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Aromatase inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and molecular modeling studies of novel phenothiazine derivatives carrying sulfonamide moiety as hybrid molecules.
Eur J Med Chem ; 134: 304-315, 2017 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-28427017
Hybrid molecules are used as anticancer agents to improve effectiveness and diminish drug resistance. So, the current study aimed to introduce twenty novel phenothiazine sulfonamide hybrids 5-22, 24 and 25 of promising anticancer activity. Compounds 11 and 13 revealed more potent anticancer properties (IC50 8.1 and 8.8 µM) than that of the reference drug (doxorubicin, IC50 = 9.8 µM) against human breast cancer cell line (T47D). To determine the mechanism of their anticancer activity, compounds 5, 6, 7, 11, 13, 14, 16, 17, 19 and 22 that showed promising activity on T47D, were evaluated for their aromatase inhibitory effect. The study results disclose that the most potent aromatase inhibitors 11 and 13 showed the lowest IC50 (5.67 µM and 6.7 µM), respectively on the target enzyme. Accordingly, the apoptotic effect of the most potent compound 11 was extensively investigated and showed a marked increase in Bax level up to 55,000 folds, and down-regulation in Bcl2 to 5.24*10-4 folds, in comparison to the control. Furthermore, the effect of compound 11 on caspases 3, 8 and 9 was evaluated and was found to increase their levels by 20, 34, and 8.9 folds, respectively, which indicates the activation of both intrinsic and extrinsic pathways. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking and computer aided ADMET studies were adopted to confirm their mechanism of action.





Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Fenotiazinas / Inibidores da Aromatase / Antineoplásicos Limite: Feminino / Humanos Idioma: Inglês Revista: Eur J Med Chem Ano de publicação: 2017 Tipo de documento: Artigo