Design, synthesis, and biological evaluation of C-12 modified ocotillol-type derivatives as novel P-glycoprotein modulators for overcoming multidrug resistance.

Ocotillol-type ginsenoside derivatives exhibit significant potential as modulators of P-glycoprotein (Pgp). To date, structural investigations of Ocotillol-type saponins have predominantly focused on modifications at the C-3 position of the A-ring, with limited exploration of the C-12 position on the C-ring. In this study, we designed and synthesized a series of C-12 modified ocotillol-type derivatives and assessed their efficacy in reversing multidrug resistance (MDR) in KBV cells. Most of the newly synthesized derivatives exhibited minimal cytotoxicity and potent MDR reversal capabilities. Notably, compound 9e emerged as the most effective agent in reversing tumor MDR in vitro, showing more than twice the potency of verapamil. Furthermore, 9e displayed high selectivity for Pgp, being 40- and 20-fold more effective than verapamil in inhibiting Rh123 efflux and enhancing doxorubicin sensitivity, respectively. Molecular docking analysis revealed that 9e possesses a unique T-shaped configuration that occupies the access channel of Pgp, obstructing the peristaltic extrusion mechanism of TM12 and TM9, thereby inhibiting the efflux function of Pgp. Overall, 9e represents a promising lead compound for the development of novel Pgp modulators to overcome MDR in cancer therapy.