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1.
J Chem Inf Model ; 63(22): 7228-7238, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-37947759

RESUMO

Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of α/ß-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound 5a, which incorporates an α-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC50 < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that 5a has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity.


Assuntos
Antineoplásicos , Moduladores de Tubulina , Humanos , Moduladores de Tubulina/química , Estrutura Molecular , Relação Estrutura-Atividade , Nocodazol/farmacologia , Tubulina (Proteína)/metabolismo , Proliferação de Células , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , Polimerização , Ensaios de Seleção de Medicamentos Antitumorais
2.
Pharmaceuticals (Basel) ; 14(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34451912

RESUMO

Cancer is the second leading cause of death, after cardiovascular diseases. Different strategies have been developed to treat cancer; however, chemotherapy with cytotoxic agents is still the most widely used treatment approach. Nevertheless, drug resistance to available chemotherapeutic agents is still a serious problem, and the development of new active compounds remains a constant need. Taking advantage of the molecular hybridization approach, in the present work we designed, synthesized, and tested the cytotoxic activity of two hybrid compounds and seven derivatives based on the structure of combretastatin A-4 and 2,3-diphenyl-2H-indazole. Practical modifications of reported synthetic protocols for 2-pheny-2H-indazole and 2,3-dipheny-2H-indazole derivatives under microwave irradiation were implemented. The cytotoxicity assays showed that our designed hybrid compounds possess strong activity, especially compound 5, which resulted even better than the reference drug cisplatin against HeLa and SK-LU-1 cells (IC50 of 0.16 and 6.63 µM, respectively), and it had similar potency to the reference drug imatinib against K562 cells. Additionally, in silico and in vitro studies strongly suggest tubulin as the molecular target for hybrid compound 5.

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