Main observation and conclusion Eleven biogenetically related polyprenylated acylphloroglucinols (PPAPs), including four novel skeletons (1—4) and five new compounds (5—9), were isolated from the flowers of Hypericum monogynum. Hypermonones A—D (1—4) represented the first example of a unique dilactone structure containing carbonyl bonded single δ‐lactone and tricyclic γ‐lactone moieties. Their structures were elucidated by NMR analysis, X‐ray crystallography, and ECD calculations. Moreover, we revised the structure of hyperibrin B to hypermonone I (9) via NMR analysis, a quantum computational chemistry method, and hypothetic biosynthetic considerations. Three compounds (5, 6, and 9) with significant MDR reversal activity (RF ranging from 61 to 223) were superior to the positive control verapamil (MCF‐7/ADR, RF: 53; HepG2/ADR, RF: 124). Mechanism study for compound 5 indicated that this compound could inhibit the function of P‐gp transport rather than its expression, and the possible recognition mechanism between compound 5 and P‐gp was predicted by molecular docking.

Hypermonins A–D (1–4), four rearranged nor-polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented skeletons, together with two new biosynthesis related PPAPs (5 and 6) were isolated and identified from the flowers of Hypericum monogynum. Hypermoins A–D represented the first examples of highly modified norPPAPs characterized by a rare 7/6/6/5-tetracyclic system. From the biogenic synthesis pathway analysis, all isolates shared the same biosynthetic intermediate, and the addition of two methyls or one methyl to this intermediate through methyltranferase could generate different types of PPAPs (1–7). Their planner structures as well as absolute configuration were confirmed via spectroscopic analysis, ECD calculation, and X-ray crystallography. All isolates potentially reversed multidrug resistance (MDR) activity in both two cancer cells, HepG2/ADR and MCF-7/ADR. Specifically, hypermoin E (5) and hyperielliptone HA (7) were found to be the best MDR modulators with the reversal fold ranging from 41 to 236, which is higher than the positive control verapamil.

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