in patients because it suffers from low systemic bioavailability. Even if the compound reaches disease cells, resistance to resveratrol emerges.

[0011] Over millennia plants have evolved strong defenses against pathogenic microbes, including viruses A plant's immune system is mediated by chemical messengers. Selective pressure has allowed some plant species to thrive by creating unique phytochemicals. These small molecules activate potent antiviral mechanisms to confer a robust immune response. Plants do not have immune cells; they rely solely on these bioactive compounds. Similar to mammals, a plant's immune response is "polyclonal". Multiple phytoalexins are activated and released in response to a viral infection. Many plant species possess diverse polyphenols with unique and potent biologic properties.

[0012] A pharmaceutical mixture of curcumin, (-)-epicatechin gallate and resveratrol was found to be synergistic in eliminating various HPV (+) cancer cell lines cancerous and precancerous tissue. (Mukherjee et al., 2017 Oncotarget. 2017 Mar 29;8(37);WO 2015 / 081319; US 2016 / 0287533, Einbond et al. 2021, Br J Cancer. 2021 Mar; 124(5):901-913). However, cancer cells become resistant to resveratrol contributing to its limited clinical efficacy with resveratrol-based drugs (Colin DJ. et al., Cell Death Dis. 2014 Nov 20;5(l l):el533, Aires V, et al. Nutrients. 2019 Sep 4; 11(9) 2098; Park D, et al. Sci Rep. 2016 Feb 23;6:21772; Nie JH, et al. Int J Mol Sci. 2019 Jan 7;20(l): 191 ; Amintas S, et al. Journal of Functional Foods, Volume 99, December 2022, 105345. doi.org / 10. 1016 / j.jff.2022.105345).SUMMARY OF THE INVENTION

[0013] The present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereofwhereinX1and X2are independently selected from OH and OR1;X3and X4are independently selected from OH and OCH3; and

[0014] The present application also includes a method of treating or preventing a disease, disorder or condition caused by a papillomavirus infection, comprising administering a therapeutically effective amount of one or more compounds of Formula I as defined in claim 1, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to a subject in need thereof

[0015] In some embodiments, the method comprises administering an effective amount of two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with a curcuminoid and a catechin.

[0016] The present application includes a method of treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising administering to the subject, an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0017] In some embodiments, the method comprises administering to the subject, an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with a curcuminoid and a catechin.

[0018] The present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereofwhereinX1and X2are independently selected from OH and OR1;X3and X4are independently selected from OH and OCHs;andin combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0019] The present application also includes a method of treating or preventing a disease, disorder or condition caused by a papillomavirus infection, comprising administering a therapeutically effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to a subject in need thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0020] In some embodiments, the method comprises administering to the subject, an effective amount of one or more compounds of Formula I in combination with pterostilbene, or a pharmaceuticallyacceptable salt, prodrug and / or solvate thereof, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in further combination with a curcuminoid and a catechin.

[0021] The present application also includes a pharmaceutical composition comprising one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin,whereinX1to X4are as defined above.

[0022] In some embodiments, the pharmaceutical composition comprises one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin,

[0023] In some embodiments, the composition comprises two or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0024] The present application includes a pharmaceutical composition for treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin.

[0025] The present application includes a pharmaceutical composition comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0026] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole.DETAILED DESCRIPTIONI. Definitions

[0027] Unless otherwise indicated, the definitions and embodiments described in this section and in other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0028] All features disclosed in the specification, including the claims, abstract, and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Each feature disclosed in the specification, including the claims, abstract, and drawings, can be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise

[0029] The term “composition of the application” or “composition of the present application” and the like as used herein refers to a composition comprising one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, a curcuminoid and a catechin; pterostilbene, or a salt, prodrug and / or solvate thereof, a curcuminoid and a catechin; or a combination of one or more compounds Formula I, or a salt, prodrug and / or solvate thereof, pterostilbene, or a salt, prodrug and / or solvate thereof, and optionally a curcuminoid and a catechin.

[0030] The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0031] The term “consisting essentially of’, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and / or steps.

[0032] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ± 5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0033] As used in this application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise.

[0034] In embodiments comprising an “additional” or “second” component, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0035] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and / or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process / method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so

[0036] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present.

[0037] The term “cell” as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.

[0038] The term “subject” as used herein includes all members of the animal kingdom including mammals. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0039] The term “pharmaceutically acceptable” means compatible with the treatment of subjects.

[0040] The term “pharmaceutically acceptable carrier” or vehicle means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with an active ingredient (for example, one or more compounds of the application) to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0041] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.

[0042] An acid addition salt suitable for, or compatible with, the treatment of subjects is any nontoxic organic or inorganic acid addition salt of any basic compound.

[0043] A base addition salt suitable for, or compatible with, the treatment of subjects is any nontoxic organic or inorganic base addition salt of any acidic compound.

[0044] The term “solvate” as used herein means a compound, or a salt of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered.

[0045] The term “prodrug” as used herein means a compound, or salt of a compound, that, after administration, is converted into an active drug.

[0046] The term “viral infection” as used herein refers to an invasion of cells or bodily tissues by one or more foreign, undesirable viruses.

[0047] The term “administered” as used herein means administration of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, prodrug and / or solvate thereof or compositions comprising a compound or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to a cell either in cell culture or in a subject

[0048] As used herein, the term “effective amount”, “therapeutically effective amount” or “antiviral-effective amount” means an amount of a compound or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, or compositions comprising a compound or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, that is effective, at dosages and for periods of time necessary to achieve the desired result, including therapeutic and prophylactic results.

[0049] The term “subject” as used herein includes all members of the animal kingdom, including mammals, and suitably refers to humans. Thus the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0050] The term “pharmaceutical composition” as used herein refers to a composition of matter for pharmaceutical use.

[0051] The term “parenteral” as used herein means taken into the body or administered in a manner other than through the gastrointestinal tract.

[0052] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of a disease, disorder or condition, stabilized (i.e. not worsening) state of a disease, disorder or condition, preventing spread of a disease, disorder or condition, delay or slowing of a disease, disorder or condition progression, amelioration or palliation of a disease, disorder or conditionstate, diminishment of the reoccurrence of a disease, disorder or condition, inhibiting or reducing a disease, disorder or condition and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment.

[0053] “Palliating” an infection and / or disease means that the extent and / or undesirable clinical manifestations of an infection and / or disease are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the infection and / or disease.

[0054] The term “prevention” or “prophylaxis” or “prophylactic” and the like as used herein refers to a reduction in the risk or probability of a subject becoming afflicted with a viral infection and / or a disease caused by a viral infection or manifesting a symptom associated with a viral infection or a disease caused by a viral infection.

[0055] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds, that is effective, at dosages and for periods of time necessary to achieve a desired result.

[0056] The term “disease, disorder or condition caused by a papillomavirus infection” means that the disease, disorder or condition to be treated is affected by and / or modulated by either direct or indirect, a papillomavirus infection.

[0057] When used, for example, with respect to the methods of treatment, uses, compositions and kits of the application, a subject, for example a subject “in need thereof’ is a subject who has been diagnosed with, is suspected of having, may come in to contact with, and / or was previously treated for a papillomavirus infection or a disease caused by a papillomavirus infection.

[0058] The term “papillomavirus” as used herein refers a virus of the papillomaviridae family

[0059] The term “human papillomavirus infection” or “HPV infection” is an infection of a human papillomavirus.

[0060] The term “resveratrol” as used herein refers to a compound having the chemical name: (E)- 5-(4-hydroxystyryl)benzene- 1,3 -diol or trans-3,5,4'-trihydroxystilbene and having the following chemical structure and numbering

[0061] The term "resveratrol resistant cancer" refers a cancer showing very low sensitivity to treatment with resveratrol so that the symptoms thereof are not improved, relieved, alleviated, or treated by the resveratrol. The resveratrol resistant cancer can be a cancer originally resistant to treatment with a resveratrol, or the resveratrol resistant cancer can be a cancer not originally resistant to resveratrol.II. Methods and Uses of the Application

[0062] The Applicant has identified certain plant species, for example medicinal rhubarb plant species, which contain trans-resveratrol and further investigated other diphenylethylene compounds present in the plant species for anti-papillomavirus activity such as anti-human papillomavirus (HPV) activity. To the best of the Applicant’s knowledge, the medicinal rhubarb plant species has not been previously investigated for anti-papillomavirus compounds.

[0063] In an embodiment, a drug screen of the other identified natural diphenylethylene compounds present in the medicinal rhubarb plant species (including Rheum rhaponticum and Rheum rhabarbarum) that were known to contain resveratrol was performed. Of the other compounds identified, candidate diphenyl ethylene phytochemicals were selected which possessed the 1,2-diphenyl ethylene scaffold in the trans configuration. The selected diphenylethylene compounds were tested to establish a dose-response curve based on their ability to eliminate HPV-18 (+) HeLa cells. This HPV-18 (+) HeLa cervical cancer line was also used to develop subclonal populations of HeLa cells, demonstrating strong resistance to resveratrol, designated HeLa-GSl. The most active of the identified compounds (IC50 < 30 pM) were then tested against a newly developed resveratrol-resistant cell line, HeLa-GSl. The Applicants identified diphenyl ethylenes compounds having unexpectedly good cytotoxicity against HPV (+) cells.

[0064] The Applicant then investigated the activity of combinations of the identified diphenylethylene compounds and in further combination with a curcuminoid, such as curcumin, and a catechin, such (-)-epigallocatechin gallate (EGCg), and found compound combinations demonstrating high and synergistic anti-papillomavirus activity. i) Methods and uses of compounds of Formula I

[0065] The present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereofwhereinX1and X2are independently selected from OH and OR1;X3and X4are independently selected from OH and OCH3; and

[0066] The present application also includes a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, for treating or preventing a papillomavirus infection in a subject; a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, for preparation of a medicament for treating or preventing a papillomavirus infection in a subject; and one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, for use to treat or prevent a papillomavirus infection in a subject.

[0067] In some embodiments, the papillomavirus infection is an infection of at least one papillomavirus. In some embodiments, the papillomavirus infection is a human papillomavirus (HPV) infection. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from 1 (HPV-1), 2 (HPV-2), 3 (HPV-3), 4 (HPV-4), 5 (HPV-5), 6 (HPV-6), 8 (HPV-8), 11 (HPV-11), 16 (HPV-16), 18 (HPV-18), 21 (HPV-21), 22 (HPV-22), 23 (HPV-23), 27 (HPV-27), 29 (HPV-29), 31 (HPV- 31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 57 (HPV-57) 58 (HPV-58), 59 (HPV-59) and 68 (HPV-68). In some embodiments, the HPV infection is aninfection of one or more HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. In some embodiments, HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 cause cancer. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from HPV genotypes 16 and 18. In some embodiments, the HPV infection is an infection of HPV genotype 16. In some embodiments, the HPV infection is an infection of HPV genotype 18. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from 1, 3, 27, 29, and 57. In some embodiments, the HPV genotypes are selected from 1, 3, 27, 29, or 57 cause common warts. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from 1, 2, 3, 4, 27, 29, and 57. In some embodiments, the HPV genotypes selected from 1, 2, 3, 4, 27, 29, and 57 cause plantar warts such as deep palmoplantar warts.

[0068] As the compounds of Formula I have been shown active against the HPV-16 (+) and HPV- 18 (+) cervical cancer cell lines and resveratrol resistant cancer cell lines, the compounds of Formula I have are useful for treating diseases, disorders or conditions caused by a papillomavirus infection

[0069] Accordingly, the present application also includes a method of treating or preventing a disease, disorder or condition caused by a papillomavirus infection, comprising administering a therapeutically effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to a subject in need thereof

[0070] The present application also includes a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for treatment or prevention of a disease, disorder or condition caused by a papillomavirus infection, as well as a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for the preparation of a medicament for treatment or prevention of a disease, disorder or condition caused by a papillomavirus infection. The application further includes one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for use in treating or preventing a disease, disorder or condition caused by a papillomavirus infection.

[0071] In some embodiments, the disease, disorder or condition caused by a papillomavirus infection is a papillomavirus-related cancer or precancer (dysplasia). In some embodiments, the disease, disorder or condition caused by a papillomavirus infection is papillomavirus-related cancer. In some embodiments, the papillomavirus-related cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer and skin cancer, and combinations thereof. In some embodiments, the papillomavirus-related cancer is cervical cancer.

[0072] In some embodiments, the papillomavirus-related cancer is a cancer caused by one or more HPV genotypes selected from 16 (HPV-16), 18 (HPV-18), 31 (HPV-31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 58 (HPV-58), 59 (HPV-59) and 68 (HPV-68).In some embodiments, the papillomavirus-related cancer is a cancer caused by one or both HPV genotypes 16 (HPV-16) and 18 (HPV-18). In some embodiments, the papillomavirus-related cancer is a cancer caused by HPV genotype 16 (HPV-16). In some embodiments, the papillomavirus-related cancer is a cancer caused by HPV genotype 18 (HPV-18).

[0073] In some embodiments, the papillomavirus-related cancer is a papillomavirus-related cancer as defined above that is resveratrol resistant. Therefore, in some embodiments, the papillomavirus-related cancer is a resveratrol resistant cancer. Accordingly, in some embodiments, the disease, disorder or condition caused by a papillomavirus infection is a resveratrol resistant cancer.

[0074] In some embodiments, the disease, disorder or condition caused by a papillomavirus infection is selected from warts and laryngeal papilloma and combinations thereof In some embodiments, the disease, disorder or condition caused by a papillomavirus infection is warts. In some embodiments, the warts are caused by one or more of HPV-1, HPV-2, HPV-3, HPV-4, HPV-6, HPV-8, HPV-11, HPV-27, HPV-29, and HPV-57. In some embodiments, the warts are selected from common warts, flat warts, filiform warts, mosaic warts, plantar warts, periungual warts, anal warts and genital warts and combinations thereof. In some embodiments, the genital warts are selected from vaginal and anal warts and combinations thereof. In some embodiments, the warts are plantar warts.

[0075] In some embodiments, the compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof treats or prevents a papillomavirus infection or treats or prevents a disease, disorder or condition caused by a papillomavirus infection by inhibiting papillomavirus replication.

[0076] In some embodiments, one of X1and X2is OR1and the other of X1and X2is OH. In some embodiments, X1is ORxand and X2is OH.

[0077] In some embodiments, R1has the following configuration:

[0078] In some embodiments, X1and X2are both OH.

[0079] In some embodiments, X3and X4are both OH. In some embodiments, X3and X4are both OCHj. In some embodiments, one of X3and X4is OH and the other of X3and X4is OCH3. In some embodiments, X3is OH and X4is OCH3.

[0080] In some embodiments, the one or more compounds of Formula I are selected from one or more compounds listed belowor a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0081] The Applicants have shown that combinations of two or more compounds of Formula (I) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, have improved activity or work synergistically against various cancer cells lines. Accordingly, in some embodiments, the methods and uses comprise administering to the subject, an effective amount of two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0082] In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 0.5:1 to about 1:10, about 05:1 to about 1:8, about 05:1 to about 1:5, about 05:1 to about 1:4, about 05:1 to about 1:375, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, or about 1:1 to about 1:2. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, about 1:1 to about 1:2. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in molar ratio of about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in molar ratio of about 1:1.

[0083] The Applicants have further shown that combinations of one or more compounds of Formula (I) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, in further combination with a curcumin and a catechin have improved activity in various cancer cells lines. Accordingly, in some embodiments, the methods and uses comprise administering to the subject, an effective amount of one ormore compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with a curcuminoid and a catechin.

[0084] In an exemplary embodiment, the Applicants have shown that the combinations of two or more compounds of Formula (I) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, in further combination with a curcumin and a catechin have further improved activity and work synergistically against various cancer cell line. Accordingly, in some embodiments, the methods and uses comprise administering to the subject, an effective amount of two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with a curcuminoid and a catechin.

[0085] In some embodiments, the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, are administered or used in a molar ratio of about 1-16:0.25-4: 1-40, about 1-16: 1-4: 10-40, about 1-10: 1-3 : 1-30, about 4-12: 1-3: 15-35, or about 6-8:2-3:20-30 of the curcuminoid to the catechin to the of the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, are administered or used in a molar ratio of about 1-16: 1-4:10-40, about 1-10: 1-3 :1-30, about 4-12: 1-3: 15-35 or about 6-8:2-3 :20-30 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, are administered or used in a molar ratio of about 16:2:25, about 8:4:25, about 4: 1:20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, are administered or used in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0086] In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 0.5: 1 to about 1 : 10, about 0.5: 1 to about 1 :8, about 0.5: 1 to about 1 :5, about 0.5: 1 to about 1 :4, about 0.5: 1 to about 1 :3.75,about 0.5: 1 to about 1 :4, about 1 : 1 to about 1 :4, about 1 :1 to about 1 :3.75, about 1: 1 to about 1:3, or about 1 : 1 to about 1 :2. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 0.5: 1 to about 1 :3.75, about 0.5: 1 to about 1 :4, about 1 : 1 to about 1 :4, about 1 : 1 to about 1:3.75, about 1 : 1 to about 1 :3, about 1 :1 to about 1 :2. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 1 :8, about 1 :5, about 1 :4, about 1 :3.75, about 1 :3, about 1:2 or about 1 : 1. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in molar ratio of about 1 :4, about 1 :3.75, about 1 :3, about 1 :2 or about 1 :1. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in molar ratio of about 1 : 1.

[0087] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bi sdemeth oxy curcumin, tetrahydrobisdemethoxycurcumin, or a curcumin ester and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0088] In one embodiment, the curcuminoid is tetrahydrocurcumin.

[0089] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate, ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)- GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epi gallocatechin gallate.

[0090] In an exemplary embodiment, the compound of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is selected from 1-1 (isorhaponti genin) and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0091] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 16:2:25, about 8:4:25, about 4: 1 :20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to 1-3 or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt,prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25. Accordingly, in an exemplary embodiment, the present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with a curcuminoid and a catechin, wherein the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25.

[0092] In another exemplary embodiment, the two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25. In some embodiments, the 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are further administered or used in molar ratio of about 1 :3.75 of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to I- 1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. Accordingly, in an exemplary embodiment, the present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with a curcuminoid and a catechin,wherein the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are T-l (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25, and the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1 :3.75. ii) Methods and uses of compounds of Pterostilbene

[0093] In some embodiments, the Applicants have shown that pterostilbene has activity against resveratrol resistant cell lines. Accordingly, the present application includes method of treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising administering to the subject, an effective amount of pterostilbene,or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0094] The present application also includes a use of pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, for treating a resveratrol resistant cancer in a subject; a use of pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, for preparation of a medicament for treating or preventing a resveratrol resistant cancer in a subject; and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, for use to treat or prevent a resveratrol resistant cancer in a subject.

[0095] In some embodiments, the resveratrol resistant cancer is a papillomavirus-related cancer or precancer (dysplasia). Therefore, in some embodiments, the methods and uses of pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are for treating or preventing resveratrol resistant papillomavirus-related cancers or precancers.

[0096] In some embodiments, the resveratrol resistant cancer is papillomavirus-related cancer. In some embodiments, the papillomavirus-related cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer and skin cancer, and combinations thereof. In some embodiments, the papillomavirus-related cancer is cervical cancer.

[0097] In some embodiments, the papillomavirus-related cancer is a cancer caused by one or more HPV genotypes selected from 16 (HPV-16), 18 (HPV-18), 31 (HPV-31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 58 (HPV-58), 59 (HPV-59) and 68 (HPV-68). In some embodiments, the papillomavirus-related cancer is a cancer caused by one or both HPV genotypes 16 (HPV-16) and 18 (HPV-18). In some embodiments, the papillomavirus-related cancer is a cancer caused by HPV genotype 16 (HPV-16). In some embodiments, the papillomavirus-related cancer is a cancer caused by HPV genotype 18 (HPV-18).

[0098] In some embodiments, pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof treats or prevents resveratrol resistant papillomavirus-related cancer or precancer by inhibiting papillomavirus replication.

[0099] The Applicants have further shown that pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, in combination with a curcumin and a catechin have further improved activity against various cancer cells lines. Accordingly, in some embodiments, the methods and uses comprise administering to the subject, an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with a curcuminoid and a catechin.

[0100] In some embodiments, the curcuminoid, the catechin and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 1-16:0.25-4: 1-40, about 1-16: 1-4: 10-40, about 1-10: 1-3:1-30, about 4-12: 1-3 :15-35, or about 6-8:2- 3:20-30 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, , the curcuminoid, the catechin and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 1-16: 1-4: 10-40, about 1-10: 1-3: 1-30, about 4-12: 1-3: 15-35 or about 6-8:2-3:20-30 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 6:2:25, about 8:4:25, about 4: 1 :20, about 4:2:25, about 8:1 :25, about 4:1 :6, or about 8:2:25 of the curcuminoid to the catechin to the pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments,the curcuminoid, the catechin and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0101] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bi sdemeth oxy curcumin, tetrahydrobisdemethoxycurcumin, or a curcumin ester and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0102] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)- GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epigallocatechin gallate.

[0103] In an exemplary embodiment, the curcuminoid is curcumin and the catechin is (-)- epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25. Accordingly, the present application includes method of treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising administering to the subject, an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, in combination with a curcuminoid and a catechin, wherein the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25 iii) Methods and uses of combinations of compounds of Formula I and pterostilbene

[0104] The Applicants have shown that combinations of one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof have improved activity and work synergistically against various cancer cells lines.

[0105] Accordingly, the present application also includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereofwhereinX1to X4are as defined above for Formula I. in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0106] The present application also includes a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for treating or preventing a papillomavirus infection in a subject; a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for preparation of a medicament for treating or preventing a papillomavirus infection in a subject; and one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for use to treat or prevent a papillomavirus infection in a subject.

[0107] In some embodiments, the papillomavirus infection is an infection of at least one papillomavirus. In some embodiments, the papillomavirus infection is a human papillomavirus (HPV) infection. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from 1 (HPV-1), 2 (HPV-2), 3 (HPV-3), 4 (HPV-4), 5 (HPV-5), 6 (HPV-6), 8 (HPV-8), 11 (HPV-11), 16 (HPV- 16), 18 (HPV-18), 21 (HPV-21), 22 (HPV-22), 23 (HPV-23), 27 (HPV-27), 29 (HPV-29), 31 (HPV- 31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 57 (HPV-57) 58 (HPV-58), 59 (HPV-59) and 68 (HPV-68). In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) In some embodiments, HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 cause cancer. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from HPV genotypes 16 and 18. In some embodiments, the HPV infection is an infection of HPV genotype 16. In some embodiments, the HPV infection is an infection of HPV genotype 18. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from 1, 3, 27, 29,and 57. In some embodiments, HPV genotypes selected from 1, 3, 27, 29, or 57 cause common warts. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from 1 , 2, 3, 4, 27, 29, and 57. In some embodiments, HPV genotypes selected from 1, 2, 3, 4, 27, 29, and 57 cause plantar warts such as deep palmoplantar warts.

[0108] The present application also includes a method of treating or preventing a disease, disorder or condition caused by a papillomavirus infection, comprising administering a therapeutically effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to a subject in need thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0109] The present application also includes a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for treatment or prevention of a disease, disorder or condition caused by a papillomavirus infection, as well as a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for the preparation of a medicament for treatment or prevention of a disease, disorder or condition caused by a papillomavirus infection. The application further includes one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for use in treating or preventing a disease, disorder or condition caused by a papillomavirus infection.[001 10] In some embodiments, the disease, disorder or condition caused by a papillomavirus infection is a papillomavirus-related cancer or precancer (dysplasia). In some embodiments, the disease, disorder or condition caused by a papillomavirus infection is papillomavirus-related cancer. In some embodiments, the papillomavirus-related cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer and skin cancer, and combinations thereof. In some embodiments, the papillomavirus-related cancer is cervical cancer.

[0111] In some embodiments, the papillomavirus-related cancer is a cancer caused by one or more HPV genotypes selected from 16 (HPV-16), 18 (HPV-18), 31 (HPV-31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 58 (HPV-58), 59 (HPV-59) and 68 (HPV-68). In some embodiments, the papillomavirus-related cancer is a cancer caused by one or more HPV genotypes selected from 16 (HPV-16) and 18 (HPV-18).. In some embodiments, the papillomavirus-relatedcancer is a cancer caused by one or both HPV genotypes 16 (HPV-16) and 18 (HPV-18). In some embodiments, the papillomavirus-related cancer is a cancer caused by HPV genotype 16 (HPV-16). In some embodiments, the papillomavirus-related cancer is a cancer caused by HPV genotype 18 (HPV-18).

[0112] In some embodiments, the papillomavirus-related cancer is a papillomavirus-related cancer as defined above that is resveratrol resistant. Therefore, in some embodiments, the papillomavirus-related cancer is a resveratrol resistant cancer. Accordingly, in some embodiments, the disease, disorder or condition caused by a papillomavirus infection is a resveratrol resistant cancer.

[0113] In some embodiments, the disease, disorder or condition caused by a papillomavirus infection is selected from warts and laryngeal papilloma and combinations thereof. In some embodiments, the disease, disorder or condition caused by a papillomavirus infection is warts. In some embodiments, the warts are caused by one or more of HPV-2, HPV-3, HPV-4, HPV-27, HPV-29, and HPV-57. In some embodiments, the warts are selected from common warts, flat warts, filiform warts, mosaic warts, plantar warts, periungual warts and genital warts and combinations thereof In some embodiments, the genital warts are selected from vaginal and anal warts and combinations thereof. In some embodiments, the warts are plantar warts.

[0114] In some embodiments, the compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof treats or prevents a papillomavirus infection or treats or prevents a disease, disorder or condition caused by a papillomavirus infection by inhibiting papillomavirus replication.

[0115] In some embodiments, one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 8:1 to about 1 : 10, about 4: 1 to about 1 :10, about 2: 1 to about 1 : 10, about 8: 1 to about 1 :5, about 4: 1 to about 1 :5, about 2: 1 to about 1 :5, about 0.5:1 to about 1 : 10, about 0.5: 1 to about 1 :8, about 0.5: 1 to about 1 :5, about 0.5: 1 to about 1 :4, about 0.5: 1 to about 1:3.75, about 0.5:1 to about 1 :4, about 1 : 1 to about 1 :4, about 1 :1 to about 1 :3.75, about 1 : 1 to about 1 :3, about 1 : 1 to about 1 :2. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 0 5: 1 to about 1 :3.75, about 0.5: 1 to about 1 :4, about 1 : 1 to about 1 :4, about 1 : 1 to about 1 :3.75, about 1 : 1 to about 1 :3, about 1 : 1 to about 1:2. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceuticallyacceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 1 :8, about 1 :5, about 1 :4, about 1 :3.75, about 1 :3, about 1 :2 or about 1 : 1. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in molar ratio of about 1 :5, about 1 :4, about 1 :3.75, about 1 :3, about 1 :2 or about 1 : 1. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in molar ratio of about 1 :5 to about 1 : 1. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in molar ratio of about 1 :5. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in molar ratio of about 1 :3 75 In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and are administered or used in molar ratio of about 1 : 1.

[0116] The Applicants have further shown that combinations of one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in further combination with a curcumin and a catechin have improved activity and work synergistically against various cancer cells lines. Accordingly, in some embodiments, the methods and uses comprise administering to the subject, an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in further combination with a curcuminoid and a catechin.

[0117] In some embodiments, the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 1-16:0.25-4: 1-40, about 1-16: 1-4: 10-40, about 1-10: 1-3:1-30, about 4-12: 1-3 : 15-35, or about 6-8:2- 3:20-30 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and theone or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 16: 1-4: 10-40, about 1-10: 1-3 : 1-30, about 4-12: 1-3 : 15-35 or about 6-8:2-3:20- 30of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 16:2:25, about 8:4:25, about 4: 1 :20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0118] In some embodiments, the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are administered or used in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0119] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bi sdemethoxy curcumin, tetrahydrobi sdem ethoxy curcumin, a curcumin ester and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0120] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC) and epigallocatechin (EGC) (-)- epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)- gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epigallocatechin gallate.

[0121] In an exemplary embodiment, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of 1-1 (isorhapontigenin) or a pharmaceuticallyacceptable salt, prodrug and / or solvate thereof, to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 3.75: 1. In some embodiments, the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25.

[0122] In another exemplary embodiment, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)- epigallocatechin gallate, and the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1 :5 to about 1 : 1. another exemplary embodiment, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1 :5. In some embodiments, the molar ratio 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1 : 1. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25. Accordingly, in an exemplary embodiment, the present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, and further in combination with a in further combination with a curcuminoid and a catechin, whereinthe one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1 :5 or about 1 : 1, and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25.

[0123] In the context of treating or preventing a papillomavirus infection or a disease caused by a papillomavirus infection as described above an effective amount, of the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof is an amount that, for example, reduces the papillomavirus infection compared to the papillomavirus infection without administration of the compound(s), or a salt, prodrug and / or solvate thereof. By “reduces the papillomavirus infection”, it is meant, for example, a reduction in the amount of the viral load in the subject and / or a reduction in the symptoms of the infection. By “reduces”, it is meant, for example, any detectable decrease or reduction in the amount of the papillomavirus in the presence of the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof, compared to otherwise the same conditions except in the absence of the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof.

[0124] Effective amounts may vary according to factors such as the disease state, age, sex and / or weight of the subject. The amount of the one or more given compound that will correspond to such an amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of papillomavirus infection of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. The effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom.

[0125] In an embodiment, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof, is / are administered or used as soon as possible after exposure or possible exposure to the papillomavirus. In an embodiment, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, thepterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof, is / are administered or used until treatment of the papillomavirus infection is achieved. For example, until complete elimination of the papillomavirus is achieved, or until the number of papillomavirus has been reduced to the point where the subject’s defenses are no longer overwhelmed and can kill any remaining viruses.

[0126] In an embodiment, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof, is / are administered or used as soon as possible before an expected exposure to the papillomavirus.

[0127] In an embodiment, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof is / are administered at least once a week. However, in another embodiment, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof is / are administered to the subject from about one time per two weeks, three weeks or one month In another embodiment, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof is / are administered about one time per week to about once daily. In another embodiment, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof is / are administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the papillomavirus infection or the disease, disorder or conditions caused by the papillomavirus infection genotype, the age of the subject, the concentration and / or the activity of the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof. It will also be appreciated that the effective dosage of a compound or compounds used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required. For example, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof is / are administered to the subject in an amount and for duration sufficient to treat the subject.

[0128] In an embodiment, the subject is a mammal. In another embodiment, the subject is human. In an embodiment, the subject is a non-human animal. Accordingly, the compounds, methods and uses of the present application are directed to both human and veterinary papillomavirus infections or diseases, disorders or conditions caused by a papillomavirus infection.

[0129] The one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof is / are either used or administered alone or in combination with other known agents useful for treating a papillomavirus infection or one or more diseases, disorders or conditions caused by a papillomavirus infection as described herein.

[0130] When used or administered in combination with other agents or therapies, it is an embodiment that the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof, is / are used or administered contemporaneously with those agents or therapies. As used herein, “contemporaneous administration” or “contemporaneous use” of compounds, agents or therapies to a subject means providing at least two of the compounds, agents and therapies so that they are biologically active in the individual at the same time. The exact details of the administration or use will depend on the pharmacokinetics of the compounds, agents or therapies in the presence of each other, and can include administering or using the compounds, agents or therapies within a few hours of each other, or even administering or using one compound, agent or therapy within 24 hours of administration or use of other(s), if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, the compounds, agents or therapies will be administered or used substantially simultaneously, i.e., within minutes of each other, or in a single composition in the case of administration or use of two or more compounds or agents. It is a further embodiment of the present application that a combination of compounds, agents or therapies is administered to a subject or used in a non-contemporaneous fashion.

[0131] In an embodiment of the methods and uses of the application, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof is / are administered or used orally In an embodiment, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof is / are administered or used parenterally. In an embodiments, the parenteral administration is topical administration.

[0132] The dosage of the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof can vary depending on many factors such as the pharmacodynamic properties of the compound(s), the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound(s) in the subject to be treated. One of skill in the art can determine the appropriate dosage(s)based on the above factors. The one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of compound(s) from about 0.01 pg / cc to about 1000 pg / cc, or about 0.1 pg / cc to about 100 pg / cc. As a representative example, oral dosages of the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg per day. For parenteral administration or use, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg will be administered or used. For oral administration or use, a representative amount is from about 0 001 mg / kg to about 10 mg / kg or about 0 1 mg / kg to about 10 mg / kg For administration or use in suppository form, a representative amount is from about 0.1 mg / kg to about 10 mg / kg. In an embodiment of the application, compositions are formulated for oral administration or use and the compounds are suitably in the form of tablets containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient per tablet. The one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof may be administered or used in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three, four, five or six daily doses.

[0133] In an embodiment the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et ai., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0134] An acid addition salt suitable for, or compatible with, the treatment of subjects is any nontoxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic,succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In an embodiment, the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non- pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0135] A base addition salt suitable for, or compatible with, the treatment of subjects is any nontoxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropyl amine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethyl amine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0136] Solvates of the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof or the pterostilbene, or a salt, prodrug and / or solvate thereof include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[0137] The one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, or the pterostilbene, or a salt, prodrug and / or solvate thereof may further exist in varying polymorphic forms and itis contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.

[0138] The one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, or the pterostilbene, or a salt, prodrug and / or solvate thereof may further be radiolabeled and accordingly all radiolabeled versions of the compounds of the application are included within the scope of the present application. The compounds of the application also include those in which one or more radioactive atoms are incorporated within their structure.

[0139] In some embodiments, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, and / or the pterostilbene, or a salt, prodrug and / or solvate thereof are in the form of a pharmaceutically acceptable solvate. In some embodiments, the compound of one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, and / or the pterostilbene, or a salt, prodrug and / or solvate thereof are a neutral form (i .e. not a salt).III. Compositions of the Application i) Compositions comprising compounds of Formula I

[0140] The compounds of Formula I are suitably formulated in a conventional manner into compositions using optionally one or more carriers.

[0141] Therefore, the present application also includes a composition comprising one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin,whereinX1to X4are as defined above for Formula I in the “Methods and Use of the Application”.

[0142] In some embodiments, the composition further comprises a carrier.

[0143] The compound of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is suitably formulated into pharmaceutical compositions for administration to subjects in abiologically compatible form suitable for administration in vivo. Accordingly, the present application further includes pharmaceutical composition comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin,whereinX1to X4are as defined above for Formula I in the “Methods and Use of the Application”.

[0144] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0145] In some embodiments, the composition comprises two or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In an exemplary embodiment, the composition comprises two compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0146] In some embodiments, when the composition comprises two compounds, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 0.5:1 to about 1:10, about 0.5:1 to about 1:8, about 05:1 to about 1:5, about 0.5:1 to about 1:4, about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, or about 1:1 to about 1:2. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, about 1:1 to about 1:2. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1. In some embodiments, the twocompounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in molar ratio of about 1 : 1.

[0147] In some embodiments, the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, are present in the composition in a molar ratio of about 1-16:0.25-4:1-40, about 1-16: 1-4:10-40, about 1-10:1- 3: 1-30, about 4-12: 1-3: 15-35, or about 6-8:2-3 :20-30 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, are present in the composition in a molar ratio of about 16: 1-4: 10-40, about 1-10: 1-3:1-30, about 4-12: 1-3: 15- 35 or about 6-8:2-3 :20-30 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 16:2:25, about 8:4:25, about 4: 1 :20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0148] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bi sdemeth oxy curcumin, tetrahydrobisdemethoxycurcumin, or a curcumin ester and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0149] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)- GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epigallocatechin gallate.

[0150] In an exemplary embodiment, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is selected from 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0151] In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin the catechin is (-)-epigallocatechin gallate and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25. Accordingly, in an exemplary embodiment, the present application includes a pharmaceutical composition comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin, wherein the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin the catechin is (-)-epigallocatechin gallate and the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25.

[0152] In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1 :3.75 of 1-3 or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to 1-1 or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1 :3 75 of 1-3 or apharmaceutically acceptable salt, prodrug and / or solvate thereof to 1-1 or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25.

[0153] The one or more, suitably two or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is suitably used on its own but will generally be administered in the form of a composition in association with an acceptable carrier. Depending on the mode of administration, the composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, and optionally a curcuminoid and a catechin and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of an acceptable carrier, all percentages by weight being based on the total composition ii) Compositions of compounds of Pterostilbene

[0154] Pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is suitably formulated in a conventional manner into compositions using optionally one or more carriers. Pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo.

[0155] Therefore, the present application also includes a pharmaceutical composition for treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin,

[0156] In some embodiments, the pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is present in an amount that is effective to treat or prevent a resveratrol resistant cancer in a subject.

[0157] In some embodiments, the present application includes a method for treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising administering one or more compositions comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin, to the subject.

[0158] In some embodiments, the present application also includes a use of one or more compositions comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin for treating or preventing a resveratrol resistant cancer in a subject in need thereof. The present application also includes a use of one or more compositions comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin for preparing a medicament for treating or preventing a resveratrol resistant cancer in a subject in need thereof. Also included is one or more compositions comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin for use to treat or prevent a resveratrol resistant cancer in a subject in need thereof.

[0159] In some embodiments, the resveratrol resistant cancer is as defined in the “Methods and Uses of compounds of Pterostilbene”.

[0160] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0161] In some embodiments, the curcuminoid, the catechin and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1-16:0.25-4:1-40, about 1-16: 1-4:10-40, about 1-10: 1-3 :1-30, about 4-12: 1-3 : 15-35, or about 6-8:2-3:20-3 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof In some embodiments, the curcuminoid, the catechin and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, are present in the composition in a molar ratio of about 1-16:1-4: 10-40, about 1-10: 1-3: 1-30, about 4-12: 1-3: 15-35 or about 6-8:2-3:20-30 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, are present in the composition in a molarratio of about 16:2:25, about 8:4:25, about 4:1 :20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0162] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bisdem ethoxy curcumin, tetrahydrobisdemethoxycurcumin or a curcumin ester and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0163] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC) and epigallocatechin (EGC), (-)- epi gall ocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)- gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epigallocatechin gallate.

[0164] In exemplary embodiment, the curcuminoid is curcumin and the catechin is (-)- epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25. Accordingly, in an exemplary embodiment, the present application includes a pharmaceutical composition for treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and a catechin, wherein the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25

[0165] The pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is suitably used on its own but will generally be administered in the form of a composition in association with an acceptable carrier. Depending on the mode of administration, the composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and optionally a catechin and from about 1wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of an acceptable carrier, all percentages by weight being based on the total composition. iii) Combination Compositions

[0166] The present application also includes a composition comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereofwhereinX1to X4are as defined above for Formula I in the “Methods and Use of the Application”, in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,

[0167] In some embodiments, the composition further comprises a carrier.

[0168] The present application also includes a pharmaceutical composition comprising one or more compound of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,whereinX1to X4are as defined above for Formula I in the “Methods and Use of the Application”,in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,

[0169] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0170] In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 8:1 to about 1:10, about 4:1 to about 1:10, about 2:1 to about 1:10, about 8:1 to about 1:5, about 4:1 to about 1:5, about 2:1 to about 1:5, about 0.5:1 to about 1:10, about 0.5:1 to about 1:8, about 0.5:1 to about 1:5, about 0.5:1 to about 1:4, about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, about 1:1 to about 1:2. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, about 1:1 to about 1:2. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1. In some embodiments, the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in molar ratio of about 1:5 toabout 1 : 1. In some embodiments, the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in molar ratio of about 1 :5. In some embodiments, one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1 :3.75. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1 : 1.

[0171] In some embodiments, the composition further comprises a curcuminoid and a catechin.

[0172] In some embodiments, the curcuminoid, the catechin and the one or more compounds ofFormula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1-16:0.25-4:1-40, about 1-16: 1-4:10-40, about 1-10: 1-3 :1-30, about 4-12: 1-3 : 15-35, or about 6-8:2-3:20-30 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1-16: 1-4: 10-40, about 1-10: 1-3 : 1-30, about 4-12:1-3:15-35 or about 6-8:2-3:20-30 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 6:2:25, about 8:4:25, about 4: 1 :20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments, the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt,prodrug and / or solvate thereof are present in the composition in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0173] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bi sdemethoxy curcumin, tetrahydrobisdemethoxycurcumin or a curcumin ester and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0174] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epi gall ocatechin gallate (EGCG or EGCg), epicatechin (EC) and epigallocatechin (EGC), (-)- epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)- gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epigallocatechin gallate

[0175] In an exemplary embodiment, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are selected from 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate. In an exemplary embodiment, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate.

[0176] In another exemplary embodiment, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate, the curcuminoid is curcumin and the catechin is (- )-epigallocatechin gallate and the molar ratio 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 3.75:1. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate. In some embodiments, the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25.

[0177] In another exemplary embodiment, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments,, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate. In some embodiments, the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1:5 to about 1 : 1. In another exemplary embodiment, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In some embodiments,, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate. In some embodiments, the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1 :5. In some embodiments, the molar ratio of 1-3 (piceatannol) to pterostilbene or a pharmaceutically acceptable salt, prodmg and / or solvate thereof is about 1 : 1 In some embodiments, the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25. Accordingly, in some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)- epigallocatechin gallate; and the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1 :5 to about 1 :1 and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate; and the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1 :5 and the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25. In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptablesalt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate; and the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1 : 1 and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25. Accordingly, in an exemplary embodiment, the present application includes a pharmaceutical composition comprising one or more compound of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, and in further combination with a curcuminoid and a catechin, wherein the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate; and the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 1 : 1 or about 1 :5 and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25.

[0178] The one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and / or pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are suitably used on its own but will generally be administered in the form of a composition in association with an acceptable carrier. Depending on the mode of administration, the composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and / or pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and optionally a curcuminoid and a catechin and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of an acceptable carrier, all percentages by weight being based on the total composition.

[0179] In some embodiments of the application the pharmaceutical compositions of the application are used in the treatment of any of the diseases, disorders or conditions described herein.

[0180] Therefore, the present application further includes a method or use for treating or preventing a papillomavirus infection or for treatment or prevention of a disease, disorder or condition caused by a papillomavirus infection including a resveratrol resistant cancer by administering or using a composition of the application.

[0181] The one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof, optionally the curcuminoid and the catechin are administered to a subject or used in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, administration may be by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, minipump, topical or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0182] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0183] In some embodiments, a composition is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, an excipient is incorporated and a composition is in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, oral rinse, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate), lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such asEudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations Examples of modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions are formulated, for example as liposomes or those wherein active compound(s) is / are protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried com starch

[0184] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); nonaqueous vehicles (e.g , almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p- hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0185] It is also possible to freeze-dry compositions and use the lyophilizates obtained, for example, for the preparation of products for injection.

[0186] In some embodiments, administration is parenterally. For example, solutions are prepared in water suitably mixed with a surfactant such as pegylated oils, polysorbates and sorbitan esters. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the artwould know how to prepare suitable formulations. For parenteral administration, sterile solutions are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiment, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or earners will be selected to be appropriate to allow the formation of an aerosol.

[0187] In some embodiments, compositions are formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with or without an added preservative In some embodiments, the compositions take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compositions are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0188] Methods of sterilization are well known in the art, and include, for example, terminal sterilization via autoclave or irradiation, or sterilization via filtration such as aseptic filtration.

[0189] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders. For administration to the sinus cavity, the compositions are conveniently delivered by irrigation such as with a nasal irrigation device. For intranasal administration or administration by inhalation, the compositions are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gassuch as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound(s). Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of active compound(s) and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.

[0190] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine is used. Compositions suitable for buccal or sublingual administration include sublingual solutions or sublingual suspensions, wherein a carrier, for example, water is used. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter

[0191] Suppository forms are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter); glycerinated gelatin; other glycerides including stearoyl polyoxyl-32 glycerides and glyceryl dibehenate; hydrogenated vegetable oils; mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol including PEG-8 distearate; and phosphatidylcholine. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1 30-1533 for further discussion of suppository dosage forms.

[0192] In some embodiments the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof, or combinations thereof, optionally the curcuminoid and the catechin, are coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, in some embodiments, the polymers belong to a class of biodegradable polymers useful in achieving controlled release of a compound, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycy anoacryl tes and crosslinked or amphipathic block copolymers of hydrogels.

[0193] Administration may also be accomplished using nano-carrier systems, such as liposomes, micelles, nanoparticles, nano-emulsions, lipidic nano-systems and the like (see for example, Bhat, M. et al. Chem. and Phys, of Lipids, 2021, 236, 105053).

[0194] In some embodiments, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof optionally the curcuminoid and the catechin may be coupled with viral, non-viral or other vectors. Viral vectors may include retrovirus, lentivirus, adenovirus, herpesvirus, poxvirus, alphavirus, vaccinia virus or adeno-associated viruses Non- viral vectors may include nanoparticles, cationic lipids, cationic polymers, metallic nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres. Nanoparticles may include silica, lipid, carbohydrate, or other pharmaceutically acceptable polymers

[0195] In some embodiments, the compositions of the application are formulated as a suppository, a cream, gel, foam, spray, film, sponge, tablet, capsule, emulsion, solution, lotion, nanofiber, suspension, particles, nanoparticles, a bio-adhesive, or an oral rinse

[0196] In some embodiments, the compositions of the application are formulated as a cream.

[0197] In some embodiments, the cream comprises about 10 wt% to about 30 wt%, about 15 wt% to about 25 wt%, about 15 wt% to about 20 wt% or about 20 wt% or of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, and a curcuminoid and a catechin and from about 90 wt% to about 70 wt%, about 85 wt% to about 75 wt%, about 85 wt% to about 80 wt% or about 80 wt% acceptable carrier, all percentages by weight being based on the total composition. In some embodiments, the cream comprises about 15 wt% to about 20 wt% of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, and the curcuminoid and the catechin.

[0198] In some embodiments, the cream will comprise from about 10 wt% to about 30 wt%, about 15 wt% to about 25 wt%, about 15 wt% to about 20 wt% or about 20 wt% of the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, a curcuminoid and optionally a catechin and from about 90 wt% to about 70 wt%, about 85 wt% to about 75 wt%, about 85 wt% to about 80 wt% or about 80 wt% of an acceptable carrier, all percentages by weight being based on the total composition. In some embodiments, the cream comprises about 15 wt% to about 20 wt% of the one or more compounds of the pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and optionally the curcuminoid and the catechin.

[0199] In some embodiments, the cream will comprise from about 10 wt% to about 30 wt%, about 15 wt% to about 25 wt%, about 15 wt% to about 20 wt% or about 20 wt% of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and / or pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and optionally a curcuminoid and a catechin and from about 90 wt% to about 70 wt%, about 85 wt% to about 75 wt%, about 85 wt% to about 80 wt% or about 80 wt% acceptable carrier, all percentages by weight being based on the total composition. In some embodiments, the cream comprises about 15 wt% to about 20 wt% of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and / or pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and optionally the curcuminoid and the catechin,

[0200] In some embodiments, the acceptable carrier is selected from Pluronic™, lecithin, organogel, Lipoderm®, Vanpen®, Aladerm®, Perme8, Ellage®, VersaBas®e Cream, VersaBase® Lotion, VersaBase® Gel, VersaBase® Anhydrous HRT, XemaTop®, Mucolo and anhydrous gels In some embodiments, the acceptable carrier is Ellage®

[0201] In some embodiments, a device comprising a composition of the application is placed into the oral cavity or anal cavity as a pellet, tablet, capsule, foam, or fdm.

[0202] In some embodiments, compositions of the application are formulated to be attached to, incorporated into, or covering a vaginal device or a device that is inserted into oral or anal cavity, or placed in contact with the skin. In some embodiments, the vaginal device is a tampon, tampon-like device, ring, pessary, tablet, capsule or pellet, sponge, foam, or female condom.

[0203] In some embodiments, compositions of the application are formulated to be attached to, incorporated into, coated onto, or imbedded into a condom.

[0204] In an embodiment, the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, and / or pterostilbene, or a salt, prodrug and / or solvate thereof, and optionally the curcuminoid and the catechin are administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising the one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, and / or pterostilbene, or a salt, prodrug and / or solvate thereof, and optionally the curcuminoid and the catechin, along with an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0205] The one or more compounds of Formula I, or a salt, prodrug and / or solvate thereof, the pterostilbene, or a salt, prodrug and / or solvate thereof optionally the curcuminoid and the catechin may be used alone to treat or prevent a papillomavirus infections or a disease, disorder or condition caused by a papillomavirus infection including a resveratrol resistant cancer in combination with another known agent useful for treating or preventing a papillomavirus infection or a disease, disorder or condition caused by a papillomavirus infection including a resveratrol resistant cancer.

[0206] It is an embodiment that another known agent useful for treating or preventing to treat or prevent a papillomavirus infection or a disease, disorder or condition caused by a papillomavirus infection including a resveratrol resistant cancer are administered or used according to treatment protocol that is known the other known agents.

[0207] In some embodiments, compounds of Formula I and pterostilbene are available from commercial sources, for example isorhaponti genin, rhapontigenin, piceatannol, pterostilbene, rhaponticin, and astringin are available from available from Millipore Sigma Aldrich (Burlington, Massachusetts, United States, USA).

[0208] In one embodiment, provided is a pharmaceutical composition, selected from the group consisting of:8 pM of curcumin, 2 pM of (-)-epigallocatechin gallate and 25 pM of piceatannol;8 pM of curcumin, 2 pM of (-)-epigallocatechin gallate and 25 pM pterostilbene;8 pM of curcumin, 2 pM of (-)-epigallocatechin gallate, 12.5 pM of piceatannol and 12.5 pM pterostilbene; and8 pM of curcumin, 2 pM of (-)-epigallocatechin gallate, 4.2 pM of piceatannol and 20.8 pM of pterostilbene.

[0209] In another embodiment, provided is a pharmaceutical composition, selected from the group consisting of: tetrahydrocurcumin, (-)-epigallocatechin gallate and pinostilbene at a molar ratio of 4: 1 : 12.5; tetrahydrocurcumin, (-)-epigallocatechin gallate and pterostilbene at a molar ratio of 4:1:12.5; tetrahydrocurcumin, (-)-epigallocatechin gallate, piceatannol and pterostilbene at a molar ratio of4:1:6.25:6.25; tetrahydrocurcumin, (-)-epigallocatechin gallate, piceatannol and pterostilbene at a molar ratio of4: 1:2 1 :10.4;tetrahydrocurcumin, (-)-epigallocatechin gallate and pterostilbene at a molar ratio of 1 : 1 : 1 ; and curcumin, (-)-epigallocatechin gallate and pterostilbene at a molar ratio of 1 : 1 :1 .EXAMPLES

[0210] The following non-limiting examples are illustrative of the present application. Representative commercially available sources of the components of the formulations of the invention are as follows:*References:1. Sabinsa. Curcumin C3 Complex®. Available at: https: / / sabinsa.ca / products-from-sabinsa / 127-curcumin-c3-complex. Accessed on July 7. 20242. Sabinsa. Curcumin C3 Reduct FAQ. Sabinsa website, https: / / sabinsa.com / newsroom / sabinsa-products-faq / curcumin-c3- reduct-faq. Published July 9. 2024. Accessed July 9, 2024.

[0211] In the following examples, all tested compounds or combinations thereof were incubated with HPV (+) cancer cells for 72 hours, and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine the half-maximal inhibitory concentration (IC50). Every experiment had six biologic replicants at each drug dose, and the listed values represent the mean. The IC50 values were determined by Quest Graph™ IC50 Calculator using a parameter logistic regression model.

[0212] Cell Culture and MTT assay:1. Hela cells were cultured in DMEM medium containing 10% FBS, lOO U / ml penicillin and 100 pg / ml streptomycin at a 37°C humidified incubator and an atmosphere of 5% CO2 (vol / vol) in a T75 flask. The semi-confluent cells were trypsinized, pelled down, resuspended in the DMEM medium. After cell counting were done, about 4000 cells were seeded in each well of the 96 well plates and cultured overnight in the above condition.2. Each well received 1% of ITS in DMEM. The medium was replaced in each well with 200 pL of the corresponding drug solution. Each dilution was tested in 6 wells. The cells were treated with the drugs for 72 h in a cell culture incubator.3. After 72hr, the effect of the drug was measured by MTT assay. Cells were washed with PBS, then 100 pL 1% ITS in DMEM, and 50 pL of MTT reagent were added to each well. The cells were incubated for 4hr at 37°C. The reaction was terminated by a stop solution. The plate was incubated at 37°C humidified incubators overnight in a sealed plastic bag and the absorbance was recorded at 570 nm using an absorbance plate reader. Background correction was achieved using separate wells without cells containing all other reagents.4. The IC50 was calculated.Example 1Identification of exemplary compounds of the application from Rheum L.

[0213] A chemical drug screen for diphenylethylene compounds from the plant genus Rheum L.(rhubarb) and in particular, the species Rheum rhaponticum L. and Rheum rhabarbarum was first done using original HPV-18 positive HeLa cells.

[0214] Highly active compounds were identified that were found to have slight modifications in the number and type of functional groups compared to resveratrol. Table 1 shows six natural diphenylethylene compounds that were identified to have the most potent cytotoxic effect against HPV-18 Hela cells from the rhubarb species examined.Table 1 : Trans diphenylethylene compounds identified in rhubarb plant species

[0215] Table 2 shows the dose-response effects of from the MTT assay for each of the identified natural diphenyl ethylene compounds in authenticated HPV-18 (+) HeLa cells.Table 2: Effects of diphenylethylene compounds in HPV-18 positive HeLa cells

[0216] As can be seen from Table 2, all the identified compounds had an IC50 of < 30 pM. The most active compounds were found to be piceatannol, pterostilbene, rhapontigenin, and resveratrol, which all had an IC50 of about 10 pM against HeLa cells (pterostilbene = 7.55 pM, resveratrol =7.92 pM, rhapontigenin=8.0 pM, piceatannol=8.0 pM). Isohapontigenin was effective but found to be about three times less potent than the other four compounds with an IC50 of about 27.07 pM. The next most potent natural diphenylethylene compound identified in the drug screen of Rheum rhaponticum L. and Rheum rhabarbarum species was desoxyrhapontigenin (also called 4'-O-Methylresveratrol). This compound was found to have an IC50 of about 38.32 pM.Example 2Evaluation of exemplary compounds in resveratrol-resistant cell line, HeLa-GSl

[0217] The polyphenol, trans-3, 5, 4'-trihydroxy stilbene (resveratrol), is known to have anti-human papillomavirus (HPV) effects. However, cancer cells become resistant to resveratrol, and this is one main reason for the limited clinical efficacy with resveratrol-based drugs (Colin D.J. et al., Cell Death Dis. 2014 Nov 20;5(l l):el533).

[0218] To overcome the limitations in the prior art, a resveratrol -resistant cell line was developed from the HPV- 18 (+) cervical cancer cell line HeLa. This mutated cell line was named HeLa-GSl and was found to demonstrate considerable resistance to resveratrol. Authenticated original HeLa cells were obtained from American Type Culture Collection (Manassas, Virginia, USA) and used to generate Table 1 results. HeLa-GSl cells were developed by having the parent cell line passage over long periods of time in cells incubated in the presence of resveratrol. The IC50 of resveratrol in original HeLa cells on repeat experiments ranged from 7-1 1 pM, with an average IC50 value of 7.9189 pM. Meanwhile, on repeat experiments, the IC50 of resveratrol in HeLa-GSl cells ranged from > 80 pM to complete resistance, with the average IC50 of 11 1 .251 pM.

[0219] The four most active identified compounds from Example 1 and resveratrol were evaluated in the resveratrol -resistant cell line, HeLa-GSl . Table 3 shows the dose-response results of the identified diphenylethylene compounds using an MTT assay in the resveratrol-resistant cells line, HeLa-GSl .Table 3: Effects of diphenylethylene compounds in resveratrol resistant HeLa-GSl cells

[0220] As can be seen from Table 3, the IC50 values for the identified compounds in HeLa-GSl cells are as follows, starting with the most potent compound: pterostilbene= 8.34pM, rhapontigenin=11.47pM, piceatannol=28.99pM, and isorhapontigenin =41.18pM. This data shows that there is a variation in the efficacy of the compounds. For example, pterostilbene was found to be five times more potent than isorhapontigenin and about three times more potent than piceatannol Meanwhile, resveratrol-treated cells demonstrated overt resistance, with > 90% of HeLa-GSl cells viable at the highest dose tested (50 pM), confirming the unique properties of identified compounds that have not been reported in any prior art in HPV-infected cells.

[0221] Like many plant polyphenols, resveratrol modulates a diverse number of cellular pathways. It was previously shown (Einbond et al. 2021, Br J Cancer. 2021 Mar;124(5):901-913) that resveratroleliminates several HPV (+) cell lines, in cancerous and precancerous tissue. Prior to cell death, resveratrol upregulated pro-apoptotic gene, and affected cell cycle regulators like p53. Moreover, the compound suppressed the HPV viral transcripts E6 & E7, which induces malignant transformation and maintains cancer cell growth. Meanwhile, trans-stilbene, which is identical to resveratrol except lacking any functional groups, was not cytotoxic to HPV (+) cancer cells even at very high doses.Example 3Evaluation of exemplary compounds in HPV-16-positive cervical cancer cell line CaSki

[0222] Resveratrol and the four diphenylethylene compounds identified in the initial screen (see Example 1) were further tested against the HPV- 16-positive cervical cancer cell line, CaSki 50% of the world's cervical cancers are known to be HPV-16 positive cancers Tables 4 and 5, shows the MTT assay data for each of these compounds in CaSki cells.Table 4: Effects of isorhapontigenin, rhapontigenin & trans-resveratrol in HPV 16 positive CaSki cellsTable 5: Effects of piceatannol & pterostilbene in HPV 16 positive CaSki cellsAs can be seen from Tables 4 and 5, the IC50 values of the identified compounds are as follows, starting with the most potent compound: resveratrol=5.96pM, isorhapontigenin=8.48pM, pterostilbene=11.25pM, piceatannol= 16.55 pM, rhaponti enin= 173.07 pM.Example 4Evaluation of exemplary compounds in HPV-16-positive cervical cancer cell line SiHa

[0223] A further dose-response analysis was done using the HPV-16 (+) cervical cancer cell line, SiHa, to confirm the results observed in HPV- 16-positive cervical cancer CaSki cell line. Table 6 shows the MTT viability data and the IC50 values for trans-resveratrol, isorhapontigenin, piceatannol, pterostilbene, and rhapontigenin in the HPV-16 (+) cancer cell line, SiHa.Table 6: Effects of diphenylethylene compounds in HPV-16 positive SiHa cells

[0224] As can be seen by the data in Table 6, the cytotoxicity results for the identified compounds in the HPV-16 (+) cancer cell line, SiHa parallel the values observed with CaSki cells. For example, the IC50 values were found to be as follows: resveratrol=12.4347pM, isorhapontigenin=8.9131 M, pterostilbene=8.7824pM, piceatannol=21.9006pM, showing that these compounds all had potent efficacy against SiHa cells. Meanwhile, the IC50 for rhapontigenin was 130.39pM, again this compound was not effective in another HPV-16 positive cell line, it was about ten times less potent than resveratrol. Examples 1-4 above show that different diphenylethylene compounds can cause differing anti-papillomavirus (e.g anti -HP V) effects.

[0225] Table 7 provides a summary of the testing results of examples 1 to 3.Table 7Example 5Combination comprising exemplary compounds of Formula I and / or Pterostilbene

[0226] Cancer and HPV (+) cells develop resistance to resveratrol, limiting its use. Another important limitation of resveratrol-based drugs seen in shown clinical trial data is that resveratrol and resveratrol derivatives have significant bioavailability issues. They are poorly absorbed into the systemic circulation because of low solubility and rapid degradation. Thus, achieving low target tissue concentrations and leading to no or limited biologic efficacy. To attempt to overcome these limitations, combinations of two or more exemplary diphenyl ethylene compounds of Formula I or combinations of pterostilbene have been examined. It was observed that combination of these compounds work synergistically against HPV (+) cells. The data showed that a lower IC50 level was achieved when using combinations of diphenylethylene compounds of Formula I (compared to when administered alone). A synergistic combination of compounds would reduce the required cytotoxicity dose at the target tissue, and help combat the inherent issues in achieving adequate drug concentration of resveratrol based drugs.

[0227] Further, resveratrol and some of the natural diphenylethylene compounds are phytoalexin compounds, used by plants to fend off microbial disease in a polyclonal manner (with multiple compounds). Accordingly, drug combinations were examined.

[0228] The most potent exemplary diphenylethylene compounds of Formula I, isorhapontigenin and piceatannol, were examined in combination with each other and each in combination with pterostilbene, in doublet drug combinations. For initial combination drug testing, a molar ratio of 1 : 1 of the two compounds to be tested was used. Concentrations were started at the IC50 dose for each compound, and the dose was doubled or halved to get a full range of a dose-response effect. To demonstrate how the combination doses were derived for testing, Table 8 lists the concentrations for the 1 :1 molar mixture of exemplary compounds isorhapontigenin and piceatannol. As noted in the example above, the IC50 values of the compounds were as follows: pterostilbene (8pM), isorhapontigenin (30 pM), piceatannol (8pM). Table 9 shows the IC50 of these initial pair mixtures in Hela cells.Table 8: Exemplary concentrations of 1: 1 molar mixtures of isorhapontigenin and piceatannolTable 9: Isorhapontigenin (Iso), Piceatannol (Pice), Pterostilbene (Pte) Drug Combinations: Pair Combination Testing in Hela cells

[0229] *Note; Testing of pairs was started at the IC50 for each compound at a 1 : 1 molar ratio. Iso IC50= 30 uM, Pice IC50= 8uM and Ptero IC50=8uM. Doses of pairs where then doubled and halved to obtain a dose response range.

[0230] Table 9 shows that piceatannol plus pterostilbene at a molar ratio of 1 : 1 ratio was the most potent pair combination demonstrating an ICso of 4.308.Example 6Evaluation of molar ratios of exemplary compounds

[0231] After the pairing of piceatannol plus pterostilbene was identified from Example 5, further drug combination testing was done to determine the optimal molar ratio for the combination of piceatannol plus pterostilbene.

[0232] Since the initial molar ratio was 1: 1 piceatannol to pterostilbene, the following additional ratios were considered: 8:1, 4: 1, 2;1, 1 :2, 1 :3, 1 :4, 1 :5, and the following molar ratios of piceatannol to pterostilbene were selected for further testing 8: 1, 1 : 1, 1 :3, and 1 :5.

[0233] Table 10 shows the IC>o values for piceatannol, and pterostilbene as individual drugs against Hele cells, while Table 1 1 shows the IC50 values for the combination of piceatannol to pterostilbene at various ratios in Hela cells.Table 10: IC50 of piceatannol and pterostilbene in Hela cellsTable 11 : IC50 of piceatannol and pterostilbene drug combination in Hela cells*Pice = piceatannol, Ptero=pterostilbene*Each Pice:Ptero pair mixture was tested at 4 molar ratios, ratio 8: 1, 1 : 1, 1:3 and 1 :5**Total drug is the pM amount of pice+ptero used to achieve the IC50 effect at a specific drug pair ratio.

[0234] The IC50 data in Table 11 again showed that the combination of piceatannol and pterostilbene at a molar ratio of 1 : 1 had marked potency and was highly synergistic. This pice:ptero (1 : 1) pair increased the cytotoxicity by 600% compared to piceatannol alone and was 800% more potent compared to pterostilbene alone. While the combination of piceatannol and pterostilbene at a ratio of 8: 1 demonstrated a good IC50, and the combination of piceatannol and pterostilbene at a molar ratio of 1 :3 and 1 :5, also demonstrated good potency.’ . The data in Tables 10 and 11 shows the effects at these ratios are only additive (e.g., the IC50 of piceatannol is 7.3388 uM and the IC50 of pterostilbene is 9.2021 uM). However, the combination of piceatannol and pterostilbene at a molar ratiol : l had an IC50 of 1.0373 uM showing strong synergy of these two compounds at this molar ratio.Example 7Combination compositions comprising exemplary compounds of Formula I and / or pterostilbene, a curcumin and a catechin

[0235] Plant polyphenols, such as resveratrol, modulate a diverse number of cellular pathways. As described above, the polyphenol, trans-3,5,4'-trihydroxystilbene (resveratrol), is known to have anti-human papillomavirus (HPV) effects Moreover, a pharmaceutical mixture of curcumin (32 pM), epicatechingallate (8 pM) & resveratrol (100 pM) was found to be synergistic in eliminating HPV (+) cancer cell lines (Mukherjee et al., 2017 Oncotarget. 2017 Mar 29;8(37); WO 2015 / 081319; US 2016 / 0287533, Einbond et al. 2021, Br J Cancer. 2021 Mar,124(5):901-913). Therefore, whether the piceatannol or piceatannol and pterostilbene in combination would have superior cytotoxic in further combination with curcumin and (-)- epigallocatechin gallate (EGCg) was investigated. The data in examples 1-4 demonstrate that pterostilbene overcomes resistance to resveratrol in HeLa-GSl cells. Examples 5 and 6 above further show that exemplary compounds of Formula I in combination or in combination with pterostilbene are more potent compared to the individual diphenyl ethylene compounds of Formula I or pterostilbene. For example, it was found that exemplary compound piceatannol in combination with pterostilbene at a molar ratio of 1: 1 had an IC50 of 1.0373 uM, which was 7-9 times more potent than piceatannol or pterostilbene individually.

[0236] Table 12 shows the IC50 values of exemplary compound piceatannol, or pterostilbene in combination with curcumin and (-)-EGCG, named T-Pice & T-Ptero respectively. Also shown are the IC50 values of exemplary compound piceatannol in combination with exemplary compound pterostilbene in a molar ratio of 1 : 1 and a molar ratio 1 :5 and in further combination with curcumin and (-)-EGCG, T- Pice:Ptero (1 : 1) and T-Pice:Ptero (1 :5) respectively. The combination of piceatannol and pterostilbene was found to act synergically in Example 4. Table 12 shows all 4 tested combinations and the doses at which they were tested. All the combinations had equal amounts of curcumin, EGCG, and an equal amount of the diphenyl ethylene component in the combinations. These 4 combinations were tested in HPV-positive cell lines, CasKi, HeLa, and in the resveratrol-resistant cell line, HeLa-GSl . The data in Table 12 shows all 4 mixtures had strong efficacy against these HPV cell lines.Table 12: Testing of piceatannol and pterostilbene ratios in a curcumin & EGCG formulation: IC50 of piceatannol & Pterostilbene Pairs in HPV (+) cells*

[0237] All formulations comprise curcumin and (-)-EGCg ((-)-epigallocatechin gallate) at a molar ratio of 8:2.

[0238] Diphenylethylene compounds were added to create drug combinations with the following ratios:T-Pice = curcumin (8 pM) + (-)-EGCg (2 pM) + pice (25 pM)T-Ptero = curcumin (8 pM) + (-)-EGCg (2 pM) + ptero (25 pM)T-Pice:Ptero (1 :1) = curcumin (8 pM) + (-)-EGCg (2 pM) + pice (12.5 pM) + ptero (12.5 pM)T-Pice:Ptero (1:5) = curcumin (8 pM) + (-)EGCg (2 pM) + pice (4.2 pM)+ptero (20.8 pM)

[0239] All mixture ratios had equal amounts of diphenylethylene compounds used for comparisons. As a control, curcumin and (-)-EGCg were evaluated individually in HPV-18 positive HeLa cells (Table 13) and HeLa-GSl cell lines (Table 13)Table 13: Effects of Curcumin and (-)-EGCg in HPV-18 positive HeLa cellsExample 8 Investigation of Combination index

[0240] To quantify synergy when the observed IC50’s are close, we use the well-established method by Chow-Talallay (Chou T. C., Cancer Res. (2010) 70(2):440-6) to determine a combination index which defines using chemical mass action equations the median dose effect and the combination index (CI) and is defined as follows: CI > 1 drug antagonism, CI = 1 additive effect, CI < 1 drug synergy

[0241] Table 14 shows the combination index for each of the four mixtures at the drug IC50, IC75, IC90 and IC95.Table 14. Combination Index determination of drug mixture for synergy, antagonism, or additive effectsCombo IC50 _ IC75 _ IC90 _ IC95T-Pic 1.02676 0.78174 0.64760 0.59439T-Pte 1.24054 1.31701 1.40775 1.47903T-l :l 1.03984 0.91003 0.83008 0.79439T-l :5 1.19238 1.09842 1.02965 0.99351

[0242] Drug Abbreviations: Curcumin (Cure), (-)-EGCG (Epi), Piceatannol (Pice), Pterostilbene (Ptero)

[0243] Drug Combination (molar ratio):T-Pic: (Curc+Epi+Pice [32:8:100])T-Pte : (Curc+Epi+Ptero [32:8: 100])T-l : 1 : (Curc+Epi+Pice+Ptero [32:8:50:50])T-l :5 : (Curc+Epi+Pice+Ptero [32:8:16.67:83.33])The data in Table 14 shows that not all the mixtures are optimal over the entire dose-range tested. Some mixtures have a CI value > 1, indicating that that mixture is not effective as a drug combination at that ratio and dose effect. However, the data shows that the mixture T-l : 1 which is piceatannol and pterostilbene at a 1 : 1 molar ratio, plus curcumin and (-)-EGCg is a highly potent combination which is synergistic at thehighest doses and additive at the IC50. Mixtures in Table 14 are derived through combinatorial testing, and effects are validated by experimentation.

[0244] Table 15 and Table 16 shows the full statistical output of the data in Table 14 which is a summary of the CI values for each mixture.Table 15: Combination Index (CI) Data for Drug Combo: T-Pic (Curc+Epi+Pice [32:8:100])Table 16 : Combination Index (CI) Data for Drug Combo: T-Pte (Curc+Epi+Ptero [32:8:100])Example 9 Evaluation of exemplary combination compositions comprising compounds of Formula I and / or pterostilbene, and a curcuminoid and a catechin

[0245] Compounds of Formula I, alone or in combination with pterostilbene, exhibit potent anti- HPV activity when further combined with curcumin and (-)-epigallocatechin gallate (EGCg), as demonstrated in Examples 6-8 above. It was also discovered that specific curcuminoid compounds unexpectedly increase the activity of the disclosed diphenyl ethylene mixtures.

[0246] Curcumin (or diferuloylmethane) is a yellow crystalline compound isolated from turmeric (Curcuma longa L., Zingiberaceae) and is the main curcuminoid present in turmeric. Additionally, this medicinal root contains demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids are natural phenols that can exist in at least two tautomeric forms, keto and enol. Tetrahydrocurcumin, a metabolite of curcumin, is a reduced form of the compound Curcumin contains an a, f>- unsaturated carbonyl group, while tetrahydrocurcumin lacks a,P-dienes. Similarly, demethoxycurcumin and bisdemethoxycurcumin can be reduced to form tetrahydrodemethoxy curcumin and tetrahydrobisdemethoxycurcumin.

[0247] To develop additional embodiments of the diphenylethylene mixtures, the inventors examined the effects of curcumin and tetrahydrocurcumin individually on the HPV (+) CaSki cell line. The IC50 of curcumin was 4.9722 pM, and the IC50 of tetrahydrocurcumin was 30.2386 pM, showing that curcumin is six times more potent than its reduced form (Table 17). Similarly, in SiHa cells, tetrahydrocurcumin was markedly weaker, with an IC50 of 87.7979 pM, compared to curcumin, which had an IC50 of 14.0525 pM (Table 18). This shows that curcumin is 500% more potent than reduced curcumin (tetrahydrocurcumin) against these HPV (+) cancer cells. Similarly, in resveratrol resistant Hela-GSl cells curcumin was more effective than tetrahydrocurcumin by 200% (Table 18). Unexpectedly, when used in our derived diphenylethylene mixtures, combinations with tetrahydrocurcumin were superior and more effective compared to mixtures with natural curcumin.

[0248] The inventors tested mixture T-l :5, described in Example 7 above, which contains the following: curcumin (32 pM), EGCG (8 pM), piceatannol (16.67 pM), and pterostilbene (83.33 pM). This was compared to an equal amount of the mixture containing the reduced form of curcumin: tetrahydrocurcumin (32 pM), EGCG (8 pM), piceatannol (16.67 pM), and pterostilbene (83.33 pM). This combination was designated TW-1:5. In vitro testing was conducted in HeLa cells at various concentrations as described in Table 19. The IC50 of TW-E5 was observed to be 1.2395 pM, while the mixture withcurcumin, T-l :5, had an IC50 of 2.4196 pM. In contrast to the comparison of curcumin versus tetrahydrocurcumin (when used individually), where tetrahydrocurcumin was found to be 500% weaker, the diphenylethylene mixture of the invention using tetrahydrocurcumin (TW-1 :5) was 100% more potent.Table 17 Effects of curcumin & tetrahydrocurcumin in HPV positive CaSki cellsTable 18. Effects of curcumin & tetrahydrocurcumin in HPV positive SiHa & HeLa-GSl cellsTable 19. Effects of curcumin & tetrahydrocurcumin in HPV positive HeLa cellsMixture Compositions (compounds and molar ratios)TW-1:5 = tetrahydrocurcumin (32 pM ) + EGCG (8 pM ) + Piceatannol (16.67 pM) +Pterostilbene (83.33 pM) T-l:5 = curcumin (32 pM ) + EGCG (8 pM ) + Piceatannol (16.67 pM) +Pterostilbene (83.33 pM)Example 10In vivo Anti-viral efficacy of exemplary diphenylethylene mixtures using the MmuPV-1 vaginal papillomas mouse model

[0249] The mus musculus papillomavirus 1 (MmuPVl) mouse model is known in the art to be a crucial tool in papillomavirus research. MmuPVl infects laboratory mice, making it the first rodent papillomavirus capable of such infection, thus offering the opportunity to study papillomavirus biology and pathogenesis. MmuPVl can infect both cutaneous and mucosal (oral and genital) tissues of mice, closely mimicking human papillomavirus (HPV) infections. This model is unique and allows for viral host examination, as well as preclinical assessment of drugs for antiviral efficacy. The MmPV / mouse model was used to evaluate diphenylethylene mixtures to see if they had in vivo activity against mouse vaginal papillomas. The study aimed to assess the ability to deliver drug intravaginally and determine if antiviral effects could be seen against MmuPV-1 Parameters used to assess an anti-viral effect included: 1) MmuPVl viral DNA copy number in vaginal and anal swabs, 2) Histological assessment of papillomas for virological assessments upon the termination of the study. Experimental methods have been previously detailed. In brief, NU / J heterozygous mice with the Foxnlnu / +genotype were used. These mice were subcutaneously injected with 3 mg of progesterone in the form of Depo-Provera, diluted in 100 microliters of PBS. Three days post-injection, the mice were sedated, and Doctors' Brush Picks were gently rotated 15times in the vaginal canals to create minor abrasions. After twenty-four hours, the mice were anesthetized again, and 25 pl of a sterilized viral suspension was pipetted into their vaginal canals.A study involving 25 adult female heterozygous Nu / J mice (purchased from Jackson Labs) followed this protocol. After a 7-day quarantine, on Day 0, mice in Groups A-E were inoculated with MmuPV-1 at vaginal and anal sites. On Day 7, all mice received 25 pl of a formulated compounds into the vaginal canal using a soft plastic pipette tip, with treatments administered five times per week for up to five weeks. The study included five groups (A-E), with one placebo group as a control to assess local treatment effects. Vaginal lavages were performed every Monday to determine viral copy numbers (weeks 3 and 4), which were then analyzed to calculate viral DNA titers. At the study's conclusion, histological assessments of vaginal canal were conducted and immunohistochemistry was used to identify MmuPVl using an anti-E4 protein probe. Mixtures tested are shown in Table 20. To further determine if tetrahydrocurcumin is superior to curcumin to mixtures where tested which were identical except for the curcuminoid, designated TW-Pinostilbene and T-Pinostilbene). Additionally, T-Pterostilbene was examined and a positive control.Table 20. Mice Groups A - E and diphenylethylene mixtures in MmuPVl StudyTW-Pinostilbene A 5 50ulT-PinostilbeneT-Pterostilbene C 5 50ulCidofovirPositive CoVehicle E 5 5OulMixture Compositions (compounds and molar ratios)TW-Pinsotilbcnc = tetrahydrocurcumin (32 pM ) + EGCG (8 M ) + Pinostilbcnc(100 pM)T-Pinsotilbene = curcumin (32 pM ) + EGCG (8 pM ) + Pinostilbene(100 pM)T-Pterostilbene = curcumin (32 pM ) + EGCG (8 pM ) + Pinostilbene(100 pM)Table 21 . Change in Q-PCR signal from week 3 to week 4

[0250] During weeks 3 and 4 of the study, vaginal lavage viral loads were measured to assess the acute effects of drugs and the feasibility of intravaginal delivery. A positive effect on viral load changes between weeks 3 and 4 was noted (Table 20). Short-term drug exposure reduced the rate of viral replication in Groups A. C, and the positive control group compared to vehicle-treated mice.

[0251] Group A, which contained a mixture of tetrahydrocurcumin (32 pM), EGCG (8 pM), and pinostilbene (100 pM), showed statistically significant inhibition of viral replication (p = 0.0244). In contrast, the mixture containing curcumin (32 pM), EGCG (8 pM). and pinostilbene (100 pM) was not effective in reducing viral replication (p = 0.1508). The mixture T-Pterostilbene (p = 0.0397) and the positive control (p = 0.0317) did exhibit significant responses in suppressing MmuPVl compared to vehicle-treated mice.

[0252] The study continued for a total of five weeks, at which time the animals were autopsied, and histopathological assessments of the lower reproductive tract were performed. Histopathology using an anti-MmuPVl E4 protein probe for immunohistochemistry demonstrated MmuPVl infections along the vaginal canal epithelium, indicated by brown - stained cells. Groups A and C showed intense immune reactions around MmuPVl positive areas.

[0253] In conclusion, intravaginal delivery was feasible and effective in attenuating viral growth. The mixture containing T-Pterostilbene was particularly potent in suppressing viral replication, while the mixture with tetrahydrocurcumin was again noted to have enhanced antiviral effects in vivo.Example 11In vivo Anti-viral efficacy of exemplary diphenylethylene mixtures using the cottontail rabbit papillomavirus / Rabbit model

[0254] The Cottontail Rabbit Papillomavirus (CRPV) model, established in the 1930s, is considered a gold standard for studying human papillomavirus (HPV) pathogenesis and testing anti-HPV treatments. This model closely mimics human HPV infections and disease progression, including the development of papillomas and cancers. It has been pivotal in developing and testing both prophylactic and therapeutic HPV vaccines by providing insights into immune responses and vaccine efficacy. CRPV infections in rabbitsrecapitulates human HPV infections, making it possible to studying viral pathogenesis and therapeutic in ten entions.

[0255] Initial in vivo testing of diphenylethylene mixtures in the MmuPVl / mouse model demonstrated significant antiviral activity. To further evaluate these mixtures, the inventors developed a novel self-emulsify ointment formulation for the mixtures and assessed their delivery and dosing strategies using the CRV / rabbit preclinical in vivo model. This study focused on the number of papillomas developed at infection sites and the growth rate and size of papillomas over a six-week treatment period.

[0256] The experimental plan was based on previously published protocols. Twenty- five adult New Zealand White rabbits of both sexes were purchased from Inotiv and quarantined for 14 days. On Day 0, each rabbit was inoculated with 5 pg / site of wild type (wt-CRPV) DNA at two sites and 25 pl / site of a mutant virus (mE8-CRPV) at two other sites. From Day 10, rabbits in the LI and L2 groups received drug treatments, while R-sites (R1 and R2) were left untreated as internal controls for papilloma growth. Topical treatments began on Day 10, administered five times weekly (Monday through Friday, twice daily) to the left-side papillomas only. Papillomas were measured weekly in three axes (length x width x height) in mm. Data was entered into a spreadsheet, and calculations were conducted to determine the geometric mean diameter of each papilloma, mean ± SEM for each group, and Student’s t-test between each paired group. Plots were made of papilloma size vs. time, and weight changes were also plotted. Skin / papilloma sites were monitored photographically, a summary of mixtures and treatment groups are in Tables 22 and 23. Compositions are as follows:

[0257] Group A: TW-SD1 = tetrahydrocurcumin (32 pM) + EGCG (8 pM) + Pinostilbene (100 pM)

[0258] Group B: TW-SD2 = tetrahydrocurcumin (32 pM) + EGCG (8 pM ) + Pterostilbene (100 pM)

[0259] Group C, TW-L 1 = tetrahydrocurcumin (32 pM ) + EGCG (8 pM ) + Piceatannol (50 pM) +Pterostilbene (50 pM)

[0260] Group D: TW-L5 =tetrahydrocurcumin (32 pM) + EGCG (8 pM) + Piceatannol (16.67 pM) +Pterostilbene (83.33 pM)

[0261] Group E: T-SD1 (Positive Control) = curcumin (32 pM ) + EGCG (8 pM ) + Pterostilbene (100 pM)Table 22.. Experimental groups and treatments dosing

[0262] Summary of findings. It was found that as a class the combination of a curcuminoid and catechin and diphenylethylene has potent activity' in the CRPV / rabbit model. Complete suppression of wild-ty pe CRPV and the mutant m8CRPV was seen during the 5 weeks treatment for all treatment Groups except A [TW-SD1 = tetrahydrocurcumin (32 pM) + EGCG (8 pM) + Pinostilbene (100 pM)]. This mixture did not contain a diphenylethylene compound derived from the medicine Rhubarb screened and discussed in Example 1 & 2 of the sections above. This mixture contained a resveratrol derivative called trans inostilbene, (3,4'-dihydroxy-5-methoxystilbene), a mono methoxy derivative of resveratrol shown to have activity during standardizations. This compound did not completely suppress the papillomas during treatment like Groups B-E, confirming not all resveratrol derivatives have equal efficacy. Meanwhile, Group B which has one of the potent diphenylethylene compounds identified (TW-Pterostilbene), when used in equal amounts in our cream performed better than TW-Pinostilbene in suppressing the size of the wild-type and mutant CRPV papillomas at the end of 11 weeks following study.

[0263] The inventors further compared among all groups. The highest potency was seen in Group B. C, D. A steady increase in papilloma size in untreated groups (Rl, R2) for all three treatments was observed. In the positive control group, T-SD1 (containing Pinostilbene) exhibited a slower growth rate in treated groups (LI, L2) compared to untreated groups, resulting in a drug-induced reduction of 30.6% for wild-type CRPV and 36.4% for mutant CRPV at 10 weeks. Two lead mixtures were discovered as extremely effective. Group D (TW-L5) demonstrated a significant reduction in papilloma size in treated groups, with adrug-induced reduction of 82% for wild-type CRPV and 81.9% for mutant CRPV at end of 10 weeks. Lead #2 (TW-Ll) showed the most substantial reduction, with a drug-induced reduction of 92% for wild-type CRPV and 85.7% for mutant CRPV at 10 weeks. Overall, Lead #2 (TW-L l) proved to be the most effective treatment in reducing papilloma size, followed by Lead #1 (TW-L5), with the positive control (T-SD1) being the least effective among the three.The positive control group (Group E). which received T-SDl(Pinostilbene), showed no cures in both wild-type and mutant CRPV warts (Table 23) . with 0 out of 5 rabbits cured (0%) in each category. In contrast, Group D treated with TW-L5 (containing Piceatannol & Pterostilbene at a molar ratio of 1 :5) demonstrated a cure rate of 40% for wild-type CRPV warts, curing 2 out of 5 rabbits, and a 60% cure rate for mutant CRPV warts, curing 3 out of 5 rabbits. Group C treated with TW-L l (5 (containing Piceatannol & Pterostilbene at a molar ratio of 1: 1) exhibited the highest efficacy, curing 3 out of 4 rabbits (75%) with wild-type CRPV warts and 2 out of 4 rabbits (50%) with mutant CRPV warts (Table 23 and 24)Table 23 . Treatment Groups and Cure Rates for Papilloma in RabbitsNote: Lesions receiving no treatment had 0 cures seen in wild-type and mE8 CRPV papillomasTable 24. Summary of Papilloma Reduction in Treated Groups in Remaining LesionsExample 12 Certain Formulation EmbodimentsIn one embodiment of the invention, the formulation comprises by percentage of weight:Tetrahydrocurcumin: 6%EGCg: 2%Piceatannol: 2%Pterostilbene: 10.86%Propylene Glycol : 8%Diethylene Glycol Monoethyl Ether NF 8%Pharmaceutically Acceptable Carrier: 63.14%In one embodiment, the pharmaceutically acceptable carrier is:Ingredient Concentration Operable RangeMedium-Chain T riglycerides NF 60.0000% from about 10% to about 90%C10-18 Triglycerides 12.3000% 6% to 16%Glyceryl Ricinoleate 1 .5000% 0.8% to 2%Ceteth-20 0.6000% 0.3% to 1 %Steareth-20 0.6000% 0.3% to 1 %PEG-32 Stearate 10.0000% from about 1% to about 20%Glyceryl Stearate 8.0000% from about 1% to about 15%Phosphatidylcholine 2.9325% 1 % to 10%Propylene Glycol 1.7500% 1 % to 10%Alcohol 0.1000% 0.1 % to 1 %Soy Acid 0.0500% 0.05% to 0.5%Sunflower Seed Oil Glyceride 0.1500% 0.1 % to 1 .5%Tocopherol 0.0125% 0.01 % to 0.15%Ascorbyl Palmitate 0.0005% 0.0004% to 0.005%Poloxamer 407 2.0000% from about 1% to about 25%Total 100%The above the pharmaceutically acceptable carrier is an anhydrous, self-emulsifying ointment composition that enhances the delivery and stability of the active pharmaceutical ingredients. The formulation improved contact time and adherence within the vaginal environment, formed micelles upon contact with vaginal moisture, and mitigated the risk of hydrolysis and oxidation of the active pharmaceutical ingredients, thereby enhancing drug stability- and efficacy.Example 13Certain Other Pharmaceutically Acceptable Carrier Embodiments

[0264] The following the pharmaceutically acceptable carriers can also be used in the formulations of the invention:

[0265] Carrier A: An aqueous penetration enhancing gel-cream composition that enhances the transdermal and transmucosal delivery of the active pharmaceutical ingredients the active pharmaceutical ingredients . The composition comprises lecithin, poloxamer 407, isopropyl myristate and propylene glycol. This formulation has good adhesion to mucosal surfaces, has gel and cream like aesthetics and improves delivery' of a variety of APIs.

[0266] Carrier B: A topical, cosmetically elegant, penetration enhancing oil in water (O / W) emulsion that improves the delivery of active pharmaceutical ingredients the activepharmaceutical ingredients through intact human and animal skin. The composition comprises phosphatidylcholine, isopropyl myristate, cetearyl alcohol and ceteareth-20 as key ingredients to create the permeation enhancement as well as polyacry lamide and dimethicone to improve cosmetic elegance.

[0267] Carrier C: A Topical or Vaginal Penetration Enhancing O / W Emulsion (Cream) that improves the delivery of active pharmaceutical ingredients the active pharmaceutical ingredients into and through human and animal skin or vaginal tissue. The composition comprises lecithin, urea, isopropyl palmitate, isopropyl myristate, glyceryl stearate, PEG-40 stearate as key ingredients to improve permeation of APIs.

[0268] Carrier D: A topical water in oil (W / O) Emulsion (Cream), with high moisturizing properties for superficial delivery of active pharmaceutical ingredients the active pharmaceutical ingredients . This heavier cream forms a moisturizing barrier over the skin and releases actives on the skin’s surface. The composition comprises petrolatum, urea, stearyl alcohol, lanolin alcohol, PEG-40 stearate and mineral oil as key ingredients to form the thick emulsion with good barrier formation.

[0269] Carrier E: An anhydrous (low water activity ) permeation enhancing topical ointment, with superior cosmetic elegance (silky feel) and excellent spreadability. The composition comprises phosphatidylcholine, PEG- 16 macadamia glycerides, PEG-8 caprylic / capric glycerides as key ingredients for delivery, in a carrier of dimethicone and caprylyl methicone, with poly silicone- 11 and PEG-12 dimethicone / PPG-20 crosspolymer to provide viscosity and a cosmetically elegant feel.

[0270] Carrier F: An anhydrous (low water activity) self-emulsifying vaginal cream with good mucoadhesion, designed to deposit active pharmaceutical ingredients the active pharmaceutical ingredients onto the surface of the vaginal mucosa. The composition comprises PEG-32 stearate, glyceryl stearate, poloxamer 407 and glyceryl ricinoleate as key ingredients in a carrier of medium chain triglyceride oil. The formulation has a gel-cream like aesthetic and an attribute of low-leakage from the vagina once instilled.

[0271] Carrier G: A topical oil in water (O / W) non-ionic lamellar emulsion (Cream) for superficial delivery of active pharmaceutical ingredients, with a soft / smooth cosmetically elegant feel. The composition comprises emulsifying wax, ethylhexyl stearate and cyclopentasiloxane as key ingredients, and a natural preservative system that is free from parabens and formaldehyde donors.

[0272] Carrier H: A topical oil in water (O / W) emulsion, with a lotion consistency that is highly moisturizing, for superficial delivery of active pharmaceutical ingredients. The composition comprises ethylhexyl stearate, cyclopentasiloxane, PEG- 100 Stearate, glycery l stearate, PEG / PPG-18 / 18 dimethicone and sorbitol as key ingredients for the physicochemical attributes of the lotion and API release.

[0273] Carrier I: An aqueous topical gel for superficial delivery of active pharmaceutical ingredients the active pharmaceutical ingredients , with a soft “velvety'’ feel once dry on surface of the skin. The composition comprises ammonium acryloyldimethyltaurate / VP copolymerin a water based carrier as the key ingredient responsible for the physicochemical characteristics (drug release and cosmetic aesthetics) of the gel system.

[0274] Carrier J: A topical oil in water (O / W) emulsion (Cream) for the superficial delivery of active pharmaceutical ingredients the active pharmaceutical ingredients in patients with sensitive skin or atopic dermatitis (eczema) or psoriasis. This composition comprises polyglyceryl-3 cetearyl ether olivate, carapa guaianesis seed oil, theanine, vitis vinifera (grape)seed extract, xylitylglucoside, boswelia serrata resin extract, phosphatidylcholine, phosphatidylglycerol and brassica campestris sterols as key ingredients API delivery and skin calming, with dimethicone and cyclopentasiloxane for film formation and cosmetic elegance.Example 14Evaluation of exemplary combination compositions comprise Pterostilbene, and a curcuminoid and a catechin

[0275] Mixture T-Pterostilbene containing curcumin (8 pM) + EGCG (2 pM) + pterostilbene (25 pM) was further examined, and two additional mixtures were created as follows:

[0276] T-Ptero (1: 1: 1) Equimolar: curcumin (10 pM) + EGCG (10 pM) + pterostilbene (10 pM)

[0277] T-Ptero (25:2:8): curcumin (10 pM) + EGCG (10 pM) + pterostilbene (10 pM)

[0278] These mixtures were tested in HeLa cells (Table 25). The data indicates that the mixture of T-Ptero in the ratio 8:2:25 is the most potent, with an IC50 of 2.433 pM. This ratio is the exemplified molar concentration in Examples 6-8. When reversing the molar ratio of the compounds to 25:2:8, antagonism occurs, resulting in an IC50 of 14.535 pM. The equimolar mixtire T-Ptero (1 : 1: 1) mixture also shows good potency with an IC50 of 4.570 pM, demonstrating substantial inhibitory effects. This reveals that for the diphenylethylene compound pterostilbene, a mixture with a curcuminoid and catechin is effective at this equimolar ratios.Table 25In one embodiment of the invention, the formulation comprises by percentage of weight an equimolar composition as follows:Tetrahydrocurcumin: 6.8%EGCg: 8.4%Pterostilbene: 4.7%Propylene Glycol : 8%Diethylene Glycol Monoethyl Ether NF 8%Pharmaceutically Acceptable Carrier: 63.14%In which a pharmaceutically acceptable carriers are exemplified in Examples 12 and 13 .While the present application has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

Claims

What is claimed is:

1. A pharmaceutical composition, comprising an effective amount of each of: one or more compounds of Formula I:or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, wherein;X1and X2are independently selected from OH and OR1;X3and X4are independently selected from OH and OCH3; andR1isa curcuminoid; a catechin; optionally pterostilbene or pinostilbene; and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1. wherein the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxy curcumin, tetrahydrodemethoxycurcumin bisdemethoxycurcumin, tetrahydrobisdemethoxycurcumin, a curcumin ester and combinations thereof.

3. The pharmaceutical composition of claim 1 , wherein the curcuminoid is tetrahydrocurcumin.

4. The pharmaceutical composition of claim 1. wherein the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)- ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C).

5. The pharmaceutical composition of claim 1, wherein the catechin is (-)- epigallocatechin gallate.

6. The pharmaceutical composition of claim 1, wherein the composition comprises two or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

7. The pharmaceutical composition of claim 1, wherein the composition comprises two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 0.5: 1 to about 1 : 10, about 0.5: 1 to about 1:

8. about 0.5: 1 to about 1:5, about 0.5: 1 to about 1:4, about 0.5:1 to about 1 :3.75, about 0.5: 1 to about 1 :

4. about 1 : 1 to about 1 :4, about 1: 1 to about 1:3.75, about 1 : 1 to about 1 :3, or about 1 : 1 to about 1 :

2. 2.

8. The pharmaceutical composition of claim 7, wherein the two compounds of Formula I. or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1 :4, about 1 :3.75, about 1 :3, about 1 :2 or about 1: 1.

9. The pharmaceutical composition of claim 1, wherein the curcuminoid, the catechin and the one or more, or the two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, are present in the composition in a molar ratio of about 1-16:0.25-4: 1-40, about 1-16: 1-4: 10-40, about 1-10: 1-3: 1-30, about 4-12: 1-3: 15-35, or about 6-8:2-3:20-30 of the curcuminoid to the catechin to the one or more compounds ofFormula I, or two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

10. The pharmaceutical composition of claim 9 wherein the one or more, or the two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid and the catechin are present in the composition in a molar ratio of about 8:2:25 of the one or more, or the two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, to the curcuminoid to the catechin.

11. The pharmaceutical composition of claim 1 , wherein the one or more compounds of Formula I. or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, the curcuminoid is curcumin the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25.

12. The pharmaceutical composition of claim 11, wherein the composition comprises two compounds of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, and the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

13. The pharmaceutical composition of claim 12, wherein the two compounds of Formula I. or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are 1-1 (isorhapontigenin) and 1-3 (piceatannol), the curcuminoid is curcumin and the catechin is (-)- epigallocatechin gallate, and 1-3 (piceatannol) and 1-1 (isorhapontigenin) are present in the composition in a molar ratio of about 1 :3.75 of 1-3 to I- 1.

14. A pharmaceutical composition for treating or preventing a resveratrol resistant cancer or a HPV-induced cancer or an HPV -infected cell in a subject in need thereof, comprising aneffective amount of pterostilbene or pinostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate individually thereof, a curcuminoid and a catechin.

15. The pharmaceutical composition of claim 14. wherein the curcuminoid. the catechin and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 1-16: 1-4:10-40, about 1-10:1-3:1-30, about 4-12: 1-3: 15-35 or about 6-8:2-3:20-30 of the curcuminoid to the catechin to pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

16. The pharmaceutical composition of claim 14, wherein the curcuminoid, the catechin and pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof are present in the composition in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to pterostilbene, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

17. The pharmaceutical composition of claim 14, wherein the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxy curcumin, bisdemethoxycurcumin, tetrahydrodemethoxycurcumin, tetrahydrobisdemethoxycurcumin, a curcumin ester and combinations thereof.

18. The pharmaceutical composition of claim 14, wherein the curcuminoid is curcumin.

19. The pharmaceutical composition of claim 14, wherein the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigall ocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)- ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C).

20. The pharmaceutical composition of claim 14, wherein the catechin is (-)- epigallocatechin gallate.

21. The pharmaceutical composition of claim 14, wherein the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epi gall ocatechin gallate to pterostilbene or a pharmaceutically acceptable salt, prodrug and / or solvate thereof is about 8:2:25.

22. The pharmaceutical composition according to claim 1 or 14. wherein the pharmaceutical composition is formulated as a cream or self-emulsifying ointment.

23. The phrmaceutical composition of claim 22, wherein curcuminoind is at a range of 1- 10%; catechin is at a range of 0.33 - 4%; and diphenylethylene compounds is at a range of 2% - 16%.

24. A pharmaceutical composition, selected from the group consisting of:8 pM of curcumin, 2 pM of (-)-epigallocatechin gallate and 25 pM of piceatannol;8 pM of curcumin. 2 pM of (-)-epigallocatechin gallate and 25 pM pterostilbene;8 pM of curcumin, 2 pM of (-)-epigallocatechin gallate, 12.5 pM of piceatannol and 12.5 pM pterostilbene; and8 pM of curcumin, 2 pM of (-)-epigallocatechin gallate, 4.2 pM of piceatannol and 20.8 pM of pterostilbene.

25. A pharmaceutical composition, selected from the group consisting of: tetrahydrocurcumin, (-)-epigallocatechin gallate and pinostilbene at a molar ratio of 4: 1 : 12.5; tetrahydrocurcumin, (-)-epigallocatechin gallate and pterostilbene at a molar ratio of 4: 1 : 12.5; tetrahydrocurcumin, (-)-epigallocatechin gallate, piceatannol and pterostilbene at a molar ratio of 4: 1 :6.25:6.25; tetrahydrocurcumin, (-)-epigallocatechin gallate, piceatannol and pterostilbene at a molar ratio of 4: 1:

2. 1: 10.4; tetrahydrocurcumin, (-)-epigallocatechin gallate and pterostilbene at a molar ratio of 1: 1: 1; and curcumin, (-)-epigallocatechin gallate and pterostilbene at a molar ratio of 1 : 1 : 1.

26. A method of treating or preventing a papillomavirus infection in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 1 or claim 14.

27. The method of claim 26, wherein the papillomavirus infection is a human papillomavirus (HPV) infection.

28. The method of claim 27, wherein the HPV infection is an infection of one or more HPV genotypes selected from 1 (HPV-1), 2 (HPV-2), 3 (HPV-3), 4 (HPV-4), 5 (HPV-5), 6 (HPV-6), 8 (HPV-8), 11 (HPV-11), 16 (HPV-16), 18 (HPV-18), 21 (HPV-21), 22 (HPV-22), 23 (HPV-23), 27 (HPV-27), 29 (HPV-29), 31 (HPV-31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56). 57 (HPV-57) 58 (HPV- 58), 59 (HPV-59) and 68 (HPV-68).

29. The method of claim 28, wherein the HPV infection is an infection of one or more HPV genotypes selected from HPV genotypes 16 (HPV-16) and 18 (HPV-18).

30. A method of treating or preventing a disease, disorder or condition caused by a papillomavirus infection, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 1 or 14 to a subject in need thereof.

31. The method of claim 30, wherein the disease, disorder or condition caused by a papillomavirus infection is a papillomavirus-related cancer or precancer.

32. The method of claim 31, wherein the papillomavirus-related cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer and skin cancer, and combinations thereof.

33. The method of claim 31, wherein the papillomavirus-related cancer is resveratrol resistant.

34. The method of claim 31, wherein the disease, disorder or condition caused by a papillomavirus infection is selected from warts and laryngeal papilloma and combinations thereof.

35. The method of claim 34, wherein the warts are selected from common warts, flat warts, filiform warts, mosaic warts, plantar warts, periungual warts and genital warts and combinations thereof.

36. The method of claim 35, wherein the warts are plantar warts.

37. The method of claim 36, wherein the warts are caused by one or more of HPV-1, HPV-2, HPV-3, HPV-4, HPV-5. HPV-6, HPV-11, HPV-27, HPV-29, and HPV-57.

38. A method of treating a resveratrol resistant cancer or a HPV-induced cancer or an HPV-infected cell in a subject in need thereof, comprising an the step of administering to said subject a therapeutically effective amount of the pharmaceutical composition according to claim 14.

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