Benzoxazole derivatives as new generation of anti-breast cancer agents

• Published in: Bioorganic chemistry 2020-03, Vol.96, p.103593-103593, Article 103593
• Main Authors: Omar, A.- Mohsen M.E., AboulWafa, Omaima M., El-Shoukrofy, Mai S., Amr, Mai E.
• Format: Article
• Language: English
• Subjects: 2-Substituted benzoxazoles; ADME; Anticancer activity; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; ARO enzyme; Benzoxazoles - chemistry; Benzoxazoles - pharmacology; Breast Neoplasms - drug therapy; Caspase-9 assay; Cell cycle analysis; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Docking study; Drug Design; Drug Screening Assays, Antitumor; Drug-likeness model score; EGFR enzyme; Female; Humans; MCF-7 Cells; Models, Molecular; MTT assay
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103593

[Display omitted] •New 2-(4-aminophenyl)benzoxazole derivatives were synthesized.•Most compounds were more active than CJM 126 against two breast cancer cell lines.•One compound was more potent inhibitor of EGFRWT than erlotinib.•2 compounds showed slight less potent aromatase inhibitory activity than letrozole.•Active compounds showed significant apoptosis and cell cycle arrest at G2/M phase. New 2-substituted benzoxazole derivatives were synthesized and screened for their in vitro anti-proliferative activities against MCF-7 and MDA-MB-231 cell lines. Compounds 4b, 4d and 11c eliciting the highest activity against MCF-7 cells were further assayed for their cytotoxic activities against A431 and HCC827 cancer cells in addition to their in vitro inhibition of wild and mutated epidermal growth factor receptor (EGFR) enzymes. Compound 11c was the most active against A431 cells and it displayed a potent inhibition of EGFRWT while compounds 4b and 4d elicited higher potencies than erlotinib against mutated EGFRL858R. Compounds 4a, 6c and 8a showed the most potent cytotoxic activity against MDA-MB-231 cancer cells where compounds 4a and 6c were slightly less potent aromatase (ARO) inhibitors than letrozole. MCF-7 cells treated with compounds 4b, 4d, 11c and MDA-MB-231 cells treated with compounds 4a, 6c and 8a showed remarkable over-expression of caspase-9 protein level and elicited pre G1 apoptosis and cell cycle arrest at G2/M phase in addition to high annexin V binding affinity indicating significant apoptosis. Chemo-informatic and docking properties were also predicted. Docking results revealed that docked compounds displayed binding modes with EGFR and ARO enzymes comparable to that of the reference ligands. The benzoxazole derivatives 11c and 6c possessing amide and dithiocarbamate moieties respectively were found to be potent apoptosis-inducing anti-breast cancer agents with acceptable physicochemical properties. They exert their activity via inhibition of EGFR and ARO enzymes respectively.