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 from Hypericum perforatum (St. John's wort). Compound 1 is characterized by an unprecedented 1,5-epoxyfuro[3′,4′:1,5]cyclopenta[1,2-c]oxecine ring system; compounds 2 and 3 represent the first PPAPs with a contracted B-ring leading to the unique 5/5 core skeletons; compound 4, a proposed biosynthetic precursor of 2, is defined by an oxonane-2,7-dione architecture; compound 5 features an unusual spiro[furo[3′,4′:1,5]cyclopenta[1,2-b]oxepine-3,2′-oxetane] ring system; compounds 6–8 possess a rare macrocyclic lactone ring in addition to the newly formed C-ring; and compounds 9 and 10 contain 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. Compounds 4 and 6 simultaneously 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, compound 6 showed better therapeutic effects with respect to the reduction of pathological and cognitive impairments in 3 × Tg AD mice than LY2811376. Compound 6 represents the first multitargeted natural product that could activate PP2A and simultaneously inhibit BACE1, which highlights compound 6 as a promising lead compound and a versatile scaffold in AD drug development.