Synthesis and tumor resistance reverse activities ofα-hederagenin-type ring-A fused pyrazine derivatives / 中国药理学与毒理学杂志

ABSTRACT

α-Hederagenin (H), derived from Hedera nepalensis var.sinensis, is a pentacyclic oleane-type triterpenoid that exhibits clear cytotoxicity to different tumor cell lines.In this study,a series of novel C-28 derivatives of hederagenin (H) were designed and synthesized in attempt to develop potent tumor resistance reverse activities agents. Previous research showed that H6 displayed robust reverse activity for paclitaxel resistance in KBV cells. Importantly, Co-treatment of paclitaxel with H6 significantly reduced the tumor weight to 42%. Pleasingly, H6 enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice.Mechanism studies had found that H6 activated permeability glycoprotein(P-gp)ATPase,reduced intracellular ATP levels and inhibited efflux of P-gp substrates,thus enhancing the antitumor activity of paclitaxel on KBV cells.Molecular docking analysis of homology P-gp and H6 then conducted using the Surflex-Dock module.H6 showed a high binding affinity docking score with a total score of 5.4148,much higher than that of H(0.1414).The nov-el C-28 derivatives of H was synthesized from H6 via three-step reaction. The reversal activity of all synthesized H derivatives were tested using the MTT assay.The results showed that the derivatives of nitrogen groups at C-28 displayed same even potent activity than parent compound H6.In addition,its underlying mechanism of action and in vivo activity are in explore.