Rational discovery of novel tetrahydroisoquinoline-indole derivatives as potent P-glycoprotein inhibitor against multidrug resistance in MCF-7/ADR cell.

A key strategy for overcoming multidrug resistance (MDR) involves developing inhibitors for the chemotherapy drug efflux pump, P-glycoprotein (P-gp). In this study, building on the prior exploration of the tetrahydroisoquinoline-indole scaffold and receptor-based drug design, the amino group on the indole underwent nucleophilic substitution, leading to 20 novel tetrahydroisoquinoline-benzyl-1H-indole derivatives. The exploration of structure-activity relationships (SAR) revealed that compound BP3p exhibited low cytotoxicity and potent MDR reversal activity against doxorubicin in MCF7/ADR cells (IC50 = 0.11 μM, reversal fold = 215.9), surpassing the reported P-gp inhibitor cyclosporine A. Furthermore, mechanistic studies indicate that BP3p's MDR reversal activity stems from inhibiting the efflux function of P-gp but not expression, and BP3p could bind to P-gp directly and induced a conformation change of P-gp. Moreover, molecular docking simulations further confirm that BP3p shows a strong affinity for P-gp, while 3D tumor spheroid models suggest that BP3p exhibits significant reversal activity against doxorubicin-resistant cells, underscoring its potential to overcome tumor resistance in vivo. These findings position BP3p as a promising P-gp inhibitor, offering valuable insights for the future development of novel P-gp inhibitors.