Design, synthesis and anti-cancer evaluation of novel podophyllotoxin derivatives as potent tubulin-targeting agents

AbstractA series of podophyllotoxin derivatives (M1–M16) that were selectively acylated by various phenoxy acids at the C-4 position of podophyllotoxin were synthesized, and their biological activities were also evaluated. Among them, compoundM4 showed the most potent anti-cancer activity against HeLa cells with an IC50 value of 1.64  ± 0.41 μM. Additionally, flow cytometry analysis results indicated that it could cause a remarkable cell cycle arrest at G2/M phase, but the effect on apoptosis inducing was not significant. Moreover, the expression of cell cycle relative protein CDK1 was up regulated while cyclin B1 and Cd c25C, two proteins required for mitotic initiation were down regulated. Furthermore, the confocal assay and extracellular polymerized tubulin expression analysis also demonstrated thatM4 was a potent tubulin polymerization inhibitor and the effect was comparable to that of colchicine. Finally, docking simulation results showed thatM4 could nicely bind to the colchicine binding site of tubulin which further comfirmed the tubulin inhibiton activity ofM4.
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research