Discovery of valine thiazole-containing derivatives as potent reversers of P-glycoprotein-mediated multidrug resistance.

The development of multidrug resistance (MDR) to anticancer agents following chronic treatment remains a significant obstacle in cancer chemotherapy. Overexpression of the energy-dependent drug efflux transporter P-glycoprotein (P-gp) has been identified as a major contributor to MDR. Inspired by naturally occurring MDR-reversing cyclic peptides, a series of readily accessible valine thiazole-containing derivatives were designed and synthesized as effective reversal agents against P-gp-mediated MDR based on a hybridization strategy. Structure-activity relationship (SAR) analysis demonstrated that linear valine thiazole derivatives possess greater MDR reversal activity than their macrocyclic analogs. Compound 17e displayed promising synergistic activity by significantly enhancing the therapeutic efficacy of paclitaxel (PTX) against KBV cells (IC50 = 2.8 nM, reversal fold = 288.5) without inducing obvious toxicity. 17e exhibited approximately 8-fold greater potency than verapamil (VRP), 2-fold greater potency than the third-generation P-gp inhibitor tariquidar (TAR) in KBV cells. Mechanistic studies confirmed that 17e inhibits the efflux function of P-gp in a concentration-dependent manner without affecting its expression, thereby increasing intracellular chemotherapeutic drug accumulation and causing G2/M phase arrests, which is associated with increased apoptosis. Taken together, the linear valine thiazole derivative 17e represents a promising starting scaffold for developing novel P-gp inhibitors against MDR.