Design, synthesis and biological evaluation of biaryl amide derivatives as modulators of multi-drug resistance.

The emergence of multi-drug resistance (MDR) presents a significant impediment to the efficacy of cancer treatment. Aberrant expression of ABC (ATP-binding cassette) transporters is acknowledged as one of the underlying factors contributing to MDR. P-glycoprotein (P-gp, MDR1, ABCB1), breast cancer resistance protein (BCRP, ABCG2), and MDR-associated protein 1 (MRP1, ABCC1) are members of the ABC transporter, and their over-expression usually occurs in drug-resistant tumor cells. In this work, the structure-activity relationships of the biaryl amide skeleton were systematically investigated via structural optimization step by step, which led to the identification of an exceptionally potent resistance reversal agent, D2. Compound D2 effectively reversed MDR to paclitaxel and cisplatin in A2780/T, A2780/CDDP and A549/T cell lines. It could directly bind to P-gp and downregulate the expression of both P-gp and MRP1. The treatment with D2 increased the intracellular accumulation of Rh123 and inhibited P-gp-mediated drug efflux of Rh123 in A2780/T cells. Therefore, compound D2 exhibits promising potential in overcoming multidrug resistance (MDR) induced by P-gp in cancer.