Discovery and biological evaluation of hederagenin derivatives as non-substrate inhibitors of P-glycoprotein-mediated multidrug resistance

Multidrug Resistance (MDR) is an essential cause of failure of tumor chemotherapy, and P-glycoprotein (P-gp) overexpression is one of the major causes of MDR in tumor cells. Hederagenin (HRG) derivatives showed significant inhibitory effects in P-gp-mediated tumor MDR. Herein, we designed and synthesized 30 HRG derivatives and evaluated these compounds' tumor MDR reversal ability. For the first time, we identified a potential P-gp non-substrate inhibitor of the HRG derivatives 15, which binds to non-substrate active sites in transmembrane structural domains (TMDs) with high binding affinity. Subsequent assays confirmed that 15 exerted significant tumor MDR reversal activity by binding to P-gp and inhibiting P-gp function rather than affecting its expression. It could not be pumped out of the cell by P-gp. In addition, 15 inhibited Rhodamine123 efflux, rendered the KBV cells sensitive to paclitaxel (Ptx), blocked the cells in the G₂/M phase, and induced apoptosis. Notably, 15 increased Ptx sensitivity in vivo, significantly inhibited the growth of KBV cell-derived xenograft tumors in nude mice, with a tumor suppression rate as high as 63.71 %.