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

Hyperforones A-J (), ten degraded and reconstructed polycyclic polyprenylated acylphloroglucinols (PPAPs) with six different types of unusual architectures, were isolated from (St. John's wort). Compound is characterized by an unprecedented 1,5-epoxyfuro[3',4':1,5]cyclopenta[1,2-]oxecine ring system; compounds and represent the first PPAPs with a contracted B-ring leading to the unique 5/5 core skeletons; compound , a proposed biosynthetic precursor of , is defined by an oxonane-2,7-dione architecture; compound features an unusual spiro[furo[3',4':1,5]cyclopenta[1,2-]oxepine-3,2'-oxetane] ring system; compounds possess a rare macrocyclic lactone ring in addition to the newly formed C-ring; and compounds and 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 and simultaneously displayed notable activation of PP2A (EC: 258.8 and 199.0 nM, respectively) and inhibition of BACE1 in cells (IC: 136.2 and 98.6 nM, respectively), and showed better activities than the positive controls SCR1693 (a PP2A activator, EC: 413.9 nM) and LY2811376 (a BACE1 inhibitor, IC: 260.2 nM). Furthermore, compound showed better therapeutic effects with respect to the reduction of pathological and cognitive impairments in 3 × Tg AD mice than LY2811376. Compound represents the first multitargeted natural product that could activate PP2A and simultaneously inhibit BACE1, which highlights compound as a promising lead compound and a versatile scaffold in AD drug development.