Discovery of novel combretastatin A4 derivatives as a microtubule targeting agent capable of inducing HepG-2 cell apoptosis via the mitochondria and ER stress mediated pathway.

Microtubule-targeting agents, such as paclitaxel and docetaxel, have been extensively utilized as clinically effective chemotherapeutic agents for cancer treatment. However, their efficacy may be impeded by the acquired or intrinsic resistance of tumor cells to apoptosis, in addition to their high toxicity toward normal human cells or tissues. Herein, seventeen CA-4 analogues were synthesized and characterized, followed by investigation of their antiproliferative activity using MTT assays. Among them, compound 9n exhibited the best antitumor activity against a panel of tested cancer cell lines including drug resistance cells A549/CDDP, A549/paclitaxel and MCF-7/DOX, respectively, with IC values ranging from 0.09 to 0.51 μM, and accordingly showed low toxicity toward normal liver cells HL-7702. Mechanistic studies suggested that compound 9n not only significantly inhibited tubulin polymerization and cell migration and invasion, but also effectively triggered HepG-2 cells apoptosis through the mitochondria and ER stress mediated pathway. More importantly, in HepG-2 xenograft models, compound 9n achieved 70.7 % of the antitumor inhibition rate at dose of 30 mg/kg and without obvious systemic toxicity, and accordingly exceeding to that of CA-4 (61.2 %@15 mg/kg). Collectively, these results demonstrated that compound 9n, as a promising tubulin inhibitor, has great potential for the cancer therapy.