Use of 7-Chloro-4-(phenylselanyl)quinoline as an antitumor agent for breast cancer, leukemia, sarcoma, and bladder cancer.

Description

1 / 22 Descriptive Report Use of 7-chloro-4-(phenylselanyl)quinoline as an antitumor agent for breast cancer, leukemia, sarcoma, and bladder cancer. Field of Invention

[0001] This invention patent falls under technical category A61P 35 / 00 according to the international patent classification. More specifically, this patent relates to the application of the compound 7-chloro-4-(phenylselanyl)quinoline (4-PSQ) as an antitumor agent for the treatment of breast cancer, leukemia, sarcoma, and bladder cancer. The in vitro efficacy of the compound 4-PSQ for the treatment of breast cancer, leukemia, sarcoma, and bladder cancer is demonstrated in this invention. State of the Art Cancer

[0002] Cancer is one of the leading causes of death, with GLOBOCAN 2020 estimating 19.3 million new cases and nearly 10 million deaths worldwide. In 2020, globally, female breast cancer surpassed lung cancer as the most diagnosed cancer, with 2.3 million new cases. The etiology of cancer is multifactorial, and identifying the interactions between these factors is crucial for the development of preventive and therapeutic strategies (MINISTRY OF HEALTH NATIONAL CANCER INSTITUTE JOSÉ ALENCAR GOMES DA SILVA MINISTRY OF HEALTH NATIONAL CANCER INSTITUTE. [sl], 2023). Petition 870250081505, dated 10 / 09 / 2025, page 5 / 26 2 / 22

[0003] Breast cancer is a heterogeneous disease, characterized by morphological and molecular variations, that predominantly affects women. According to the National Cancer Institute (INCA), in Brazil, for the three-year period from 2023 to 2025, an estimated 73,610 new cases are expected. This type of cancer is the most common in the country, surpassing all other types of cancer, except for non-melanoma skin cancers. In 2020, breast cancer mortality in Brazil reached 17,825 deaths; the prognosis tends to be favorable when the cancer is detected and treated early (MINISTRY OF HEALTH NATIONAL CANCER INSTITUTE JOSÉ ALENCAR GOMES DA SILVA MINISTRY OF HEALTH NATIONAL CANCER INSTITUTE. [sl], 2023).

[0004] Leukemia, a cancer of the white blood cells of generally unknown origin, is characterized by the accumulation of malignant cells in the bone marrow, replacing normal blood cells. The main subtypes include myeloid and lymphocytic leukemia, both acute and chronic, with variations in incidence according to age group. In Brazil, it is estimated that between 2023 and 2025 there will be 11,540 new cases of leukemia per year.

[0005] This cancer ranks tenth among the most frequent types in the country (MINISTRY OF HEALTH NATIONAL CANCER INSTITUTE JOSÉ ALENCAR GOMES DA SILVA MINISTRY OF HEALTH NATIONAL CANCER INSTITUTE. [sl], 2023), globally, in 2020, approximately 475,000 new cases of leukemia were registered, representing 2.5% of all types of cancer (SUNG, Hyuna et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, [sl], v. 71, n. 3, p. 209-249, 2021). Petition 870250081505, dated 10 / 09 / 2025, page 6 / 26 3 / 22

[0006] Mortality in Brazil in 2020 reached 6,738 deaths, with a risk of 3.18 per 100,000 inhabitants (MINISTRY OF HEALTH NATIONAL CANCER INSTITUTE JOSÉ ALENCAR GOMES DA SILVA MINISTRY OF HEALTH NATIONAL CANCER INSTITUTE. [sl], 2023). Sarcomas, in turn, are malignant neoplasms that originate in mesenchymal tissues, encompassing a heterogeneous group of tumors. They are divided into two main categories: soft tissue sarcomas and primary bone sarcomas, each with different staging and therapeutic approaches. These tumors are extremely varied, not only between different types, but also within the same tumor type (SKUBITZ, Keith M.; D'ADAMO, David R. Sarcoma. Mayo Clinic Proceedings, [sl], v. 82, n. 11, p. 1409-1432, 2007. Available at: http: / / www.mayoclinicproceedings.org / article / S0025619611614213 / fulltext. Accessed on: July 1, 2024).

[0007] In Brazil, INCA estimated that between 2020 and 2023, approximately 4,500 of the new cancer cases diagnosed annually would be sarcomas. Studies on the management of sarcomas in Brazil are scarce and generally limited to specific centers (R MOREIRA, Shermann B et al. Sarcoma - características e resultados em um centro de referencia oncológica no sul do Brasil / Sarcoma characteristics and results in a reference oncology center in southern Brazil. Brazilian Journal of Health Review, [sl], v. 5, n. 2, p. 4277-4292, 2022. Available at: (https: / / ojs.brazilianjournals.com.br / ojs / index.php / BJHR / article / view / 44893. Accessed July 1, 2024). Petition 870250081505, dated 10 / 09 / 2025, page 7 / 26 4 / 22

[0008] Bladder cancer (BC) is a prevalent malignancy of the urinary system, originating in the tissues of the bladder, an organ responsible for storing urine. It is the tenth most common neoplasm and the thirteenth leading cause of cancer mortality worldwide. Among men, it is the sixth most prevalent cancer and the ninth leading cause of cancer death (SUNG, H. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209-49. Medline:33538338 doi:10.3322 / caac.21660). An estimated 73% increase in annual cancer cases and an 87% increase in deaths are projected by 2040 globally. In Brazil, estimates from the National Cancer Institute (INCA) for the three-year period 2023-2025 indicate a forecast of 11,370 new cancer cases, with an estimated rate of 5.25 cases per 100,000 inhabitants.These numbers highlight the relevance of breast cancer, particularly among men, who have an estimated rate of 7.45 cases per 100,000, while women have an estimated rate of 3.14 per 100,000 (NATIONAL CANCER INSTITUTE (INCA). 2023 Estimate: Cancer Incidence in Brazil / National Cancer Institute. — Rio de Janeiro: INCA, 2022).

[0009] Cancer treatments, including surgery, chemotherapy, and radiation therapy, aim to remove or directly attack cancer cells. However, despite therapeutic advances, drug resistance and adverse effects remain significant challenges. These treatments can cure cancer in its early stages, but are often ineffective in treating cancer in advanced or recurrent stages. Petition 870250081505, dated 10 / 09 / 2025, page 8 / 26 5 / 22

[0010] By 2040, the global cancer burden is expected to increase to 28.4 million cases, with greater growth in developing countries. Significant disparities in incidence and mortality exist between different regions, requiring a global effort to improve cancer prevention, diagnosis and treatment, reduce risk factors, promote screening and early detection, and develop new safe and effective therapies. Selenium organic compounds

[0011] Organic selenium compounds have received attention from researchers due to their simple synthesis and relevant pharmacological activities. Since its discovery by Jacob Berzelius in 1817, selenium has been studied for its toxic and beneficial effects. In 1957, it was demonstrated that selenium can prevent hepatic necrosis in rats with vitamin E deficiency. In 1985, the enzyme glutathione peroxidase (GPx), which contains selenium, was identified as protecting cell membranes against lipid peroxidation, complementing the function of vitamin E. The role of selenium in GPx was discovered in 1973, and the importance of selenocysteine ​​and the selenol group in the biochemistry of mammalian cells was established in 1978. Adequate selenium intake is associated with immune function and a reduction in cardiovascular disease, as well as benefits against viral infections and sepsis (NOGUEIRA, Cristina W; BARBOSA, Nilda V; ROCHA, João B T).Toxicology and pharmacology of synthetic organoselenium compounds: an update. [sl], v. 95, p. 1179-1226, 2021. Available at: https: / / doi.org / 10.1007 / s00204-021-03003-5. Accessed on: July 1, 2024. Petition 870250081505, dated 10 / 09 / 2025, p. 9 / 26 6 / 22

[0012] The use of selenium in cancer prevention and treatment has been debated, and some studies indicate anticancer properties of compounds containing selenium in their chemical structure. Recent clinical trials show that ethaselen, derived from ebselen, is promising against lung cancer. In fact, even small structural changes in molecules can result in completely different properties. Therefore, several compounds are widely studied. The pharmacological and toxicological potential of organoselenium compounds continues to be explored, suggesting that these compounds may be promising therapeutic agents. In short, although the toxicity and efficacy of selenium have been the subject of several studies, the search for new organoselenium compounds continues, with the potential to discover safe and effective therapies for various pathologies, including cancer (NOGUEIRA, Cristina W; BARBOSA, Niida V; ROCHA, João B T.Toxicology and pharmacology of synthetic organoselenium compounds: an update. [slJ, v. 95, p. 1179-1226, 2021. Available at: https: / / doi.org / 10.1007 / s00204-021-03003-5. Accessed on: July 1, 2024). Quinolines and chloroquinolines

[0013] Alongside selenium compounds, the versatility of quinoline and its derivatives has attracted considerable attention in the field of drug development. This heterocycle has wide applicability, being explored in different areas of medicinal chemistry. Furthermore, its structural diversity allows the synthesis of molecules with varied pharmacological profiles, expanding therapeutic possibilities. Petition 870250081505, dated 10 / 09 / 2025, page 10 / 26 7 / 22

[0014] A variety of quinoline derivatives have been used as antiviral, anticancer, antibacterial, antifungal, anti-obesity, and anti-inflammatory agents (JUNG, Yongwoo et al. 8-(Tosylamino)quinoline inhibits macrophage-mediated inflammation by suppressing NF-κB signaling. Acta Pharmacologica Sinica 2012 33:8, [slJ, v. 33, n. 8, p. 1037-1046, 2012. Available at: https: / / www.nature.com / articles / aps201252. immunomodulatory activity. 1-amino-isoquinolines prepared via silver triflacetate cyclization of o-alkynylbenzaldoximes with isocyans.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences, [slJ, v. 51, no. 1, p. 196-203, 2014. Available at: https: / / pubmed.ncbi.nlm.nih.gov / 24099679 / . Accessed on: 2 Jul. 2024).

[0015] In particular, 7-chloroquinoline derivatives are biologically active units and exhibit a wide range of pharmacological activities (Marcus VN et al. Synthesis and in vitro antitubercular activity of a series of quinoline derivatives. Bioorganic and Medicinal Chemistry, [s. 1.], v. 17, n. 4, p. 1474-1480, 2009; SINGH, Pardeep et al. Synthesis, docking and in vitro antimalarial evaluation of bifunctional hybrids derived from β-lactams and 7-chloroquinoline using click chemistry. https: / / pubmed.ncbi.nlm.nih.gov / 22172698 / ). Petition 870250081505, dated 10 / 09 / 2025, p. 11 / 26 8 / 22

[0016] Due to its importance as a substructure in a wide variety of synthetic and natural products, considerable efforts have been directed towards the development of new structures based on 7-chloroquinoline. Based on the main pharmacological properties of quinoline and selenium derivatives, the synthesis of the synthetic compound 4-PSQ (Figure 1) was planned, a molecule that combines the quinoline nucleus with an organoselenium substituent. Since then, studies have been conducted to investigate the pharmacological potential of 4-PSQ. By modulating pro-inflammatory markers and oxidative stress, 4-PSQ has been reported to be effective in preclinical models of anxiety (PALTIAN, Jaini J et al. The anxiolytic effect of a promising quinoline containing selenium with the contribution of the serotonergic and GABAergic pathways: Modulation of parameters associated with anxiety in mice. [s. 1·], 2020. Available at: https: / / doi.Org / 10.1016 / j.bbr.2020.112797.2023; REIS, Angélica S. et al. 4-phenylselenyl-7-chloroquinoline, a novel multitarget compound with anxiolytic activity: Contribution of the glutamatergic system. Journal of Psychiatric Research, [s. l.J, v. 84, p. 191-199, 2017), nocicepção (PINZ, Mikaela et al. 4-Phenylselenyl-7-chloroquinoline, a new quinoline derivative containing selenium, has potential antinociceptive and anti-inflammatory actions. European Journal of Pharmacology, [s. 1.], v. 780, p. 122-128, 2016. Disponível em: http: / / dx.doi.Org / 10.1016 / j.ejphar.2016.03.039; SILVA, Vanessa D.G. et al. Further analysis of acute antinociceptive and antiinflammatory actions of 4-phenylselenyl-7-chloroquinoline in mice. Fundamental and Clinical Pharmacology, [s. 1.], v. 31, n. 5, p. 513-525, 2017). Petição 870250081505, de 10 / 09 / 2025, pág. 12 / 26 9 / 22

[0017] Há também relatos para doença de Alzheimer (PINZ, Mikaela P. et al. Current advances of pharmacological properties of 7-chloro4-(phenylselanyl) quinoline: Prevention of cognitive deficit and anxiety in Alzheimer’s disease model. Biomedicine and Pharmacotherapy, [s. l.], v. 105, p. 1006-1014, 2018), dermatite atópica (VOSS, Guilherme T. et al. Therapeutic and technological potential of 7-chloro-4-phenylselanyl quinoline for the treatment of atopic dermatitis-like skin lesions in mice. Materials Science and Engineering C, [s. l.], v. 84, p. 90-98, 2018), toxicidades hepáticas e renais (da Motta, Ketlyn P. et al. 7-Chloro-4(phenylselanyl) quinoline reduces renal oxidative stress induced by oxaliplatin in mice. Canadian journal of physiology and pharmacology, [s. l.], 2021. Disponível em: https: / / pubmed.ncbi.nlm.nih.gov / 34015230 / . Acesso em: 1 ago. 2021; LEMOS, Briana B. et al.Role of 7-chloro-4-(phenylselanyl) quinoline in the treatment of oxaliplatin-induced liver toxicity in mice. Canadian Journal of Physiology and Pharmacology, [sl], v. 99, n. 4, p. 378-388, 2021), hypothalamic obesity (Rodrigues, Karline C., Bortolatto CF, Motta KP, Oliveira RL, Paltian JJ, Kruger R., Roman SS, Boeira SP, Alves D., Wilhelm EA, Luchese C.,5 The neurotherapeutic role of a selenium-functionalized quinoline in hypothalamic obese rats. Psychopharmacology, [sl], v. 238, n. 7, 2021. Available at: https: / / pubmed.ncbi.nlm.nih.gov / 33740091 / . Petition 870250081505, dated 10 / 09 / 2025, p. 13 / 26 10 / 22

[0018] O composto 4-PSQ atua também na neurotoxicidade induzida por oxaliplatina (REIS, Angélica S. et al. Interface of Aging and Acute Peripheral Neuropathy Induced by Oxaliplatin in Mice: Target-Directed Approaches for Na+, K+—ATPase, Oxidative Stress, and 7-Chloro-4-(phenylselanyl) quinoline Therapy. Molecular Neurobiology 2021 59:3, [s. l.], v. 59, n. 3, p. 1766-1780, 2022. Disponível em: https: / / link.springer.com / article / 10.1007 / s12035021-02659-5. Acesso em: 14 mar. 2022; REIS, Angélica S. et al. Advances in the Understanding of Oxaliplatin-Induced Peripheral Neuropathy in Mice: 7-Chloro-4-(Phenylselanyl) Quinoline as a Promising Therapeutic Agent. Molecular Neurobiology, [s. l.], v. 57, n. 12, p. 5219-5234, 2020; REIS, Angélica S. et al. Pharmacological modulation of Na+, K+-ATPase as a potential target for OXA-induced neurotoxicity: Correlation between anxiety and cognitive decline and beneficial effects of 7-chloro-4(phenylselanyl) quinoline. Brain Research Bulletin, [s. l.], v. 162, n. March, p. 282-290, 2020), neuropatia periférica (PALTIAN, Jaini J et al. 7-Chloro-4-(Phenylselanyl) Quinoline Is a Novel Multitarget Therapy to Combat Peripheral Neuropathy and Comorbidities Induced by Paclitaxel in Mice. [s. l.], v. 1, p. 3, 2022. Disponível em: https: / / doi.org / 10.1007 / s12035-022-02991-4. Acesso em: 30 ago. 2023; VOSS, Guilherme T. et al. Contribution of antioxidant action of 7-chloro-4-(phenylselanyl)quinoline to treat streptozotocin-induced diabetic neuropathy in mice. New Journal of Chemistry, [s. l.], v. 46, n. 41, p. 19773-19784, 2022. Disponível em:https: / / pubs.rsc.org / en / content / articlehtml / 2022 / nj / d2nj02823 a. Acesso em: 30 ago. 2023). Petição 870250081505, de 10 / 09 / 2025, pág. 14 / 26 11 / 22

[0019] In addition, it acts on aging (LUCHESE, Cristiane et al. Role of 7-chloro-4-(phenylselanyl) quinoline as an anti-aging drug fighting oxidative damage in different tissues of aged rats. [sl], 2019. Available at: https: / / doi.org / 10.1016 / j.exger.2019.110804. Accessed on: Aug. 30, 2023), Parkinson's-like disease (DE FREITAS COUTO, Shanda et al. 7chloro-4-(phenylselanyl) quinoline prevents dopamine depletion in a Drosophila melanogaster model of Parkinson's-like disease. Journal of Trace Elements in Medicine and Biology, [sl], v. 54, p. 232-243, 2019. Available at: https: / / doi.org / 10.1016 / j.jtemb.2018.10.015. Accessed on: August 30, 2023) and diabetes-like phenotype (DE AQUINO SILVA, Daiane et al. 7-chloro-4-(phenylselanyl) quinoline co-treatment prevent oxidative stress in diabetic-like phenotype induced by hyperglycidic diet in Drosophila melanogaster. [sl], 2020. Available at: https: / / doi.org / 10.1016 / j.cbpc.2020.108892. Accessed on: August 30, 2023).4-PSQ presents a multi-target profile, acting in an integrated manner in the modulation of neuroplasticity and in the regulation of myeloperoxidase enzyme activity. This characteristic suggests a relevant therapeutic potential, as it allows influencing different biological pathways simultaneously (PINZ, Mikaela et al. 4-Phenylselenyl-7-chloroquinoline, a new quinoline derivative containing selenium, has potential antinociceptive and anti-inflammatory actions. European Journal of Pharmacology, [sl], v. 780, p. 122-128, 2016). Petition 870250081505, dated 10 / 09 / 2025, page 15 / 26 12 / 22

[0020] Atua na enzima acetilcolinesterase (PINZ, Mikaela P. et al. Current advances of pharmacological properties of 7-chloro-4(phenylselanyl) quinoline: Prevention of cognitive deficit and anxiety in Alzheimer’s disease model. Biomedicine and Pharmacotherapy, [s. l.], v. 105, p. 1006-1014, 2018), Ca2+-ATPase (PALTIAN, Jaini J et al. 7-Chloro—4-(Phenylselanyl) Quinoline Is a Novel Multitarget Therapy to Combat Peripheral Neuropathy and Comorbidities Induced by Paclitaxel in Mice. [s. l.], v. 1, p. 3, 2022. Disponível em: https: / / doi.org / 10.1007 / s12035-022-02991-4. Acesso em: 30 ago. 2023), Mg2+-ATPase e Na+, K+-ATPase (REIS, Angélica S. et al. Interface of Aging and Acute Peripheral Neuropathy Induced by Oxaliplatin in Mice: Target-Directed Approaches for Na+, K+—ATPase, Oxidative Stress, and 7-Chloro-4(phenylselanyl) quinoline Therapy. Molecular Neurobiology 2021 59:3, [s. l.], v. 59, n. 3, p. 1766-1780, 2022. Disponível em: https: / / link.springer.com / article / 10.1007 / s12035-021-02659-5).

[0021] The compound 4-PSQ is also capable of acting on the levels of neural cell adhesion molecules and polysialyltransferase enzyme (BARTH, Anelise et al. 7-Chloro-4-(Phenylselanyl) Quinoline with Memory Enhancer Action in Aging Rats: Modulation of Neuroplasticity, Acetylcholinesterase Activity, and Cholesterol Levels. Molecular Neurobiology, [sl], 2019), cholesterol levels, oxidative status (BARTH, Anelise et al. 7-Chloro-4-(Phenylselanyl) Quinoline with Memory Enhancer Action in Aging Rats: Modulation of Neuroplasticity, Acetylcholinesterase Activity, and Cholesterol Levels. Molecular Neurobiology, [sl], 2019; VOGT, Ane G. et al. Organoselenium group is critical for the antioxidant activity of 7-chloro-4phenylselenyl-quinoline. Petition 870250081505, dated 10 / 09 / 2025, p. 16 / 26 13 / 22

[0022] Other pathways of 4-PSQ action are in neuroinflammation (PALTIAN, Jaini J et al. 7-Chloro-4-(Phenylselanyl) Quinoline Is a Novel Multitarget Therapy to Combat Peripheral Neuropathy and Comorbidities Induced by Paclitaxel in Mice. [sl], v. 1, p. 3, 2022. Available at: https: / / doi.org / 10.1007 / s12035-022-02991-4. GABAergic pathways: Modulation of parameters associated with anxiety in mice. [sl], 2020. Available at: https: / / doi.org / 10.1016 / j.bbr.2020.112797. compound with anxiolytic activity: Contribution of the glutamatergic system.Further analysis of acute antinociceptive and anti-inflammatory actions of 4-phenylselenyl-7-chloroquinoline in mice. Fundamental and Clinical Pharmacology, [sl], v. 31, n. 5, p. 513-525, 2017).

[0023] In addition, factors related to neurogenesis have also been reported for 4-PSQ (PALTIAN, Jaini J et al. The anxiolytic effect of a promising quinoline containing selenium with the contribution of the serotonergic and GABAergic pathways: Modulation of parameters associated with anxiety in mice. [sl], 2020. Available at: https: / / doi.org / 10.1016 / j.bbr.2020.112797. Petition 870250081505, dated 10 / 09 / 2025, p. 17 / 26 14 / 22

[0024] Paclitaxel-induced peripheral neuropathy is a painful condition associated with the use of the drug, which impacts patients' quality of life, causing anxiety and cognitive impairment. Our research group investigated the therapeutic potential of 4-PSQ and demonstrated that the compound reduced mechanical and thermal hypersensitivity, anxiety, and cognitive impairment in mice with paclitaxel-induced peripheral neuropathy, attributing these effects to the modulation of oxidative stress and the reduction of neuroinflammation (PALTIAN, Jaini J et al. 7-Chloro-4-(Phenylselanyl) Quinoline Is a Novel Multitarget Therapy to Combat Peripheral Neuropathy and Comorbidities Induced by Paclitaxel in Mice. [s. 1.], v. 1, p. 3, 2022. Available at: https: / / doi.org / 10.1007 / sl2035-022-02991-4. Accessed on: Aug. 30, 2023).

[0025] We also investigated oxaliplatin-induced peripheral neuropathy. In this study, we identified that 4-PSQ reduced hypersensitivity and normalized reactive species levels, in addition to improving the activity of antioxidant enzymes such as catalase, GPx, and superoxide dismutase (REIS, Angélica S. et al. Advances in the Understanding of Oxaliplatin-Induced Peripheral Neuropathy in Mice: 7-Chloro-4-(Phenylselanyl) Quinoline as a Promising Therapeutic Agent. Neurobiologia Molecular, [s. 1.], v. In the continuation of the studies, we investigated oxaliplatin-induced neurotoxicity and found that 4-PSQ reduced anxiety and cognitive impairment in mice. Petition 870250081505, dated 10 / 09 / 2025, p. 18 / 26 15 / 22

[0026] Furthermore, the compound modulated Na+, K+-ATPase activity and decreased corticosterone levels (REIS, Angélica S. et al. Pharmacological modulation of Na+, K+-ATPase as a potential target for OXA-induced neurotoxicity: Correlation between anxiety and cognitive decline and beneficial effects of 7-chloro-4(phenylselanyl) quinoline. Brain Research Bulletin, [slJ, v. 162, n. March, p. 282-290, 2020). Finally, we evaluated the impact of aging on oxaliplatin-induced acute peripheral neuropathy. We observed that aging exacerbated neuropathy, but 4-PSQ reversed hypersensitivity by modulating GPx and superoxide dismutase activities, as well as partially restoring Na+, K+-ATPase activity.

[0027] These studies indicate that 4-PSQ is a promising prototype for the treatment of peripheral neuropathy and its comorbidities, especially those induced by chemotherapy (REIS, Angélica S. et al. Interface of Aging and Acute Peripheral Neuropathy Induced by Oxaliplatin in Mice: Target-Directed Approaches for Na+, K+—ATPase, Oxidative Stress, and 7-Chloro-4-(phenylselanyl) quinoline Therapy. Molecular Neurobiology 2021 59:3, [s. 1.], v. 59, n. 3, p. 1766-1780, 2022. Available at: https: / / link.springer.com / article / 10.1007 / sl2035-021-02659-5. Accessed on: March 14, 2022.

[0028] In this context, considering the need to develop safer and more effective antitumor agents capable of reducing adverse effects and overcoming resistance, 4-PSQ presents significant pharmacological potential. This molecule represents a promising strategy in the search for new compounds with antitumor properties. Petition 870250081505, dated 10 / 09 / 2025, p. 19 / 26 16 / 22 Prior art search

[0029] Background searches for this patent revealed work that is only partially relevant to the present invention. Such work will be described below in order to provide context for the current state of the art. However, none of this work anticipates or suggests any of the objectives of the present invention.

[0030] Document BR102017022414A2 refers to the use of 4-PSQ in the prophylaxis of Alzheimer's disease. This document differs from the present invention, since the pharmacological activity desired in said document does not have similarity to that of the present invention.

[0031] Document BR102016030110A2 describes the use of compound 4-PSQ as a therapeutic agent for inflammatory skin diseases, including its use alone or in combination with a film for topical application. This document differs from the present invention because the pharmacological activities discussed therein are not the same as those targeted in this invention.

[0032] Documents ES2217392T3, ES2387938T3, BR102017022404A2, BR102016026228A2, ES2794006T3, BR112021002267A2, ES2801874T3, ES2325077T3 and WO2010142836A1 describe the synthesis and therapeutic use of different compounds. These documents differ from the present invention because the molecular structures studied are distinct from the structure of the present invention. Petition 870250081505, dated 10 / 09 / 2025, p. 20 / 26 17 / 22 Summary of the Invention

[0033] The present invention aims to propose the use of the synthetic compound 7-chloro-4-(phenylselanyl)quinoline (4PSQ) as an antitumor agent for breast, leukemia, sarcoma and bladder cancers. The in vitro efficacy of the 4-PSQ compound as an antitumor agent for breast, leukemia, sarcoma and bladder cancer is demonstrated in the present invention. Description of Figures and Tables

[0034] In order to better define and clarify the content of this patent application, the corresponding figures and tables are presented below. In this way, the aim is to facilitate the understanding of the scope of the protection claimed, as well as to objectively illustrate the innovative and applicable aspects of the proposal.

[0035] Figure 1 shows the chemical structure of the synthetic derivative 7-chloro-4-(phenylselanyl)quinoline (4-PSQ).

[0036] Figure 2 demonstrates the in vitro cytotoxic effect of the synthetic derivative 7-chloro-4-(phenylselanyl)quinoline (4-PSQ) on (A) breast, (B) leukemia, and (C) sarcoma tumor cell lines. Data are presented as mean ± SD from three independent experiments. Different letters indicate statistical differences between means. A p-value <0.05 was considered significant in all analyses. Petition 870250081505, dated 10 / 09 / 2025, page 21 / 26 18 / 22

[0037] Figure 3 demonstrates the in vitro cytotoxic effect of the synthetic derivative 7-chloro-4-(phenylselanyl)quinoline (4-PSQ) on human bladder cancer cell lines (A) 5637; (B) T24 and (C) RT4. Data are presented as mean ± SD of three independent experiments. Different letters indicate statistical differences between means. A p-value <0.05 was considered significant in all analyses.

[0038] Figure 4 demonstrates the in vitro cytotoxic effect of the synthetic derivative 7-chloro-4-(phenylselanyl)quinoline (4-PSQ) in combination with the antitumor drug Paclitaxel in the HCC1954 breast cancer cell line. Data are presented as mean ± SD from three independent experiments. Different letters indicate statistical differences between means. A p-value <0.05 was considered significant in all analyses.

[0039] Table 1 presents the minimum concentration data required for 50% inhibition of cells (IC50) in the different cell lines. The data are presented as mean ± SD of three independent experiments. Detailed Description of the Invention Synthesis of 7-chloro-4-phenylselanyl-quinoline (4-PSQ)

[0040] For the synthesis of 4-PSQ, an aromatic nucleophilic substitution procedure is employed between diphenyl diselenide and 4,7-dichloroquinoline, using potassium hydroxide as a base (Figure 1) (SAVEGNAGO, Lucielli et al. Synthesis and antioxidant properties of novel quinoline-chalcogenium compounds. Tetrahedron Letters, [sl], v. 54, n. Petition 870250081505, dated 10 / 09 / 2025, pp. 22 / 26 19 / 22 Cell culture

[0041] HCC1954, HL-60, S180, 5637, T24, and RT4 cells were obtained from the Rio de Janeiro Cell Bank (PABCAM, Federal University of Rio de Janeiro, RJ, Brazil). HCC1954 cells were cultured in modified RPMI-1640 medium (containing high glucose and HEPES). HL-60 and 5637 cells were cultured in RPMI-1640 culture medium. S180, T24, and RT4 cells were cultured in Dubelcco Mem (DMEM) medium. All media were supplemented with 10% fetal bovine serum. All cell culture supplies were obtained from Vitrocell Embriolife. Cell lines were maintained in an incubator at 37 °C with 5% CO2 and 95% humidity. Cellular cytotoxicity

[0042] The determination of the viability of breast cancer, leukemia, and sarcoma cells exposed to the compound in question, 4-PSQ, is performed using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) colorimetric reduction assay. After reaching 90% confluence, the cells are distributed in 96-well plates at a density of 2x10⁴ cells per well, in a volume of 100 μL of the culture medium suitable for the cell line, and should be maintained for 24 hours under appropriate culture conditions. At the end of this period, the cells are subjected to treatment with the compound 4-PSQ at different concentrations, diluted in dimethyl sulfoxide (DMSO) (at a maximum concentration of 5%), as described below: Petition 870250081505, dated 10 / 09 / 2025, pp. 23 / 26 20 / 22

[0043] 4-PSQ concentrations in different strains: HCC1954: 5, 20, 60, 100, 120 and 140 μM S180: 20, 40, 80, 120, 140 and 160 μM HL-60: 2, 5 20, 60, 100, 120 e 140 μM 5637: 1, 3, 5, 7, 10, 20 e 60 μM T24: 5, 20, 60, 100, 140, 180, e 220 μM RT4: 5, 6, 7, 10, 20, 60 e 100 μM

[0044] For this, 100 μL of culture medium containing 4-PSQ in the appropriate dilutions should be added to the contents already present in the 96-well plate, which should be incubated again for 48 hours. At the end of the incubation period, the culture medium should be removed and cytotoxicity analysis using the MTT assay should be performed according to the manufacturer's instructions (Sigma Aldrich). The absorbance of each well should be determined in a microplate reader at a wavelength of 492 nm. The percentage of cell proliferation inhibition is determined using the following formula: growth inhibition = (1 Absorbance of treated cells / Absorbance of control cells) x 100%. All observations need to be validated by at least three independent experiments, performed in triplicate. Determination of the antitumor activity of 4-PSQ

[0045] The tests performed to validate this invention show that the compound 4-PSQ has the use as an antitumor therapeutic agent claimed herein, against the cell lines HCC1954, HL60, S180, 5637, T24 and RT4. Petition 870250081505, dated 10 / 09 / 2025, pp. 24 / 26 21 / 22

[0046] Furthermore, selectivity for tumor cell lines is observed, since in the non-tumor cell line used as a control, the observed activity was of lower incidence, as illustrated in Figure 2D. Analyzing the graphs, the dose-dependent behavior of the compound is also observed. Table 1 shows the minimum concentration values ​​to inhibit 50% of cell growth (IC50), allowing us to infer the potency of the compound in different types of tumors. Table 1. IC50 lineage (pM) HCC1954 23.58 ± 5.57 HL-60 5.60 ± 2.49 S180 68.29 ± 10.36 5637 8.04 ± 1.2 T24 145 ± 18.6 RT4 9.48 ± 0.68 Examples

[0047] To allow a better understanding of the present invention and to clearly demonstrate the technical advances achieved, examples of possible combinations for this invention are now presented. In accordance with the potential applications of the present invention and by way of illustration only, without intending to limit in any way the scope of the present invention, possible uses for it are described below. Example 1 - Combination of 4-PSQ with Paclitaxel

[0048] Drug combination therapy is a promising therapeutic strategy to overcome drug resistance and improve the effectiveness of monotherapy regimens in cancer, targeting multiple components of this complex disease. In the context of developing new drugs, this is an even more interesting strategy. Petition 870250081505, dated 10 / 09 / 2025, pp. 25 / 26 22 / 22

[0049] In this sense, the evaluation of the synthetic derivative 7-chloro4-(phenylselanyl)quinoline (4-PSQ) in combination with the chemotherapeutic agent Paclitaxel is preferably performed using the soluble MTT reduction technique (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) to insoluble formazan in the HER2-positive human breast cancer cell line (HCC1954). The culture conditions are the same as described above in this document.

[0050] The cells are subjected to treatment with different concentrations of 4-PSQ (5, 20, 60, 100, 120 and 140 μM), Paclitaxel (5, 10, 15, 25, 35 and 50 nM), as well as the combination of both at these same concentrations, not being limited to only these concentration combinations. Figure 4 shows the result of this combination. The IC50 values ​​for the isolated antitumor agents 4-PSQ and Paclitaxel are 23.58 ± 5.57 μM and 21.22 ± 2.02 nM, respectively.After combining both, the IC50 value in relation to the concentrations of Paclitaxel used was 21.23 ± 3.80 nM. This data demonstrates that the benefits of 4-PSQ, such as its aid in peripheral neuroapathy caused by Paclitaxel, can be used in combination therapy with the antitumor drug Paclitaxel without compromising the activity of this drug. Petition 870250081505, dated 10 / 09 / 2025, p. 26 / 26

Claims

1 / 2 CLAIMS 1. Synthetic organic compound called 7-chloro-4(phenylselanyl)quinoline (4-PSQ) characterized as an antitumor agent for the treatment of breast cancer, leukemia, sarcoma and bladder cancer.

2. Synthetic organic compound called 7-chloro-4(phenylselanyl)quinoline (4-PSQ) with the applications claimed in 1, characterized by a pharmaceutical formulation for the following routes of administration: oral, sublingual, parenteral, intravesical, cutaneous, nasal, ophthalmic, auricular, pulmonary, vaginal and rectal.

3. Synthetic organic compound called 7-chloro-4(phenylselanyl)quinoline (4-PSQ) with the applications claimed in 1, characterized by presentation in the following pharmaceutical forms: tablet, capsule, lozenges, dragees, powders for reconstitution, drops, syrup, oral solution, suspension, sublingual tablets, injectable solutions and suspensions, topical solutions, ointments, creams, lotion, gel, patches, nasal sprays and drops, eye drops and ophthalmic ointments, ear drops or otic drops and ear ointments, aerosol, vaginal tablets, creams, ointments, ovules, suppositories and enemas.

4. Synthetic organic compound called 7-chloro-4-(phenylselanyl)quinoline (4-PSQ) with the applications claimed in 1, characterized by being formulated or co-formulated in nanoparticles or based on nanotechnology.

5. Synthetic organic compound called 7-chloro-4(phenylselanyl)quinoline (4-PSQ) with the applications claimed in 1, characterized by being administered in combination with one or more anti-neoplastic agents.

6. Synthetic organic compound called 7-chloro-4-(phenylselanyl)quinoline (4-PSQ) with the applications claimed in 1, characterized by use in human or veterinary patients.

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