Design, concise synthesis and evaluation of novel amide-based combretastatin A-4 analogues as potent tubulin inhibitors

As our ongoing work, a novel series of the amide-based CA-4 analogues were successfully designed, synthesized, and explored for their biological evaluation. Among these compounds, 7d and 8a illustrated most potent antiproliferative activity toward A549, HeLa, HCT116, and HT-29 cell lines. Most importantly, these two compounds didn't display noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies revealed that analogue 8a was identified as a novel tubulin polymerization inhibitor with an IC₅₀ value of 6.90 μM, which is comparable with CA-4. The subsequent investigations unveiled that analogue 8a not only effectively caused cell cycle arrest at the G₂/M phase but also induced Apoptosis in A549 cells via a concentration-dependent manner. The molecular docking revealed that 8a could occupy well the colchicine-binding site of tubulin. Collectively, these findings indicate that amide-based CA-4 scaffold could be worthy of further evaluation for development of novel tubulin inhibitors with improved safety profile.

Antiproliferative activity; CA-4 analogues; Structure-activity relationship; Tubulin.