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ID: ALA4325852
Journal: Eur J Med Chem
Title: Design, synthesis, and discovery of ocotillol-type amide derivatives as orally available modulators of P-glycoprotein-mediated multidrug resistance.
Authors: Ren Q, Yang G, Guo M, Guo J, Li Y, Lu J, Yang Q, Tang H, Li Y, Fang X, Sun Y, Qi JG, Tian J, Wang H.
Abstract: Multidrug resistance (MDR) is a major cause of failure in cancer treatment, in which the overexpression of P-glycoprotein (Pgp) plays a crucial role. Herein, a novel class of ocotillol-type amide derivatives has been designed, synthesized, and evaluated for their ability to reverse MDR. The structure-activity relationship of the reversal activity was analyzed. Ten compounds showed promising chemo-reversal ability, among which the 24R-ocotillol-type amide derivative 6c with an N-Boc-hexanoyl unit exhibited the most potency in reversing paclitaxel resistance in KBV cells. Compound 6c could inhibit Pgp-mediated rhodamine123 efflux function via stimulating Pgp-ATPase activity and exhibited high binding affinity with Pgp in molecular docking studies. Importantly, compound 6c enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice after oral administration. These results indicate that ocotillol-type amide derivatives are promising lead compounds for overcoming MDR in cancer.
CiteXplore: 30347326