Platinum (IV) complexes, methods of making, compositions containing, and methods of using the same

Abstract

A platinum (IV) complex having the structure of Formula I: wherein: X, X', Y, Y', and Z are each independently an electron donor ligand, R1-R5 are each independently a functional group, L is a linking unit, and n is selected from the group consisting of 0, a positive charge, and a negative charge. Various methods include a step of manufacturing the platinum (IV) complex for treating a cancer, a tumor, or an infection in a subject with the platinum (IV) complex. Pharmaceutical compositions include the platinum (IV) complex.

Description

Technical Field

[0001] This invention relates to platinum-based anticancer, antitumor, and anti-infective drugs. More specifically, this invention relates to platinum-based anticancer chemotherapy drugs and anti-infective drugs. Background Technology

[0002] Platinum-based anticancer drugs are currently the most widely used chemotherapy agents in clinical practice. It is estimated that over 50% of cancer patients receiving chemotherapy use platinum-based drugs alone or in combination with other anticancer drugs. However, the therapeutic efficacy of platinum-based drugs is often limited by severe side effects and cancer cell resistance. For example, current chemotherapy agents can be activated in non-pathological tissues, causing damage to normal tissues.

[0003] While certain specific cytotoxic platinum complexes are also known for medical use (see, for example, US Patent No. 2018 / 155382A1, published June 7, 2018, and assigned to City University of Hong Kong, the entire contents of which are incorporated herein by reference), additional complexes are still desired.

[0004] Traditional platinum-based anticancer complexes kill cancer cells by binding to their DNA and inducing DNA damage. However, the therapeutic efficacy of these drugs is limited by factors such as low platinum-DNA binding efficiency, poor selectivity between cancer cells and normal cells, and drug resistance in cancer cells (e.g., enhanced DNA repair capabilities).

[0005] Ultraviolet (UV) and visible light photoactivated drugs (including prodrugs in this article) are known and have been shown, for example, to have antitumor activity. However, serious problems exist in the practical application of these photoactivated drugs, such as side effects, phototoxicity and cytotoxicity in non-lesion tissues, drug resistance, oxygen dependence, and the weak tissue penetration of UV-Vis light, which limits their applicability only to lesions near the skin surface and / or other internal body cavity regions accessible to UV / visible light sources. This may severely limit their use and / or efficacy.

[0006] Bacteria are known to rapidly develop resistance and transfer that resistance to conventional antibiotics. Furthermore, traditional antimicrobial photodynamic therapy (APDT) agents strongly rely on intracellular drug accumulation to exert their antibacterial effects. Therefore, the bacterial cell wall and cell membrane are significant obstacles to the successful application of APDT and related drugs.

[0007] Therefore, given the inherent limitations of current technology, there remains a need to develop additional platinum-based therapies that can overcome these limitations and effectively treat cancer, tumors, and / or infections, as well as to develop anticancer and antibacterial agents with controllable activation properties and targeted specificity, and platinum complexes that can effectively overcome drug resistance through precise and controllable mechanisms of action. Furthermore, tetravalent platinum prodrugs, upon photoactivation, can be transformed into strong oxidants to oxidize intracellular biomolecules related to cell survival and generate reactive oxygen species (ROS), lipid peroxides, etc., to disrupt the intracellular redox balance and kill cancer cells or bacteria, thus meeting the need to overcome the limitations of traditional therapeutic drugs. Summary of the Invention

[0008] One embodiment of the present invention relates to a platinum(IV) complex of formula I:

[0009]

[0010] X, X', Y, Y', and Z are each an independent electron donor ligand, R1 to R5 are each an independent functional group, L is a connecting unit, and n is a group composed of 0, positive charge, and negative charge.

[0011] One embodiment of the present invention relates to various methods for manufacturing the platinum(IV) complex described herein. One embodiment of the present invention relates to a method for treating a subject with cancer, tumor, or infection, comprising the steps of administering an effective dose of the platinum(IV) complex described herein to the subject and administering near-infrared light irradiation (NIR) to the subject. One embodiment of the present invention relates to a pharmaceutical composition containing the platinum(IV) complex described herein.

[0012] Without being limited to theory, the present invention is believed to provide one or more benefits, such as novel and improved photooxidants and photo-oxidation; improved treatment of cancer, tumors and / or infections; reduced patient toxicity; novel and improved therapeutic targets; reduced phototoxicity compared to UV treatment; enhanced anticancer and antibacterial therapies and compositions; controllable activation at specific times and locations; reduced side effects; platinum complexes that overcome cisplatin resistance, platinum resistance, PDT resistance, etc.; and methods for disrupting intracellular redox balance to kill cancer cells or bacteria. Attached Figure Description

[0013] Figure 1 An embodiment of the synthesis steps for complex 4 (i.e., formula II(c)) and complex 5 (i.e., formula II(a)) is shown;

[0014] Figure 2 An embodiment of the synthesis of complex 6 (i.e., formula II(d)) and complex 7 (i.e., formula II(b)) is shown;

[0015] Figure 3 DMSO- is shown d Compound 1 in 6 1 H NMR analysis;

[0016] Figure 4 DMSO- is shown d Compound 2 in 6 1 H NMR analysis;

[0017] Figure 5 This shows ligand 3 in CDCl3. 1 H NMR analysis;

[0018] Figure 6 This shows ligand 3 in CDCl3. 13 C NMR analysis;

[0019] Figure 7A ESI-MS analysis of ligand 3 is shown;

[0020] Figure 7B The HPLC chromatogram of ligand 3 is shown;

[0021] Figure 8 DMSO- is shown d Complex 4 in 6 1 H NMR analysis;

[0022] Figure 9 DMSO- is shown d Complex 4 in 6 13 C NMR analysis;

[0023] Figure 10 DMSO- is shown d Complex 4 in 6 195 Pt NMR analysis;

[0024] Figure 11A The ESI-MS analysis of complex 4 is shown;

[0025] Figure 11B The HPLC chromatogram of complex 4 is shown;

[0026] Figure 12 DMSO- is shown d Complex 5 in 6 1 H NMR analysis;

[0027] Figure 13 DMSO- is shown d Complex 5 in 6 13 C NMR analysis;

[0028] Figure 14DMSO- is shown d Complex 5 in 6 195 Pt NMR analysis;

[0029] Figure 15A The ESI-MS analysis of complex 5 is shown;

[0030] Figure 15B The HPLC chromatogram of complex 5 is shown;

[0031] Figure 16 DMSO- is shown d Complex 6 in 6 1 H NMR;

[0032] Figure 17 DMSO- is shown d Complex 6 in 6 13 C NMR analysis;

[0033] Figure 18 DMSO- is shown d Complex 6 in 6 195 Pt NMR analysis;

[0034] Figure 19A The ESI-MS analysis of complex 6 is shown;

[0035] Figure 19B The HPLC chromatogram of complex 6 is shown;

[0036] Figure 20 DMSO- is shown d Complex 7 in 6 1 H NMR analysis;

[0037] Figure 21 DMSO- is shown d Complex 7 in 6 13 C NMR analysis;

[0038] Figure 22 DMSO- is shown d Complex 7 in 6 195 Pt NMR analysis;

[0039] Figure 23A The ESI-MS analysis of complex 7 is shown;

[0040] Figure 23B The HPLC chromatogram of complex 7 is shown;

[0041] Figure 24A The RP-HPLC (254 nm) chromatogram of complex 4 is shown;

[0042] Figure 24B The RP-HPLC (254 nm) chromatogram of complex 5 is shown;

[0043] Figure 24C The RP-HPLC (254 nm) chromatogram of complex 6 is shown;

[0044] Figure 24D The RP-HPLC (254 nm) chromatogram of complex 7 is shown;

[0045] Figure 25A The RP-HPLC (254 nm) chromatogram of complex 4 is shown;

[0046] Figure 25B The RP-HPLC (254 nm) chromatogram of complex 5 is shown;

[0047] Figure 25C The RP-HPLC (254 nm) chromatogram of complex 6 is shown;

[0048] Figure 25D The RP-HPLC (254 nm) chromatogram of complex 7 is shown;

[0049] Figure 26A The percentage of complex 4 remaining after irradiation and without irradiation is shown;

[0050] Figure 26B The percentage of complex 5 (10 μM) remaining after irradiation and without irradiation is shown;

[0051] Figure 26C The percentage of complex 6 (10 μM) remaining after irradiation and without irradiation is shown;

[0052] Figure 26D The percentage of complex 7 (10 μM) remaining after irradiation and without irradiation is shown;

[0053] Figure 27A The viability of Escherichia coli (DH5α) after irradiation and without oxaliplatin treatment was demonstrated;

[0054] Figure 27B The viability of Escherichia coli (DH5α) after carboplatin treatment and before and after irradiation was demonstrated;

[0055] Figure 27C The viability of Escherichia coli (DH5-α) treated with compound 3 before and after irradiation was demonstrated;

[0056] Figure 27DThe viability of Escherichia coli (DH5-α) after treatment with complex 6 and before and after irradiation is shown;

[0057] Figure 27E The viability of Escherichia coli (DH5-α) after treatment with complex 7 and before and after irradiation is shown;

[0058] Figure 28A The viability of Staphylococcus aureus after irradiation and without oxaliplatin treatment was demonstrated.

[0059] Figure 28B The viability of Staphylococcus aureus after carboplatin treatment and before and after irradiation is shown.

[0060] Figure 28C The viability of Staphylococcus aureus treated with compound 3 before and after irradiation was demonstrated.

[0061] Figure 28D The viability of Staphylococcus aureus after treatment with complex 6 and before and after irradiation was shown;

[0062] Figure 28E The viability of Staphylococcus aureus after treatment with complex 7 and before and after irradiation is shown.

[0063] The accompanying drawings are for illustrative purposes only and are not necessarily drawn to scale. Detailed Implementation

[0064] Unless otherwise specified, all reactions were performed in the dark. All reagents and solvents were used as is without further purification. NMR data were recorded at room temperature using a Bruker AVANCE III 400 MHz spectrometer or a Bruker Ascend AVANCE III 600 MHz spectrometer. ESI-MS data were recorded using a liquid chromatography-mass spectrometry (API-3200 Triple-QMS / MS) system. Analytical HPLC (RPLC) was performed on a Shimadzu Prominence LC-20AT HPLC system with a reversed-phase C18 column (Phenomenex Garmin 250 × 4.60 mm, 5 μm, 110 Å). A photodiode array (PDA) detector was used to scan the absorption spectrum from 190 to 800 nm. Solvent A (H₂O containing 5% acetonitrile (ACN) and 0.01% trifluoroacetic acid (TFA)) and solvent B (ACN containing 5% H₂O and 0.01% TFA by volume) were used for gradient elution at a rate of 1.2 mL / min. The sample was eluted as follows: all by volume, 100% H₂O.

[0065] (0 min) -- 50% H2O + 50% ACN (5 min) -- 50% H2O + 50% ACN (7 min) -- 100% ACN (10 min) -- 100% ACN (13 min) -- 100% H2O (15 min). Platinum content was measured using an inductively coupled plasma optical emission spectrometer (ICP-OES) (PE Optima 8000).

[0066] Unless otherwise specified, all tests herein were conducted under standard conditions, including room temperature and test temperature of 25°C, sea level (1 atm.) pressure, and pH 7, and all measurements are in metric units. Furthermore, unless otherwise explicitly stated, all percentages, ratios, etc., herein are by weight. It should be understood that, unless otherwise specified, the materials, compounds, chemicals, etc., described herein are generally commercial and / or industrial standards available from a variety of suppliers worldwide.

[0067] As used in this article, the term "anticancer agent" refers to a compound that can kill cancer cells with or without a certain activation method.

[0068] As used herein, the terms “NIR” and “NIR-light” refer to near-infrared irradiation and near-infrared light, such as having wavelengths from about 700 nanometers (nm) to about 1400 nm; or from about 800 nm to about 1100 nm; or from about 800 nm to 1000 nm.

[0069] As used herein, the term "photodynamic therapy agent" refers to a compound that is non-toxic or low-toxic to cancer cells / tumor cells prior to activation by light irradiation; however, when irradiated with light or light of a certain wavelength, it can kill cancer cells / tumor cells directly or indirectly by generating ROS.

[0070] As used herein, the term “photooxidant” refers to a compound that is non-toxic and has a low reduction potential before photoactivation by irradiation; however, when irradiated with light or light of a specific wavelength, it can be transformed into an oxidant with a high reduction potential and can oxidize biomolecules to kill, for example, cancer cells and bacteria.

[0071] As used herein, the term “platinum resistance” refers to cells that are resistant to clinically available platinum drugs, such as bacteria, cancer cells, tumor cells, etc., and does not include platinum(IV) complexes as described herein.

[0072] As used herein, the term "prodrug" refers to a compound that has little pharmacological activity on its own, but can often be converted in vivo into a compound with significantly greater pharmacological activity.

[0073] One embodiment of the present invention relates to a platinum(IV) complex according to formula I:

[0074] Formula I.

[0075] In Formula I, X, X', Y, Y', and Z are directly bonded to platinum atoms. X, X', Y, Y', Z, and the platinum atom are collectively referred to as the "platinum moiety" herein. X, X', Y, Y', and Z are each independently an electron donor ligand; or X, X', Y, and Y' are each independently an electron donor ligand selected from the group consisting of: nitrogen-containing monodentate, bidentate, or tridentate ligands; oxygen-containing monodentate or bidentate ligands; phosphorus-containing monodentate or bidentate ligands; sulfur-containing monodentate or bidentate ligands; halogen-containing monodentate or bidentate ligands and combinations thereof; or oxygen-containing bidentate ligands; sulfur-containing monodentate or bidentate ligands; nitrogen-containing monodentate or bidentate ligands; phosphorus-containing monodentate or bidentate ligands and combinations thereof; or oxygen-containing bidentate ligands; nitrogen-containing monodentate or bidentate ligands and combinations thereof. Z can be selected from the group consisting of: oxygen-containing monodentate or bidentate ligands, sulfur-containing monodentate or bidentate ligands, nitrogen-containing monodentate or bidentate ligands, halogen-containing monodentate or bidentate ligands, and combinations thereof; or oxygen-containing monodentate or bidentate ligands; or oxygen-containing monodentate or bidentate ligands containing at least one functional group. This functional group can be, for example, a carboxylic acid group, an amino group, a hydroxyl group, a thiol group, and combinations thereof. For all the above ligands, at least one nitrogen, oxygen, halogen, sulfur, or phosphorus atom should be directly attached to the platinum center via an unpaired electron pair, and can form a coordinate covalent bond with the platinum center; thus, these groups can be attached to the platinum center and become ligands of the platinum complex. In one embodiment of this document, the ligand is a nitrogen, oxygen, and / or halogen-containing ligand, as most currently clinical platinum drugs are considered to contain these three ligands. Nitrogen, oxygen, halogen, sulfur, and phosphorus are generally considered excellent coordinating atoms, and they readily form coordinate bonds with platinum via monodentate, bidentate, or tripentate ligands. Monodentate, bidentate, and tridentate ligands used for developing platinum complexes have been widely reported in numerous papers, some of which are shown below:

[0076] In Formula I, R1 to R5 are each an independent functional group and together with the benzopyran-2-one moiety are referred to as the "aromatic moiety". This functional group can be selected from combinations of the following: hydrogen atoms, a hydrocarbon group containing 1-50 carbon atoms, a nitrogen-containing group containing 1-50 nitrogen or carbon atoms, wherein the nitrogen is directly attached to the main ring structure, an oxygen-containing group containing 1-50 oxygen or carbon atoms, wherein the oxygen is directly attached to the main ring structure, a phosphorus-containing group containing 1-50 phosphorus or carbon atoms, wherein the phosphorus is directly attached to the main ring structure, a sulfur-containing group containing 1-50 sulfur or carbon atoms, wherein the sulfur is directly attached to the main ring structure, and a halogen, wherein the halogen is directly attached to... The main ring structure and combinations thereof; or hydrogen atoms, a hydrocarbon group containing 1-50 carbon atoms, a nitrogen-containing group containing 1-50 nitrogen or carbon atoms, wherein the nitrogen is directly attached to the main ring structure, an oxygen-containing group containing 1-50 oxygen or carbon atoms, wherein the oxygen is directly attached to the main ring structure; and combinations thereof; or hydrogen atoms, a nitrogen-containing group containing 1-50 nitrogen or carbon atoms, wherein the nitrogen is directly attached to the main ring structure, an oxygen-containing group containing 1-50 oxygen or carbon atoms, wherein the oxygen is directly attached to the main ring structure, and combinations thereof. In one embodiment of this invention, R1-R5 together with the main ring structure are derivatives of coumarin or rhodamine. It is believed that by changing R1-R5, the obtained coumarin or rhodamine derivatives can be tuned to exhibit various photoproperties (e.g., different excitation and emission wavelengths). Therefore, various therapeutic targets, photoproperties, and photooxidative properties of platinum(IV) complexes can be tuned by selecting appropriate derivatives. For example, for the treatment of skin cancer, platinum (IV) complexes with relatively short excitation wavelengths are preferred because shorter wavelengths of light have higher energy, which can more effectively activate platinum (IV) complexes since deep penetration is not required for areas closer to the skin surface; while for the treatment of bladder cancer, platinum (IV) complexes with longer excitation wavelengths are preferred because tumors are usually located deeper in the body; therefore, longer wavelengths of light with better tissue penetration may be required.

[0077] The following provides some examples of the coumarin and rhodamine derivatives used in this article and their excitation wavelengths (Ex):

[0078]

[0079] In Formula I, L is the linking unit connecting the platinum-containing portion and the aromatic portion. In one embodiment of this document, the linking group is selected from the group consisting of: conjugated carbon ring structures with a total carbon number of less than 26, C 2-10 Carbon chains and combinations thereof; or at least electron-donating portions.

[0080] In Equation I, n represents the charge of the complex, which can be zero (0), positive or negative; or zero or positive; or an integer from -2 to 4; or zero.

[0081] This invention provides a novel class of platinum (IV) complexes. Without being theoretically limited, these complexes are considered photooxidants that can be used as pharmaceuticals and prodrugs; or prodrugs, and are effectively activated by near-infrared (NIR) irradiation for the treatment of diseases, particularly cancer and bacterial infections. Compared to other UV or visible light photoactivated pharmaceuticals and prodrugs, the present platinum (IV) complexes of this invention can be activated by low doses of NIR to release platinum (II) drugs. It is believed that by using NIR instead of, for example, UV light to activate the platinum (IV) complexes of this invention, treatment and use are significantly enhanced with increased penetration depth and / or reduced phototoxicity. Since the present platinum (IV) complexes are strong photooxidants, they are considered to be able to oxidize biomolecules to further enhance their anticancer and antibacterial efficacy.

[0082] Furthermore, compared to typical chemotherapy drugs, the complexes of the present invention are believed to be controllably activated by NIR irradiation, for example, in or near tumors, cancerous tissues, cancerous areas, infections, etc., to reduce side effects and damage to cells in other parts of the subject. Upon photoactivation, the complexes of the present invention can effectively oxidize intracellular biomolecules, such as proteins and lipids, and / or disrupt intracellular hemostasis to eliminate cancer cells. In doing so, the present invention effectively overcomes the resistance of cancer cells to conventional chemotherapy agents. Since current platinum (IV) complexes can directly oxidize intracellular biomolecules, bacteria, and / or cancer cells in an oxygen-independent manner, they can provide improved bioactivity while overcoming the limitations of low response rates of conventional platinum-based drugs and photodynamic therapy (PDT) agents in the hypoxic tumor microenvironment.

[0083] Embodiments of the present invention relate to the preparation of the compounds and complexes described herein, their cytotoxicity against various tumor and / or cancer cell lines, and their antibacterial activity. One embodiment of the present invention also relates to a pharmaceutical composition comprising at least one photoactivated platinum(IV) photooxidant and a pharmaceutically acceptable carrier. It is also considered that one embodiment of the platinum(IV) complexes described herein can be used as, for example, an anticancer agent, a photodynamic therapy agent, a photooxidant, or a combination thereof; or an anticancer agent; a photodynamic therapy agent; or a photooxidant.

[0084] Not intended to be theoretically limiting, the compounds of the present invention are thought to be photoactivated by NIR, such as those having wavelengths from about 700 nanometers (nm) to about 1400 nm; or from about 800 nm to about 1100 nm; or from about 800 nm to 1000 nm. It is thought that, when activated by NIRs within this range, the platinum (IV) complexes of the present invention; or the photoactivated platinum (IV) prodrugs of the present invention, can provide significant cytotoxicity against a variety of cancer cells, including platinum-resistant cancer cells.

[0085] Furthermore, the platinum (IV) complexes described herein are considered to have several advantages over current platinum-based drugs, such as, for example, controlled activation, significantly enhanced penetration and antitumor / antibacterial activity, significantly reduced toxicity to normal cells, and the potential to reduce or even prevent the development of resistance in tumors and bacteria. In addition, the platinum (IV) complexes described herein are considered to have a longer activation wavelength compared to conventional photosensitizers. This is considered advantageously to allow them to be used at greater depths from the photoactivator, and therefore at greater tissue depths. This, in turn, can achieve improved efficacy and greater penetration. Moreover, since the platinum (IV) complexes of this invention do not require oxygen for activation / efficacy, these complexes can be bioactive regardless of the presence of oxygen, even under hypoxic conditions, and are therefore more flexible and functional than existing oxygen-dependent photosensitizers, drugs, and prodrugs.

[0086] It is also believed that, since the platinum(IV) complexes of the present invention can become strong oxidants upon photoexcitation, they may also strongly disrupt components, such as lipopolysaccharides or proteins, such as those in the bacterial cell wall (if present) and / or bacterial cell membrane, to lyse and kill bacteria. Furthermore, it is believed that the platinum(IV) complexes of the present invention can also attack intracellular survival-related biomolecules, such as DNA, glutathione (GSH), and heme. Not intended to be limiting, it is believed that because the platinum(IV) complexes of the present invention are designed to disrupt bacterial cell walls and cell membranes, they do not produce or cause cross-resistance with conventional antibiotics. Therefore, it is believed that the present invention can overcome certain obstacles of conventional APDT agents. It is believed that the complexes of this invention may disrupt multiple, many, or even all biological components of the cell membrane, and that the complexes located in the tumor region can be specifically activated by irradiating the tumor region with NIR light. Furthermore, these complexes can be further conjugated with tumor-targeting groups (such as antibodies or tumor-targeting peptides) to enhance tumor-targeting capabilities. Therefore, it can be understood that the platinum (IV) complex of the present invention can generally be classified as a drug; or a prodrug.

[0087] In one embodiment of this paper, the power of the NIR can be approximately 0.01 W / cm². 2 Approximately 4W / cm 2 Or from approximately 0.1 W / cm 2 Approximately 2W / cm 2 ; or from approximately 0.2 W / cm 2 Approximately 0.8 W / cm 2This range is considered sufficient to penetrate and activate the complexes described herein, while also being safe for use in tissues, such as human tissues, to reach platinum (IV) complexes located under the skin. In one embodiment of this invention, the energy source is selected from the group consisting of continuous-wavelength lasers, pulsed lasers, and combinations thereof. In one embodiment of this invention, the pulsed laser has an emission frequency higher than 1 MHz. Not intended to be theoretically limited, it is thought that such NIRs could be applied externally, and that NIRs may be less destructive than, for example, UV light, which, due to its short wavelength and high energy, could potentially cause, for example, cancer, genetic damage, etc. Therefore, unlike other photoactivated prodrugs activated by UV or visible light, the platinum (IV) complexes of this invention are considered suitable for use as pharmaceuticals and / or prodrugs that can be irradiated by low-dose near-infrared light (e.g., 880 nm, 0.4 W / cm²). 2 ) Activation. Not intended to be theoretically limited, it is believed that the use of NIR in this invention can significantly increase penetration depth during treatment and / or reduce phototoxicity from irradiation.

[0088] In one embodiment of this document, the platinum(IV) complex is selected from the group consisting of:

[0089] ; ;

[0090] Formula II (a) Formula II (b)

[0091] ;as well as .

[0092] Formula II (c) Formula II (d)

[0093] One embodiment of the present invention relates to a pharmaceutical composition containing a platinum (IV) complex; or a platinum (IV) complex as described herein. The pharmaceutical composition may further comprise components selected from, for example, the group consisting of: additional anticancer agents, adjuvants, antibodies, binders, buffers, diluents, fillers, pharmaceutically acceptable carriers, preservatives, surfactants, contrast agents, radioactive agents, photodynamic therapy agents, photothermal therapy agents, ultrasound therapy agents, and combinations thereof; or additional anticancer agents, antibodies, adjuvants, buffers, pharmaceutically acceptable carriers, and combinations thereof; or antibodies, pharmaceutically acceptable carriers, and combinations thereof, as well as other pharmaceutical components known in the art.

[0094] In one embodiment of this invention, the antibodies, peptides, and specific tumor / bacterial targeting groups useful herein can, for example, be linked to the platinum(IV) complex of this invention and can also target cancer, tumors, or infections / bacteria. Therefore, it is believed that the platinum(IV) complex of this invention will be attracted and / or concentrated at the site of cancer, tumors, and / or infection, thereby enhancing its effectiveness during use.

[0095] One embodiment of the present invention relates to a method for manufacturing a platinum(IV) complex of formula II(a) according to the following steps: providing c,c,t -[Pt(DACH)(OH)2(ox)], providing an N-hydroxysuccinimide (NHS) ester of 3-((4-(3-(7-(diethylamino)-2-oxobenzodihydropyran-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)cololeic acid, and enabling c,c,t -[Pt(DACH)(OH)2(ox)] reacts with the NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxobenzodihydropyran-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)colloidic acid to form a platinum(IV) complex of formula II(a). Not intended to be theoretically limited, this method of preparation is considered efficient, simple, and scalable.

[0096] c,c,t- [Pt(DACH)(OH)2(ox)]: .

[0097] NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxobenzodihydropyran-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)colloidic acid:

[0098] .

[0099] Once synthesized, these complexes were characterized by spectroscopic analysis, and their activities against various cancer cell lines and different bacterial populations were analyzed. The mechanisms of action of some platinum (IV) complexes were further analyzed.

[0100] Not intended to be theoretically limited, platinum (IV) complexes are considered to be in their highest oxidation state (equal to or above 1.23 V), and because they cannot be further oxidized, they are more likely to be reduced upon photoexcitation. Furthermore, while other metal complexes (e.g., Ru, Ir, and Rh) may also exhibit photooxidation capabilities at their highest oxidation state, platinum (IV) complexes containing two axial ligands have been found to be more readily functionalized. Therefore, during the photoreduction of the platinum (IV) complexes described herein, both axial ligands are typically released, making the platinum (IV) complexes more flexible for designing multifunctional prodrugs. Thus, in one embodiment described herein, the releasable ligands themselves can possess anticancer and / or pharmaceutical activity.

[0101] Furthermore, several platinum complexes have been approved as anticancer drugs for clinical treatment, thus potentially reducing regulatory hurdles. In particular, the NIR photoactivated platinum (IV) complexes designed in this invention are considered suitable as prodrugs for the controlled release of clinical drugs for precise and targeted therapy. Therefore, platinum (IV) complexes are considered particularly suitable as NIR-activated prodrugs for the treatment and / or elimination of cancer cells and / or infections, such as those caused by bacteria, through the release of clinical drugs and / or photo-oxidation.

[0102] Therefore, it should be understood that upon activation with NIR, photoexcitation causes the platinum(IV) complexes of this invention to transform into strong oxidants, which can subsequently oxidize intracellular biomolecules, such as proteins and lipids, producing ROS, lipid peroxides, and protons. Upon exposure to NIR, these platinum(IV) complexes are thought to readily oxidize surrounding molecules and may be reduced to platinum(II), thereby releasing two axial ligands. Most intracellular biomolecules, such as proteins and lipids, are readily oxidized; therefore, in this photoreduction process, existing intracellular biomolecules are thought to act as electron donors and be oxidized, resulting in the production of reactive oxygen species (ROS), lipid peroxides, and protons, which can further inhibit and / or attack cancers, infections, bacteria, etc.

[0103] ROS and oxidized lipids may disrupt the intracellular redox balance, triggering intense oxidative stress that leads to cell death, and / or causing protons to disrupt intracellular pH homeostasis, thereby synergistically killing cancer cells and overcoming traditional drug resistance. Simultaneously, it is believed that these complexes will be reduced, releasing photosensitizing ligands and platinum(II) drugs. Platinum(II) drugs are considered suitable for chemotherapy, while photosensitizing ligands can act as PDT agents to further enhance therapeutic efficacy.

[0104] In one embodiment of this document, a method for preparing the platinum(IV) complex of formula II(b) comprises the following steps: providing the platinum(IV) complex of formula II(a), providing an NHS ester of 5,6-dimethylxanthoxanone-4-acetic acid (i.e., ligand 3), and reacting the platinum(IV) complex of formula II(a) with the NHS ester of 5,6-dimethylxanthoxanone-4-acetic acid to form the platinum(IV) complex of formula II(b). Not intended to be theoretically limited, this method of preparation is considered efficient, simple, and scalable.

[0105] In one embodiment of this document, a method for producing a platinum (IV) complex of formula II(c) comprises the following steps: providing diamino(cyclobutane-1,1-dicarboxy)dihydroxyplatinum (IV), providing an NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxobenzodihydropyran-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)cololeic acid, and reacting diamino(cyclobutane-1,1-dicarboxy)dihydroxyplatinum (IV) with the NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxobenzodihydropyran-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)cololeic acid to form a platinum (IV) complex of formula II(c). This method of production is not intended to be limiting to theory, but is considered to be efficient, simple, and scalable.

[0106] In one embodiment of this document, a method for producing a platinum (IV) complex of formula II(d) comprises the steps of: providing a platinum (IV) complex of formula II(c) and providing an NHS ester of 5,6-dimethylxanthoxanone-4-acetic acid.

[0107] .

[0108] The platinum(IV) complex of formula II(c) reacts with the NHS ester of 5,6-dimethylxanthone-4-acetic acid to form the platinum(IV) complex of formula II(d). Not intended to be theoretically limited, this method of preparation is considered efficient, simple, and scalable.

[0109] In one embodiment of this document, the complex according to Formula I may include, for example, derivatives of salicylaldehyde, acetoacetic acid, ethyl acetate, 3-oxobutyrate derivatives (e.g., methyl 3-oxobutyrate and phenyl 3-oxobutyrate), platinum (II) drugs and complexes (e.g., cisplatin, nedaplatin, and sulbine), anhydride derivatives (e.g., succinic anhydride), halogens, and carboxylic acid derivatives. We note that the ligands in this document may be directly attached to platinum (IV) atoms (i.e., equatorial ligands) or may be attached to atoms or portions attached to platinum atoms (i.e., axial ligands).

[0110] Not intended to be limiting to theory, embodiments of the invention are also thought to provide methods for treating a subject with cancer, tumor, or infection. In one embodiment herein, such a method includes the steps of administering an effective dose of a platinum (IV) complex according to formula I to the subject, and administering near-infrared light irradiation (NIR) to the subject, typically from outside the body, when determining the location of the platinum (IV) and / or the location of the cancer, tumor, or infection to be treated in vivo.

[0111] Therefore, cancer, tumors, or infections are typically located subcutaneously in the subject. In one embodiment of this document, the subcutaneous location is approximately 0.01 cm to approximately 2 cm from the irradiation site; or approximately 0.05 cm to approximately 1 cm from the irradiation site; or below the irradiation site. In one embodiment of this document, if the cancer, tumor, or infection is deep within the subject (i.e., more than approximately 2 cm below the skin surface), an optical fiber; or a laparoscopic optical fiber, can be used to deliver NIR to the subcutaneous location.

[0112] Since the effective dose of a drug is usually dependent on the patient's / subject's weight, in one embodiment of this document, the effective dose is from about 0.1 mg / kg to about 90 mg / kg; or from about 0.5 mg / kg to about 60 mg / kg; or from about 1.5 mg / kg to about 30 mg / kg, based on the patient's weight.

[0113] The present invention has also been found to be particularly effective in subjects with cancer or tumors exhibiting cisplatin resistance, platinum resistance, photodynamic therapy (PDT) resistance, etc., and therefore, in one embodiment herein, the compositions, treatments, and / or methods herein are directed at subjects with cancer or tumors exhibiting cisplatin resistance, platinum resistance, PDT resistance, or combinations thereof. In one embodiment herein, the cancer or tumor is selected from the group consisting of: breast cancer, peritoneal cancer, ovarian cancer, lung cancer, or combinations thereof; or ovarian cancer, as these have been shown to sometimes exhibit platinum resistance.

[0114] It was also found that the platinum(IV) complex described in this article can also be used to treat bacterial infections; or bacterial infections caused by bacteria selected from Gram-negative bacteria, Gram-positive bacteria and combinations thereof; or bacterial infections caused by Gram-positive bacteria.

[0115] In one embodiment of this invention, the invention can be used in combination with, for example, radiotherapy, ultrasound therapy, immunotherapy, gene therapy, and combinations thereof, to enhance the effectiveness of treatment.

[0116] Optionally, one embodiment of the invention relates to the use of a platinum(IV) complex according to formula I in the preparation of a medicament for treating cancer, tumors, infections, and combinations thereof in a subject. Herein lies one embodiment of the invention relating to the use of a platinum(IV) complex according to formula I in a subject for treating cancer, tumors, infections, and combinations thereof.

[0117] Example 1

[0118] Synthesis: The embodiments of the platinum(IV) complex of the present invention were synthesized herein as the following compounds.

[0119] Figure 1 An implementation scheme for the synthesis steps of complex 4 and complex 5 is shown.

[0120] Figure 1 Synthesis of Compound 1: Ethyl acetoacetate (1.9 mL), piperidine (125 μL), and 4-diethylaminosalicylaldehyde (0.48 g) were added to 20 mL of ethanol and stirred under reflux for 12 hours. Then, 20 mL of 3 M NaOH solution was added and refluxed for another 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and HCl solution (37%) was added to adjust the pH to 2.0 to precipitate the product. The crude product was collected by centrifugation and recrystallized in ethanol to give the pure product (yield: 80%, purity: 99%).

[0121] Figure 3 DMSO- is shown d Compound 1 in 6 1 H NMR analysis. 1 H NMR (400 MHz, DMSO- d6 ) δ8.49 (m, 1H), 7.66 (dt, J = 8.9, 2.3 Hz, 1H), 6.79 (d, J = 9.2 Hz, 1H), 6.58 (d, J = 3.4 Hz, 1H), 3.48 (d, 4H), 2.37 (s, 3H), 1.19 -1.09 (m, 6H). ESI-MS: m / z = 260.3 [M + H] + .

[0122] Figure 1Synthesis of Compound 2: Commercially available N-methyl-N-cyanoethyl-4-aminobenzaldehyde (1.0 g) was added to 30 mL of NaOH solution (5 M). Then, 3 mL of 30% H₂O₂ was added and the mixture was refluxed for 4 hours. The solution was cooled to room temperature, and the pH was adjusted to 2.0 using HCl. The crude product was extracted with 100 mL of ethyl acetate and purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate. After removing the solvent, Compound 2 was collected as a pink powder (yield: 65%, purity: 97%).

[0123] Figure 4 DMSO- was displayed d Compound 2 in 6 1 H NMR analysis. 1 H NMR (400 MHz, DMSO- d6 ) δ12.37 (s, 1H), 9.71 -9.60 (m, 1H), 7.68 (dd, J = 9.0, 3.1, 1.6 Hz, 2H), 6.88 -6.74 (m, 2H), 3.71 (d, J = 3.1 Hz, 2H), 3.07-2.97 (m, 3H), 2.50 (d, J = 7.6 Hz, 2H). ESI-MS: m / z = 206.3 [M - H] - .

[0124] Figure 1 Synthesis of ligand 3: (i.e., the NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxobenzodihydropyran-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)colloidic acid): Compound 1 (200 mg) and compound 2 (250 mg) were added to 25 mL of dichloromethane, followed by the addition of 0.1 mL of triethylamine. The mixture was refluxed for 72 hours. The solvent was then removed, and the crude product was purified by silica gel column chromatography. Pure ligand 3 was obtained by eluing with petroleum ether (50%) + ethyl acetate (50%) (yield: 42%, purity: 97%).

[0125] Figure 5 This shows ligand 3 in CDCl3. 1 H NMR analysis. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.58 (s, ¹H), 8.00 (d, J = 15.5 Hz, 1H), 7.83 (d, J= 15.5 Hz, 1H), 7.63 (d, J = 8.3Hz, 2H), 7.45 (d, J = 8.9 Hz, 1H), 6.86 (d, J = 8.3 Hz, 2H), 6.65 (dd, J = 9.0, 2.4 Hz, 1H), 6.51 (d, J = 2.3 Hz, 1H), 3.78 (t, J = 7.2 Hz, 2H), 3.47 (t, J =7.1 Hz, 4H), 3.08 (s, 3H), 2.69 (t, J = 7.0 Hz, 2H), 1.26 (d, J = 7.2 Hz, 6H).

[0126] Figure 6 This shows ligand 3 in CDCl3. 13 C NMR analysis. 13 C NMR (151 MHz, CDCl3) δ(ppm):12.50, 31.54, 38.48, 45.13, 48.07, 96.66, 108.74, 109.72, 112.01, 117.44,120.20, 123.99, 130.91, 131.61, 144.47, 148.32, 150.18, 152.73, 158.50,160.96, 175.96, 186.40.

[0127] Figure 7A The ESI-MS (electrospray ionization mass spectrometry) analysis of ligand 3 is shown: m / z = 471.2 [M + Na] + m / z = 449.2 [M + H] + . Figure 7B The HPLC chromatogram of ligand 3 is shown.

[0128] Figure 1Synthesis of complex 4 (i.e., formula II(c)): Ligand 3 (44.8 mg, 0.1 mmol) and diamino(cyclobutane-1,1-dicarboxy)dihydroxyplatinum(IV) (36 mg, 0.09 mmol) were mixed in 4 mL DMSO. 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium (TBTU, 48.2 mg, 0.15 mmol) and triethylamine (15 mg, 0.15 mmol) were added to the solution, and the mixture was stirred at 50 °C for 12 hours. After the reaction was complete, 5 mL DCM, 5 mL acetone, and 35 mL diethyl ether were added to precipitate the crude product. The crude product was collected by centrifugation and purified by HPLC to obtain complex 4. Yield: 64%, Purity: 95%.

[0129] Figure 8 DMSO- is shown d Complex 4 of 6 1 H NMR analysis. 1 1H NMR [dimethyl sulfoxide-d6 (DMSO- d6 ),400 MHz δ / ppm 8.56 (s, 1H), 7.71-7.53 (m, 5H), 6.81 (d, J = 8.9 Hz, 1H), 6.74(d, J = 8.7 Hz, 2H), 6.61 (d, J = 2.3 Hz, 1H), 6.15-5.73 (m, 6H), 3.58 (d, 2H), 3.51 (q, J = 6.9 Hz, 4H), 2.94 (s, 3H), 2.47 (s, 2H), 2.96 (d, 2H), 2.81 (d,2H), 1.75 (m, 2H), 1.15 (q, J = 15.5, 11.1 Hz, 6H), 0.84 (dd, J = 10.5, 7.0Hz, 2H).

[0130] Figure 9 DMSO- is shown d Complex 4 of 6 13 C NMR analysis. 13C NMR (151 MHz, DMSO) δ(ppm):12.85, 16.30, 29.46, 31.63, 32.54, 33.76, 38.50, 44.88, 49.02, 56.21, 96.37,108.37, 110.53, 112.18, 116.80, 119.65, 122.52, 130.92, 132.53, 143.88,148.22, 150.92, 153.17, 158.46, 160.41, 177.04, 178.87, 185.48.

[0131] Figure 10 DMSO- is shown d Complex 4 of 6 195 Pt NMR analysis. 195 Pt NMR (129 MHz, DMSO) δ (ppm): 1752.87.

[0132] Figure 11A ESI-MS analysis of complex 4 (m / z) is shown: [M+H]+ calculated C 32 H 41 N 34 O 10 Pt: 837.3, found: 837.2. Figure 11B The HPLC chromatogram of complex 4 is shown.

[0133] Figure 1 Synthesis of complex 5 (i.e., formula II(a)): Ligand 3 (50 mg), [Pt(DACH)(OH)2(ox)] (40 mg), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium (TBTU, 40 mg) and 20 µL of triethylamine were added to 3 mL of DMF and stirred at 50 °C for 12 hours. After the reaction was complete, 5 mL of acetone and 35 mL of EtO2 were added to precipitate the crude product. After centrifugation, the collected solid was purified by silica gel column chromatography using ethyl acetate / methanol as the eluent. The solvent was removed by rotary evaporation, and complex 5 was collected as a red powder and purified by HPLC (yield: 39%, purity: 96%).

[0134] Figure 12 DMSO- is shown d Complex 5 of 6 1 H NMR analysis. 1 1H NMR [dimethyl sulfoxide-d6 (DMSO- d6),400 MHz δ / ppm 8.57 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.78-7.60 (m, 4H), 7.54 (d, J = 8.5 Hz, 2H), 7.14 (s, 1H), 6.81 (d, J = 8.9 Hz, 1H), 6.74 (d, J = 8.7 Hz, 2H), 6.61 (d, J = 2.3 Hz, 1H), 3.62 (d, 2H), 3.51 (q, J =6.9 Hz, 4H), 2.94 (s, 3H), 2.47 (s, 2H), 2.04 (d, J = 21.1 Hz, 2H), 1.47 (s,4H), 1.35 – 1.23 (m, 2H), 1.14 (q, J = 15.3, 11.1 Hz, 6H).

[0135] Figure 13 DMSO- is shown d Complex 5 of 6 13 C NMR analysis. 13 C NMR (151 MHz, DMSO) δ(ppm): 12.84, 24.11, 24.21, 30.99, 31.20, 34.82, 38.33, 44.89, 48.95, 60.56,60.87, 61.88, 96.35, 108.37, 112.33, 116.74, 119.71, 130.90, 132.55, 148.26, 150.98, 153.17, 158.48, 164.33, 180.67, 185.47.

[0136] Figure 14 DMSO- is shown d Complex 5 in 6 195 Pt NMR analysis. 195 Pt NMR (129 MHz, DMSO) δ (ppm): 1409.07.

[0137] Figure 15A ESI-MS analysis of complex 5 (m / z) is shown: [M+H]+ calculated C 34 H 43N4O 10 Pt: 863.3, Certification: 863.2. Figure 15B The HPLC chromatogram of complex 5 is shown.

[0138] Example 2

[0139] Figure 2 An embodiment of the synthesis of complex 6 (i.e., formula II(d)) and complex 7 (i.e., formula II(b)) is shown.

[0140] Figure 2 Synthesis of complex 6 (i.e., formula II(d)): Complex 4 (i.e., formula II(c): 834 mg, 1 mmol) and vadimezan (DMXAA, 304 mg, 1.1 mmol) were mixed in 5 mL DMSO. TBTU (48.2 mg, 0.15 mmol) and triethylamine (15 mg, 0.15 mmol) were added to the solution, and the mixture was stirred at 50 °C for 12 h. After the reaction was complete, 5 mL DCM, 5 mL acetone, and 35 mL diethyl ether were added to precipitate the crude product. The crude product was collected by centrifugation and purified by HPLC to obtain complex 6. Yield: 70%, purity: 96%.

[0141] Figure 16 The complex 6 in DMSO-d6 is shown. 1 H NMR. 1H NMR (600 MHz, DMSO-d6) δ(ppm):8.55 (s, 1H), 8.07 (dt, J = 8.4, 2.7 Hz, 1H), 7.96 (s, 1H), 7.93 (d, J = 8.1Hz, 1H), 7.77 (dd, J = 7.4, 1.8 Hz, 1H), 7.73 (d, J = 15.5 Hz, 1H), 7.68 (d,J = 9.0 Hz, 1H), 7.62 (d, J = 15.5 Hz, 0H), 7.54 (d, J = 8.7 Hz, 2H), 7.39(t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 6.81 (dd, J = 9.1, 2.4 Hz,1H), 6.71 (d, J = 9.0 Hz, 2H), 6.60 (d, J = 2.4 Hz, 1H), 6.39 (s, 6H), 4.03(s, 2H), 3.58 (t, J = 7.4 Hz, 2H), 3.52 – 3.49 (m, 4H), 2.96 (s, 1H), 2.90(s, 2H), 2.74 (s, 2H), 2.55 (s, 4H), 2.45 – 2.40 (m, 6H), 1.74 (p, J = 8.2Hz, 2H), 1.16 (dd, J = 8.3, 5.6 Hz, 6H).

[0142] Figure 17 DMSO- is shown d Complex 6 of 6 13 C NMR analysis. 13C NMR (151 MHz, DMSO) δ(ppm): 0.09, 11.45, 12.36, 15.68, 20.21, 30.76, 31.13, 31.39, 35.77, 35.90,38.06, 44.40, 48.16, 55.56, 95.87, 107.88, 110.04, 111.73, 116.26, 118.78,119.25, 120.53, 122.15, 122.49, 123.47, 124.29, 125.62, 125.84, 125.93,130.43, 132.06, 136.57, 143.34, 144.52, 152.69, 153.44, 153.58, 157.99, 159.95, 162.29, 176.23, 176.29.

[0143] Figure 18 DMSO- is shown d Complex 6 of 6 195 Pt NMR analysis. 195 Pt NMR (129 MHz, DMSO) δ (ppm): 1960.40.

[0144] Figure 19A ESI-MS analysis of complex 6 (m / z) is shown: [M+H]+ calculated C 49 H 52 N4O 13 Pt: 1100.3, Certification: 1100.2. Figure 19B The HPLC chromatogram of complex 6 is shown.

[0145] Figure 2 Synthesis of complex 7 (i.e., formula II(b)): Complex 5 (i.e., formula II(a): 860 mg, 1 mmol) and vadimezan (DMXAA, 304 mg, 1.1 mmol) were mixed in 5 mL DMSO. TBTU (48.2 mg, 0.15 mmol) and triethylamine (15 mg, 0.15 mmol) were added to the solution, and the mixture was stirred at 50 °C for 12 h. After the reaction, 5 mL DCM, 5 mL acetone, and 35 mL diethyl ether were added to precipitate the crude product. The crude product was collected by centrifugation and purified by HPLC to obtain complex 7. Yield: 61%, Purity: 95%.

[0146] Figure 20 DMSO- is shown d Complex 7 of 6 1H NMR analysis. 1 H NMR (600 MHz, DMSO- d6 ) δ(ppm): 8.56 (s, 1H), 8.33 (s, 2H), 8.08 (dd, J = 8.0, 1.8 Hz, 1H), 8.07 (s,3H), 7.93 (d, J = 8.1 Hz, 1H), 7.79-7.70 (m, 2H), 7.70-7.59 (m, 2H), 7.57-7.51 (m, 2H), 7.39 (q, J = 7.3 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 6.81 (dd, J= 9.1, 2.4 Hz, 1H), 6.78-6.71 (m, 2H), 6.60 (d, J = 2.4 Hz, 1H), 4.06 (d, J =10.1 Hz, 1H), 3.59 (h, J = 7.5 Hz, 1H), 3.51 (q, J = 7.1 Hz, 5H), 2.93 (s,2H), 2.56-2.51 (m, 4H), 2.46-2.38 (m, 7H), 2.08-2.00 (m, 2H), 1.46 (s, 2H), 1.32 (dt, J = 22.2, 10.6 Hz, 1H), 1.16 (t, J = 7.1 Hz, 7H), 1.08-0.96 (m,1H).

[0147] Figure 21 DMSO- is shown d Complex 7 of 6 13 C NMR analysis. 13C NMR (151 MHz, DMSO) δ(ppm): 11.50, 12.36, 20.22, 23.44, 30.84, 30.91, 32.33, 33.10, 33.27, 36.63,37.88, 44.40, 48.12, 60.86, 61.04, 95.87, 107.89, 110.06, 111.91, 114.62,116.23, 118.87, 119.35, 120.63, 122.57, 123.52, 124.46, 125.45, 125.70,125.95, 130.40, 132.08, 136.45, 143.27, 144.51, 147.80, 150.39, 152.70, 153.44, 153.64, 158.00, 158.27, 159.95, 163.37, 176.30, 177.33, 177.35, 178.69, 178.95, 184.98.

[0148] Figure 22 DMSO- is shown d Complex 7 in 6 195 Pt NMR analysis. 195 Pt NMR (129 MHz, DMSO) δ (ppm): 1623.06. ESI-MS (m / z): [M+Na]+ Calculated C 51 H 54 N4O 13 Pt: 1149.0, Certification: 1149.1.

[0149] Figure 23A The ESI-MS analysis of complex 7 is shown, while Figure 23B The HPLC chromatogram of complex 7 is shown.

[0150] Example 3

[0151] The stability and photoinduced reduction of complexes 4, 5, 6, and 7 were tested. To test the stability of the complexes in the dark, PBS buffer (10 mM Na₂HPO₄, KH₂PO₄, 137 mM NaCl, 2.7 mM KCl, pH = 7.4) (with or without ascorbate (2 mM)) was incubated at 37°C with a shaker. HPLC analysis was performed at predetermined times.

[0152] The results are shown in Figure 24. Figure 24AThe RP-HPLC (254 nm) chromatogram of complex 4 (10 μM) is shown. Figure 24B The RP-HPLC (254 nm) chromatogram of complex 5 (10 μM) is shown. Figure 24C The RP-HPLC (254 nm) chromatogram of complex 6 (10 μM) is shown, as well as Figure 24D The RP-HPLC (254 nm) chromatogram of complex 7 (10 μM) is shown. Figures 24A-24D All tests shown were performed at different time points in PBS buffer containing 2 mM ascorbate.

[0153] Photoinduced reduction assays were performed, with the complex dissolved at a final concentration of 10 μM in PBS buffer (10 mM Na₂HPO₄, KH₂PO₄, 137 mM NaCl, 2.7 mM KCl, pH = 7.4) with or without ascorbate (2 mM) and incubated at 37°C. The reaction was then performed using an 880 nm laser (0.4 W / cm²). 2 Irradiate the solution for 20, 40, 60 or 80 minutes and analyze immediately by HPLC.

[0154] The results are shown in Figures 25A-25D middle. Figure 25A The RP-HPLC (254 nm) chromatogram of complex 4 (10 μM) is shown. Figure 25B The RP-HPLC (254 nm) chromatogram of complex 5 (10 μM) is shown. Figure 25C The RP-HPLC (254 nm) chromatogram of complex 6 (10 μM) is shown, as well as Figure 25D The RP-HPLC (254 nm) chromatogram of complex 7 (10 μM) in PBS buffer containing 2 mM ascorbate is shown. The solution was analyzed using an 880 nm laser or a continuous laser (0.4 W / cm²). 2 Irradiation. 1 The peak corresponds to platinum (II) drugs; 2 The peak corresponds to ligand 3; and 3 The peak corresponds to DMXAA.

[0155] Figure 26A The percentage of complex 4 (10 μM) remaining after irradiation and without irradiation is shown. Figure 26B The percentage of complex 5 (10 μM) remaining after irradiation and without irradiation is shown. Figure 26C The percentage of complex 6 (10 μM) remaining after irradiation and without irradiation is shown. Figure 26D The percentage of complex 7 (10 μM) remaining after irradiation and without irradiation is shown. Figures 26A-26DAll tests were performed in PBS buffer (pH 7.4) containing 2 mM sodium ascorbate, either in the dark or under 880 nm laser irradiation (0.4 W / cm²). 2 (This was done)

[0156] Example 4

[0157] Cytotoxicity assay:

[0158] Human lung cancer A549 cells (American Type Culture Collection, ATCC) and cisplatin-resistant A549cisR cells (ATCC) were cultured in DMEM containing 10% FBS and 100 μg / mL penicillin / streptomycin. Human ovarian cancer A2780 cells and cisplatin-resistant A2780cisR cells were cultured in RPMI-1640 containing 10% FBS, 1% L-glutamine, and 100 μg / mL penicillin / streptomycin. Human lung fibroblast MRC-5 cells (ATCC) were cultured in MEM containing 10% FBS, 1% NEAA, 1% L-glutamine, 1% sodium pyruvate, and 100 μg / mL penicillin / streptomycin. For A2780cisR and A549cisR cells, 2 μM cisplatin was added to the culture medium after attachment to maintain resistance. All cells were cultured at 37°C and 5% CO2.

[0159] Cytotoxicity profiles of various complexes against selected cell lines were obtained using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cells were seeded into 96-well plates at a density of 2,500 cells per well (for A549 and A2780) or 5,000 cells per well (for A549cisR, A2780cisR, and MRC-5) and incubated for 24 hours. Cells were then treated with medium containing various concentrations of the complexes for 6 hours. The medium was replaced with phenol red-free medium. Cells were then irradiated with near-infrared light (880 nm, 0.4 W / cm²) for 80 minutes. After irradiation, cells were further incubated in fresh medium at 37ºC for 18 hours. The medium was then removed, and cells were incubated for 2 hours with FBS-free medium containing 1 mg / mL MTT. The MTT-containing medium was removed, and 150 µL of DMSO was added to each well. Absorbance was measured at 570 and 630 nm.

[0160] The cytotoxicity of oxaliplatin, ligand 3, complex 4, and complex 5 to various cancer cell lines is shown in Table 1. Cells were treated with the specified complexes for 6 hours, the medium was replaced with fresh medium, and the cells were irradiated with or without blue light for 1 hour. The cells were then cultured for another 42 hours.

[0161] Table 1: Showing ICs50 (μM)

[0162]

[0163] * indicates that the test was conducted in darkness without illumination.

[0164] ** indicates that the test was conducted under illumination.

[0165] Example 5

[0166] Antibacterial test:

[0167] Growth medium: Lysozyme broth (LB, Invitrogen) was prepared by dissolving 3.0 g LB powder in 300 mL of ultrapure water. The LB solution was then autoclaved at 121°C for 45 minutes and cooled before adding antibiotics.

[0168] Bacteria were cultured in LB medium. Prior to the experiment, the LB stock solution containing bacteria was diluted with fresh LB medium to an OD600 of 0.005. Then, 200 µL of the diluted solution was transferred to sterile 96-well plates. The designed concentration of the complex was added, and the plates were incubated at 37°C on a shaker at 250 rpm. After 2 hours, the plates were removed and cultured under white light (400-760 nm, 4 mW / cm²) with or without light. 2 Irradiate for 10 minutes and then incubate for 22 hours. Afterward, transfer 100 μL of bacterial solution to a new 96-well plate. Record the absorbance at 600 nm using a Biotek Powerwave xs Microplate Reader. 100% viability is defined as the OD600 value of the untreated group, and 0% viability is defined as the culture medium blank.

[0169] Figures 27A-27E The viability of *E. coli* (DH5-α) after different treatments was shown. Bacteria were treated with the specified compound for 2 hours, followed by exposure to white light (400-760 nm, 4 mW / cm²). 2 Irradiate for 10 minutes. Finally, culture the bacteria for 22 hours. Figure 27A The results for oxaliplatin are shown in the figure. Figure 27B The results for carboplatin are shown in the figure. Figure 27C The results for compound 3 are shown in the figure. Figure 27D The results for complex 6 are shown in the diagram, and Figure 27E The results for complex 7 are shown in the figure.

[0170] Figures 28A-28EThe viability of Staphylococcus aureus (USASC) after different treatments is shown. The bacteria were treated with the specified compound for 2 hours, followed by exposure to white light (400-760 nm, 4 mW / cm²). 2 Irradiate for 10 minutes. Finally, culture the bacteria for 22 hours. Figure 28A The results for oxaliplatin are shown in the figure. Figure 28B The results for carboplatin are shown in the figure. Figure 28C The results for compound 3 are shown in the figure. Figure 28D The results for complex 6 are shown in the diagram, and Figure 28E The results for complex 7 are shown in the figure.

[0171] It should be understood that the above only illustrates and describes embodiments in which the present invention can be implemented, and modifications and / or changes can be made thereto without departing from the spirit of the present invention.

[0172] It should also be understood that certain features of the invention described in the context of a single embodiment for clarity may also be provided in combination in that single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided individually or in any suitable sub-combination.

[0173] All references specifically cited herein are incorporated herein by reference in their entirety. However, such citation or incorporation does not necessarily imply an acceptance of their suitability, referenceability, and / or usability as prior art to this invention, or their use as prior art against the suitability, referenceability, and / or usability of this invention.

Claims

1. A platinum (IV) complex selected from the group consisting of: Equation II(a); Formula II(b); Formula II(c); as well as Formula II(d).

2. A method for preparing the platinum(IV) complex of formula II(a) according to claim 1, comprising the following steps: A) Provides c,c,t-[Pt(DACH)(OH)2(ox)]; B) Providing an NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxobenzodihydropyran-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)cololeic acid; and C) React the c,c,t-[Pt(DACH)(OH)2(ox)] with the NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxobenzodihydropyran-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)cosyl acid to form the platinum(IV) complex of formula II(a).

3. A method for preparing the platinum(IV) complex of formula II(b) according to claim 1, comprising the following steps: A) Provides a platinum(IV) complex of formula II(a); B) Providing an NHS ester of 5,6-dimethylxanthone-4-acetic acid; and C) React the platinum(IV) complex of formula II(a) with the NHS ester of 5,6-dimethylxanthonone-4-acetic acid to form the platinum(IV) complex of formula II(b).

4. A method for preparing the platinum(IV) complex of formula II(c) according to claim 1, comprising the following steps: A) Provides diamino(cyclobutane-1,1-dicarboxyl)dihydroxyplatinum (IV); B) Providing an NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxobenzodihydropyran-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)cololeic acid; and C) Reaction of the diamino(cyclobutane-1,1-dicarboxy)dihydroxyplatinum(IV) with the NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxobenzodihydropyran-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)cosoleic acid to form the platinum(IV) complex of formula II(c).

5. A method for preparing the platinum(IV) complex of formula II(d) according to claim 1, comprising the following steps: A) Provides a platinum (IV) complex of formula II(c); B) Providing an NHS ester of 5,6-dimethylxanthone-4-acetic acid; and C) React the platinum(IV) complex of formula II(c) with the NHS ester of 5,6-dimethylxanthonone-4-acetic acid to form the platinum(IV) complex of formula II(d).

6. Use of the platinum(IV) complex of claim 1 in the preparation of a medicament for treating a subject with cancer, tumor, or infection, said medicament comprising an effective dose of the platinum(IV) complex, wherein, The platinum(IV) complex can be activated by near-infrared irradiation.

7. The use according to claim 6, wherein, The near-infrared irradiation has a wavelength of 700 nm to 1400 nm.

8. The use according to claim 6, wherein, The effective dose is from 0.1 mg / kg to 90 mg / kg, depending on the patient's weight.

9. The use according to claim 6, wherein, The cancer, tumor, or infection exhibits cisplatin resistance, platinum resistance, PDT resistance, or combinations thereof.

10. The use according to claim 6, wherein, The infection is a bacterial infection.

11. The use according to claim 10, wherein, The bacteria are Gram-negative bacteria, Gram-positive bacteria, and combinations thereof.

12. The use according to claim 6, wherein, Treat the cancer, tumor, or infection within the body.

13. The use according to claim 6, wherein, The cancer, tumor, or infection is located in the subcutaneous region of the subject.

14. The use according to claim 6, wherein, The near infrared light irradiation has a power from 0.01 W / cm 2 to 4 W / cm 2 .

15. A pharmaceutical composition comprising the platinum(IV) complex according to claim 1.

16. The pharmaceutical composition according to claim 15, wherein, The pharmaceutical composition further includes components selected from the group consisting of: additional anticancer agents, adjuvants, antibodies, binders, buffers, diluents, fillers, pharmaceutically acceptable carriers, preservatives, surfactants, contrast agents, radioactive agents, photodynamic therapy agents, photothermal therapy agents, ultrasound therapy agents, and combinations thereof.

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