Structurally diverse design and synthesis of novel 2-phenylindole amide derivatives with anti-canine breast cancer activity.
Bioorg Chem
; 153: 107788, 2024 Sep 06.
Article
em En
| MEDLINE
| ID: mdl-39265524
ABSTRACT
Breast cancer stands as the cancer with the highest incidence and mortality rates among women globally, in which triple-negative breast cancer has been ranked as the most difficult one. Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), has been exhibited notable inhibitory effect on both hormone-dependent breast cancer cells and triple-negative breast cancer cells, but showing very low in vivo effeacy. In order to obtain more effective antitumor derivatives than BZA, we have employed a structurally diverse design and synthesis of 57 novel 2-phenylindole amides for detecting their cytotoxities against triple-negative mammary cancer cell line, CMT-7364. Among them, 21 compounds demonstrated significant inhibitory activity against CMT-7364 cells (IC50 < 20 µM). Notably, compound 49 stood out, displaying both similar tumor cell inhibition (20 % reduce in IC50 value) and higher selectivity (4.6 times higher in SI value), compared to Bazedoxifene. Additionally, compound 49 exhibited desirable antitumor effects in a CMT-7364 cell-derived mouse in vivo model, achieving the best inhibition rate of 43.1 % and establishing strong molecular bonding with GP130. Our findings are also supported by comprehensive SAR and 3D-QSAR analyses. Furthermore, the best potent compound 49 was determined to block the cell cycle of canine breast cancer cells in the G0G1 phase in a time-dependent manner, by inducing apoptosis and autophagy. In conclusion, this work presents a valuable lead compound as a potential GP130 inhibitor against triple-negative breast cancer cell lines, laying the foundation for further antitumor drug development.
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01-internacional
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MEDLINE
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2024
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Article