Design, synthesis, and biological activity study of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives against...

The advent of multidrug resistance (MDR) in tumors markedly diminishes the effectiveness of anticancer therapies. P-glycoprotein (P-gp) plays a crucial role in tumor MDR by mediating the efflux of drugs and cytotoxic agents. Presently, small molecule agents targeting P-gp are among the promising therapeutic approaches to counteract MDR. In previous research, our team identified a novel class of P-gp inhibitors featuring a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline scaffold. To further delineate the structure-activity relationship, this study conducted an extensive structural optimization, synthesizing 42 novel compounds. Evaluation on the drug-resistant cell line Eca109/VCR indicated that the majority of these compounds exhibited remarkable MDR-reversing activity. Notably, the optimized compound 41 demonstrated an outstanding ability to reverse MDR, with a reversal fold of up to 467.7, surpassing the efficacy of the standard third-generation P-gp inhibitor TQ, as evidenced by plate cloning assay and flow cytometry analysis. Subsequent mechanism validation experiments-including western blotting, chemosensitization tests, and fluorescent substrate accumulation assays-complemented by molecular docking studies, confirmed that compound 41 exerts its MDR-reversing effects through P-gp inhibition. This research offers new perspectives for the development of drug sensitizers targeting resistant tumors based on the tetrahydroisoquinoline scaffold.