Design, synthesis and biological evaluation of novel tubulin inhibitors targeting colchicine sites

Tubulin, a potential target for antitumor drug discovery, contains three main binding sites for clinical inhibitors: colchicine, vinblastine, and paclitaxel. CA-4 has been reported to be a classic tubulin inhibitor targeting the colchicine site. Herein, based on the structural modification of CA-4, 48 novel compounds were designed and synthesized by selecting structural fragments with various biological activities to replace the cis double bond of CA-4. Among these compounds, compound 8p was the most effective tubulin inhibitor (IC50 = 65 nM aganist HepG2 cells). Immunofluorescence experiment confirmed the anti-tumor effect of 8p by destroying the network structure of microtubules. Further studies showed that 8p induced tumor cell apoptosis, arrested cell cycle, inhibited tumor cell migration and invasion.