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, sho...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2022-08, Vol.238, p.114439-114439, Article 114439
Main Authors: Yang, Limin, Ma, Xin, Guo, Kerong, Li, Jian, Zhang, Chong, Wu, Liqiang
Format: Article
Language:English
Subjects:
Aminophosphonates
Anti-metastasis
Antitumor
Combretastatin A4
Dual-functional antitumor conjugates
MMPs
Tublin
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Summary: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. [Display omitted] •A series of novel conjugates comprising tublin and MMPs inhibitors were designed and synthesized.•This conjugate containing tubulin and MMP inhibitor can effectivelyimprove the anti-metastatic effect of CA4.•15g could inhibit tubulin polymerization, induced cell cycle arrest, ROS generation and apoptosis of HepG2 cells.•15g showed a potent effect on resistant metastasis by decreasing the levels of the proteins MMP2 and MMP9 in the HepG2 cells.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2022.114439