Synthesis and evaluation of WK-X-34 derivatives as P-glycoprotein (P-gp/ABCB1) inhibitors for reversing multidrug resistance.

ABSTRACT: The emergence of multidrug resistance (MDR) in malignant tumors is one of the leading threats encountered currently by many chemotherapeutic agents. A proposed strategy to overcome MDR is to disable the efflux function of P-glycoprotein (P-gp/ABCB1), a critical member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells. In this study, structural modification of a third-generation P-gp inhibitor WK-X-34 based on bioisosteric and fragment-growing strategies led to the discovery of the adamantane derivative PID-9, which exhibited the best MDR reversal activity (IC₅₀ = 0.1338 μM, RF = 78.6) in this series, exceeding those of the reported P-gp inhibitors verapamil and WK-X-34. In addition, compared with WK-X-34,

SUBMITTER: Cao F 

PROVIDER: S-EPMC10880894 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature