Polyprenylated acylphloroglucinols from Hypericum monogynum and their reversal of multidrug resistance in MCF-7/ADR cells.

Hypericum monogynum L. is a plant used in traditional Chinese medicine for treating inflammatory disorders and infectious diseases. Seven new polyprenylated acylphloroglucinols (PPAPs) and seven known PPAPs were isolated from the flowers of H. monogynum. Structurally, compound 1 features the first rearranged PPAP with a fascinating spirocyclic 5/6/6 ring system, and compound 2 is the first example of a highly modified PPAP featuring a rare 6/5/5/5-tetracyclic system. Compound 7 is the first highly degraded PPAP. Their structures were elucidated through comprehensive analysis of HRESIMS, NMR spectroscopy, and electronic circular dichroism calculations. Additionally, five PPAPs exhibited potential multidrug resistance (MDR) reversal activity in MCF-7/ADR cells with reversal fold (RF) values ranging from 9 to 56. Notably, compound 3, the strongest MDR modulator, showed a reversal effect (RF = 56) superior to the positive control verapamil (RF = 53) at an equivalent concentration. Furthermore, primary mechanistic investigation indicated that compound 10 inhibits P-gp transport function without affecting its expression. The potential recognition mechanism between compound 10 and P-gp was predicted by molecular docking.