Design, synthesis and bioevaluation of novel combretastatin A-4 based derivatives as potent tubulin/HDAC6 dual-target inhibitors for cancer therapy

On the basis of our previous work, a novel series of CA-4 derivatives as tubulin/HDAC6 dual-target inhibitors were discovered by merging hydroxamic acid or benzamide group into the olefin moiety. Among them, compound 9q exhibited satisfactory antiproliferative effects on both hematological malignancies and solid tumor cells with IC₅₀ values ranging from 0.52 to 5.10 μM. The mechanism study revealed that 9q not only repressed tubulin polymerization, disrupted cellular microtubule networks but also inhibited HDAC6. Meanwhile, 9q could induce G₂/M phase arrest, and caused cell Apoptosis with a concentration-dependent manner, and also remarkably inhibited migration in HeLa cells. Most importantly, 9q effectively inhibited tumor growth in the HCT116 xenograft model without apparent toxicity. These findings indicate that 9q could be a potential lead compound for further development as an antitumor agent.

Antiproliferative activity; HDAC6; Structure-activity relationship; Tubulin.