In vivo antitumor effects of bis-benzimidazole derivatives in mouse melanoma and lung cancer models

Abstract

BACKGROUND: The development of new antitumor agents on the basis of benzimidazoles opens new opportunities for treatment of the malignant tumors, including those refractory to conventional therapies. The benzimidazole derivatives demonstrate wide spectrum of biological activities, specifically antineoplastic effects, and high-level cytotoxicity toward human’s tumor cell lines. The exploration of antineoplastic effects of new synthetic benzimidazole derivatives in in vivo models of tumor growth will help the development of the effective doses and cancer treatment regimens with the use of such compounds.

AIM: To assess the antineoplastic effects of the benzimidazole derivatives — monomeric compound MB₂Py(Ac) and dimeric compound DB₂Py(3) — in the continuous cellular models of Lewis lung carcinoma (LLC) and melanoma B16 in mice.

MATERIALS AND METHODS: In vivo assessment of antineoplastic effects was performed in the continuous mouse models of Lewis lung carcinoma (LLC) and B16 melanoma after a single intravenous injection of MB₂Py(Ac) and DB₂Py(3). Irinotecan was used as a comparator drug. Antitumor effects were measured via standard parameters, such as tumor growth inhibition (TGI%) and tumor growth rate (TGR).

RESULTS: The study compounds DB₂Py(3) and MB₂Py(Ac) used in the study doses and regimen demonstrated mild antitumor effect in the model of murine solid tumors (TGI <50%). In melanoma B16 model, the maximum tumor growth inhibition was 15% and 38.5%, respectively, for MB₂Py(Ac) and DB₂Py(3). In the lung carcinoma model, the mild effect was observed, e.g. 8% for MB₂Py(Ac) and 23.4% for DB₂Py(3). The effect of the comparator drug, irinotecan, was more expressive, although short-term. In particular, TGI achieved 52.5% for melanoma B16 and 34.5% for Lewis lung carcinoma (LLC). In general, melanoma B16 was more sensitive to the effects of both bis-benzimidazoles and irinotecan, compared to the lung carcinoma LLC.

CONCLUSION: This study shows that the dimeric compound DB₂Py(3) was the most promising among three study substances in the models of melanoma and lung carcinoma in mice. Nevertheless, its high toxicity imposes the necessity of further optimization for the clinical use. The substance MB₂Py(Ac) demonstrated lowest efficacy, although it may be also explored in the modified treatment regimens.

Keywords

bis-benzimidazoles / transplantable tumor models / antitumor effects

References

[1] Vitaku E, Smith D, Njardarson J. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals: miniperspective. Journal of Medicinal Chemistry. 2014;57(24):10257–10274. doi: 10.1021/jm501100b

[2] Vitaku E., Smith D., Njardarson J. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals: miniperspective // Journal of medicinal chemistry. 2014. Vol. 57, N 24. P. 10257–10274. doi: 10.1021/jm501100b

[3] Lee Y, Tan Y, Oon C. Benzimidazole and its derivatives as cancer therapeutics: The potential role from traditional to precision medicine. Acta Pharmaceutica Sinica B. 2023;13(2):478–497. doi: 10.1016/j.apsb.2022.09.010

[4] Lee Y., Tan Y., Oon C. Benzimidazole and its derivatives as cancer therapeutics: The potential role from traditional to precision medicine // Acta Pharmaceutica Sinica B. 2023. Vol. 13, N 2. P. 478–497. doi: 10.1016/j.apsb.2022.09.010

[5] Kozlovsky AA. Helminthic and protozoal diseases in children: a literature review. Pediatrics Eastern Europe. 2024;12(3):496–509. doi: 10.34883/PI.2024.12.3.012

[6] Козловский А.А. Глистные и протозойные заболевания у детей: обзор литературы // Педиатрия. Восточная Европа. 2024. Т. 12, № 3. С. 496–509. doi: 10.34883/PI.2024.12.3.012

[7] Maltsev DV, Spasov AA, Miroshnikov MV. Current approaches to the search of anxiolytic drugs. Bioorganics Chemistry. 2021;47(4):431–463. doi: 10.31857/S013234232103012X

[8] Мальцев Д.В., Спасов А.А., Мирошников М.В., Скрипка М.О. Современные подходы к поиску анксиолитических средств // Биоорганическая химия. 2021. Т. 47, № 4. С. 431–463. doi: 10.31857/S013234232103012X

[9] Reshetnikova AS. Hypertensive crisis: definition and classification, clinical manifestations and diagnosis, emergency care. International Student Scientific Bulletin. 2022;(5):3–20.

[10] Решетникова А.С. Гипертонический криз: определение и классификация, клинические проявления и диагностика, неотложная помощь // Международный студенческий научный вестник. 2022. № 5. С. 3–20. EDN: LATKWZ

[11] Butler MS, Vollmer W, Goodall ECA, et al. A Review of Antibacterial Candidates with New Modes of Action. ACS Infectious Diseases. 2024;10(10):3440–3474. doi: 10.1021/acsinfecdis.4c00218

[12] Butler M.S., Vollmer W., Goodall E.C.A., et al. A Review of Antibacterial Candidates with New Modes of Action // ACS Infectious Diseases. 2024. Vol. 10, N 10. P. 3440–3474. doi: 10.1021/acsinfecdis.4c00218

[13] Alzhrani Z, Alam M, Nazreen S. Recent advancements on benzimidazole: A versatile scaffold in medicinal chemistry. Mini Rev Med Chem. 2022;22(2):365–386. doi: 10.2174/1389557521666210331163810

[14] Alzhrani Z.M.M., Alam M.M., Nazreen S. Recent advancements on benzimidazole: A versatile scaffold in medicinal chemistry // Mini Reviews in Medicinal Chemistry. 2022. Vol. 22, N 2. P. 365–386. doi: 10.2174/1389557521666210331163810

[15] Halpern-Cohen V, Blumberg EA. New Perspectives on Antimicrobial Agents: Maribavir. Antimicrob Agents Chemother. 2022;66(9): e0240521. doi: 10.1128/aac.02405-21

[16] Halpern-Cohen V., Blumberg E.A. New Perspectives on Antimicrobial Agents: Maribavir // Antimicrob Agents Chemother. 2022. Vol. 66, N 9. P. e0240521. doi: 10.1128/aac.02405-21

[17] Vasava MS, Bhoi MN, Rathwa SK, et al. Benzimidazole: A milestone in the field of medicinal chemistry. Mini Rev Med Chem. 2020;20(7):532–565. doi: 10.2174/1389557519666191122125453

[18] Vasava M.S., Bhoi M.N., Rathwa S.K., et al. Benzimidazole: A Milestone in the Field of Medicinal Chemistry // Mini Rev Med Chem. 2020. Vol. 20, N 7. P. 532–565. doi: 10.2174/1389557519666191122125453

[19] García-Báez EV, Padilla-Martínez II, Cruz A, et al. 13C-NMR Chemical Shifts in 1, 3-Benzazoles as a Tautomeric Ratio Criterion. Molecules. 2022;27(19):6268–6283. doi: 10.3390/molecules27196268

[20] García-Báez E.V., Padilla-Martínez I.I., Cruz A., et al. 13C-NMR Chemical Shifts in 1, 3-Benzazoles as a Tautomeric Ratio Criterion // Molecules. 2022. Vol. 27, N 19. P. 6268. doi: 10.3390/molecules27196268

[21] Shrivastava N, Naim MJ, Alam MJ, et al.. Benzimidazole scaffold as anticancer agent: synthetic approaches and structure–activity relationship. Archiv der Pharmazie. 2017;350(6):e201700040. doi: 10.1002/ardp.201700040

[22] Shrivastava N., Naim M.J., Alam M.J., et al. Benzimidazole scaffold as anticancer agent: synthetic approaches and structure–activity relationship // Archiv der Pharmazie. 2017. Vol. 350, N 6. P. e201700040. doi: 10.1002/ardp.201700040

[23] Haider K, Yar M. Advances of benzimidazole derivatives as anticancer agents: bench to bedside. IntechOpen: London; 2022. P. 162. doi: 10.5772/intechopen.101702

[24] Haider K., Yar M. Advances of benzimidazole derivatives as anticancer agents: bench to bedside. IntechOpen: London, 2022. P. 162. doi: 10.5772/intechopen.101702

[25] Venugopal S, Kaur B, Verma A, et al. Recent advances of benzimidazole as anticancer agents. Chemical Biology & Drug Design. 2023;102(2):357–376. doi: 10.1111/cbdd.14236

[26] Venugopal S., Kaur B., Verma A., et al. Recent advances of benzimidazole as anticancer agents // Chemical Biology & Drug Design. 2023. Vol. 102, N 2. P. 357–376. doi: 10.1111/cbdd.14236

[27] Arutyunyan AF, Kostyukov AA, Korolev SP, et al. [DNA Sequence-Specific Ligands. 19. Synthesis, Spectral Properties, Virological and Biochemical Studies of DB3(n) Fluorescent Dimeric Trisbenzimidazoles]. Mol Biol (Mosk). 2023;57(3):517–527. Russian

[28] Arutyunyan A.F., Kostyukov A.A., Korolev S.P., et al. [DNA Sequence-Specific Ligands. 19. Synthesis, Spectral Properties, Virological and Biochemical Studies of DB3(n) Fluorescent Dimeric Trisbenzimidazoles] // Mol Biol (Mosk). 2023. Vol. 57, N 3. P. 517–527. Russian

[29] Susova OY, Karshieva SS, Kostyukov AA, et al. Dimeric Bis-Benzimidazole-Pyrroles DB2Py(n) — AT-Site-Specific Ligands: Synthesis, Physicochemical Analysis, and Biological Activity. Acta Naturae. 2024;16(1):86–100. doi: 10.32607/actanaturae.27327

[30] Сусова О.Ю., Каршиева С.Ш., Костюков А.А., и др. Димерные бисбензимидазолпирролы DB2Py (n)–АТ-сайт-специфичные лиганды: синтез, физико-химический анализ и исследования биологической активности //Acta Naturae (русскоязычная версия). 2024. Т. 16. № 1. С. 86–100. doi: 10.32607/actanaturae.27327

[31] Methodological recommendations for the preclinical study of the antitumor activity of medicines. Guidelines for conducting preclinical studies of medicines. Part One; Mironov AN, editor; Moscow : Grif K; 2012. P. 640–654. EDN: SDEWMP

[32] Методические рекомендации по доклиническому изучению противоопухолевой активности лекарственных средств. В кн.: Руководство по проведению доклинических исследований лекарственных средств. Часть первая / Под ред. А.Н. Миронова. — М.: Гриф и К, 2012. С. 640–654. EDN: SDEWMP

[33] Komarova EF, Morkovnik AS, Zhukovskaya ON, et al. A benzimidazole derivative as an effective antitumor agent in terms of syngeneic lung tumors and melanoma treatment. South Russian Journal of Cancer. 2022;3(1):15–21. doi: 10.37748/2686-9039-2022-3-1-2

[34] Комарова Е.Ф., Морковник А.С., Жуковская О.Н., и др. Производное бензимидазола как эффективное противоопухолевое средство в лечении сингенных опухолей легкого и меланомы // Южно-российский онкологический журнал. 2022. Т. 3, № 1. C. 15–21. doi: 10.37748/2686-9039-2022-3-1-2

[35] Roopashree R, Mohan C, Swaroop T, et al. Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice. Bioorg Med Chem Lett. 2015;25(12):2589–2593. doi: 10.1016/j.bmcl.2015.04.010

[36] Roopashree R., Mohan C.D., Swaroop T.R., et al. Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice // Bioorg Med Chem Lett. 2015. Vol. 25, N 12. P. 2589–2593. doi: 10.1016/j.bmcl.2015.04.010

[37] Rodrigues L, Tavares A, Ferreira B, et al. Inclusion complexes and self-assembled cyclodextrin aggregates for increasing the solubility of benzimidazoles. Braz J Pharm Sci. 2019;55. doi: 10.1590/s2175-97902019000117776

[38] Rodrigues L., Tavares A., Ferreira B., et al. Inclusion complexes and self-assembled cyclodextrin aggregates for increasing the solubility of benzimidazoles // Braz J Pharm Sci. 2019. Vol. 55. doi: 10.1590/s2175-97902019000117776

[39] Chang C, Ryu J, Choi J, et al. Anti-cancer effect of fenbendazole-incorporated PLGA nanoparticles in ovarian cancer. J Gynecol Oncol. 2023;34(5):e58. doi: 10.3802/jgo.2023.34.e58

[40] Chang C., Ryu J., Choi J., et al. Anti-cancer effect of fenbendazole-incorporated PLGA nanoparticles in ovarian cancer // J Gynecol Oncol. 2023. Vol. 34, N 5. P. e58. doi: 10.3802/jgo.2023.34.e58

Funding

Российский научный фондRussian Science Foundation(№ 23-25-00373)

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