Dual-functional antitumor conjugates improving the anti-metastasis effect of combretastatin A4 by targeting tubulin polymerization and matrix metalloproteinases

This study prepared different novel conjugates containing tubulin and MMP inhibitors and assessed their Anticancer effects. Typically, the conjugate 15g, which contained combretastatin A4 (CA4) and 2-(4-((diethoxyphosphono)(o-tolyl)methylamino)phenyl)acetic acid (19g) connected by an ester bond, showed the maximum effect against proliferation. Particularly, the conjugate yielded a reduced IC₅₀ value of 0.05 μM in controlling the proliferation of HepG2 cells compared to CA4 alone (0.09 μM). Systematic research indicated that 15g suppressed tubulin polymerization, induced cell cycle arrest at the G2/M phase, led to reactive oxidative stress (ROS) generation of HepG2 cells, and resulted in Apoptosis by the mitochondrial-dependent apoptotic pathway. Moreover, 15g showed a potent effect on resistant metastasis by decreasing the levels of the proteins MMP2 and MMP9 in the HepG2 cells. Therefore, this conjugate is a potentially effective approach to improve the anti-metastatic effect of CA4 with high safety.