N-(3'-(Dimethylamino)propyl)amides based on 18βH-glycyrrhetinic acid retain P-glycoprotein inhibitory and MDR-reversing activities.

Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy, primarily mediated by P-glycoprotein (P-gp/ABCB1), which actively effluxes structurally unrelated anticancer drugs. We previously reported Sol-DMAP, an 18βH-glycyrrhetinic acid-derived P-gp inhibitor that reverses chemoresistance and exhibits proapoptotic and hepatoprotective activity; however, its complicated multistep synthesis limits scalability. Here, we asked which structural fragments in the A and C rings of Sol-DMAP are critical for its biological effect. Three analogues (1-3), lacking the cyanoenone pharmacophore and bearing different C-ring moieties, were evaluated by molecular docking and confirmed to occupy the Sol-DMAP binding site within the P-gp transmembrane domain. These compounds were synthesized via a shorter route and evaluated in P-gp-overexpressing KB-8-5 and RLS40 cells. Analogues 1 and 2 significantly increased rhodamine 123 and doxorubicin accumulation and restored chemosensitivity to doxorubicin, vinblastine, and cisplatin, demonstrating broad MDR-reversing activity. Compared with Sol-DMAP, 1 and 2 retained apoptosis-inducing activity; however, removal of the cyanoenone pharmacophore abolished hepatoprotection owing to a marked reduction in antioxidant gene activation. Collectively, cyanoenone-deficient analogues 1 and 2 retain P-gp inhibition and MDR reversal while offering a substantially improved synthesis. Thus, these analogues represent promising scaffolds for more accessible P-gp inhibitors.