Unprecedented polycyclic polyprenylated acylphloroglucinols with anti-Alzheimer's activity from St. John's wort

Abstract

Hyperforones A-J (1-10), ten degraded and reconstructed polycyclic polyprenylated acylphloroglucinols (PPAPs) with six different types of unusual architectures, were isolated fromHypericum perforatum(St. John's wort). Compound1is characterized by an unprecedented 1,5-epoxyfuro[3′,4′:1,5]cyclopenta[1,2-c]oxecine ring system; compounds2and3represent the first PPAPs with a contracted B-ring leading to the unique 5/5 core skeletons; compound4, a proposed biosynthetic precursor of2, is defined by an oxonane-2,7-dione architecture; compound5features an unusual spiro[furo[3′,4′:1,5]cyclopenta[1,2-b]oxepine-3,2′-oxetane] ring system; compounds6-8possess a rare macrocyclic lactone ring in addition to the newly formed C-ring; and compounds9and10contain a newly formed six-membered C-ring, which constructed the unexpected 6/6 scaffold with the B-ring. Hypothetic biosynthetic pathways to generate these scaffolds starting from the classic [3.3.1]-type PPAPs helped to elucidate their origins and validate their structural assignments. Compounds4and6simultaneously displayed notable activation of PP2A (EC50: 258.8 and 199.0 nM, respectively) and inhibition of BACE1 in cells (IC50: 136.2 and 98.6 nM, respectively), and showed better activities than the positive controls SCR1693 (a PP2A activator, EC50: 413.9 nM) and LY2811376 (a BACE1 inhibitor, IC50: 260.2 nM). Furthermore, compound6showed better therapeutic effects with respect to the reduction of pathological and cognitive impairments in 3 × Tg AD mice than LY2811376. Compound6represents the first multitargeted natural product that could activate PP2A and simultaneously inhibit BACE1, which highlights compound6as a promising lead compound and a versatile scaffold in AD drug development.