Discovery of novel tubulin/HDAC dual-targeting inhibitors with strong antitumor and antiangiogenic potency.

A novel series of cis -diphenylethene and benzophenone derivatives as tubulin/HDAC dual-targeting inhibitors were designed and synthesized. Among them, compound 28g exhibited the most potent antiproliferative activities against six different human cancer cell lines, 28g could not only inhibited tubulin polymerization, disrupted cellular microtubule networks but also selectively inhibited class IIa HDACs, especially HDAC7 activity. Further molecular docking demonstrated 2 8g could occupy the binding pockets of tubulin and HDAC7 meanwhile. Cellular mechanism studies revealed that 28g could induce G2/M phase arrest by down-regulated expression of p-cdc2 and cell apoptosis by regulating mitochondrial membrane potential, reactive oxygen species (ROS) levels and apoptosis-related proteins (PARP, Caspase families) in a dose-dependent manner. Importantly, 28g significantly inhibited HUVEC tube formation, proliferation, migration and invasion. The inhibitory effect against angiogenesis in vivo was confirmed by zebrafish xenograft. Furthermore, 28g could effectively suppress the proliferation and metastasis of MGC-803 cells in vitro and in zebrafish xenograft. All above results indicated that 28g can act as a promising antitumor and antiangiogenic agent via targeting tubulin and class IIa HDACs. [Display omitted] • 28 g can obviously inhibit the polymerization of tubulin and has a high selectivity to HDAC-7, with an IC50 value of 0.05 μM. • 28 g showed strong potency to decrease angiogenesis in vitro and in vivo. • 28 g suppressed migration and invasion of stomach cancer in vitro and in vivo. [ABSTRACT FROM AUTHOR]