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

[Display omitted] • A series of amide-based CA-4 analogues were designed, synthesized, and evaluated for antiproliferative activity. • 7d and 8a showed most potent antiproliferative activity toward A549, HeLa, HCT116, and HT-29 cells. • All compounds didn't display noticeable cytotoxic activity on the non-tumoural cell line HEK-293. • 8a caused cell cycle arrest and apoptosis in a concentration-dependent manner. • 8a showed potent and similar tubulin polymerization inhibitory activity to CA-4 with an IC 50 of 6.90 μM. 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 IC 50 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 G 2 /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. [ABSTRACT FROM AUTHOR]

Copyright of Bioorganic & Medicinal Chemistry Letters is the property of Pergamon Press - An Imprint of Elsevier Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)