Synthesis and Biological Evaluation of 1‑(Diarylmethyl)‑1H‑1,2,4‑Triazoles and 1‑(Diarylmethyl)‑1H‑Imidazoles as a Novel Class of Anti-Mitotic Agent for Activity in Breast Cancer

Pharmaceuticals

AzizahM. Malebari¹  DeniseCoutinho Endringer²  ElisangelaFlavia Pimentel²  Brendan Twamley³  DanielaM. Zisterer⁴  Darren Fayne⁴  SeemaM. Nathwani⁴  MaryJ. Meegan⁵  PatrickM. Kelly⁵  NiamhM. O’Boyle⁵  Gloria Ana⁵  Sara Noorani⁵ 

[1] Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;Department of Pharmaceutical Sciences, University Vila Velha, Av. Comissário José Dantas de Melo, n°21, Boa Vista Vila Velha—Espírito Santo, Vila Velha 29102-920, Brazil;School of Chemistry, Trinity College Dublin, Dublin 2, Dublin DO2R590, Ireland;Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Dublin DO2R590, Ireland;Trinity Biomedical Sciences Institute, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Dublin DO2R590, Ireland;

关键词: phenstatin;    letrozole;    tubulin polymerisation inhibitor;    aromatase inhibitor;    breast cancer;    hybrid molecule;   

DOI  :  10.3390/ph14020169

来源: DOAJ

【 摘 要 】

We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)-positive MCF-7 breast cancer cells identified 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol 24 as a potent antiproliferative compound with an IC₅₀ value of 52 nM in MCF-7 breast cancer cells (ER+/PR+) and 74 nM in triple-negative MDA-MB-231 breast cancer cells. The compounds demonstrated significant G₂/M phase cell cycle arrest and induction of apoptosis in the MCF-7 cell line, inhibited tubulin polymerisation, and were selective for cancer cells when evaluated in non-tumorigenic MCF-10A breast cells. The immunofluorescence staining of MCF-7 cells confirmed that the compounds targeted tubulin and induced multinucleation, which is a recognised sign of mitotic catastrophe. Computational docking studies of compounds 19e, 21l, and 24 in the colchicine binding site of tubulin indicated potential binding conformations for the compounds. Compounds 19e and 21l were also shown to selectively inhibit aromatase. These compounds are promising candidates for development as antiproliferative, aromatase inhibitory, and microtubule-disrupting agents for breast cancer.

【 授权许可】

Unknown