2-Methoxydiol derivatives as new tubulin and HDAC dual-targeting inhibitors, displaying antitumor and antiangiogenic response

Multi-target drugs design has become an active research field because of their advantages in cancer treatment. In present study, HDAC inhibitors pharmacophore and 2-methoxyestradiol(2ME2) were combined into a new hybrid molecule for the first time. Forty-seven 2ME2 derivatives were synthesized and evaluated for anti proliferative activity. In particular, compound 4s exhibited a dual inhibition of tubulin polymerization and HDAC (IC50 = 0.06 mu M toward HDAC2) activity, as well as the most potent cytotoxicity IC50 values of 0.37-4.84 mu M against six cancer cell lines. Compound 4s remarkably disrupted microtubule networks, arrested cell cycle at G2/M phase, induced mitochondrial membrane potential collapse and eventually apoptosis in A549 cells. Notably, 4s was discovered to potently imped the tube-formation of HUVECs and prohibited the proliferation, migration, and invasion of HUVECs, as well as A549 cells. In addition, the anti-angiogenic and anti-metastasis activities were demonstrated via a zebrafish model test. All these beneficial anticancer activities together with its high selectivity toward noncancer cells, suggested 4s may deserves consideration for cancer therapy.

Automated summary

Multi-target drugs design has advantages in cancer treatment. In this study, a new hybrid molecule combining HDAC inhibitors pharmacophore and 2ME2 was synthesized and evaluated for its anticancer activities. Compound 4s exhibited dual inhibition and high selectivity against multiple cancer cell lines, as well as anti-angiogenic and anti-metastasis activities.