Adipogenesis Inhibitory Activity of Hypersampsone P from Hypericum subsessile

Abstract

Adamantane polycyclic polyprenylated acylphloroglucinols (PPAPs) with caged architecture, a special class of hybrid natural products, is specifically rich in the plant family Guttiferae, especially Hypericum or Garcinia genus. Hypersampsone P is one of Adamantane PPAPs compounds extracted from Hypericum subsessile. Here we have chosen, screened ten PPAPs and identified one of them showed an activity in inhibiting of adipocytes differentiation. Particularly, the compound, hypersampsone P, blunted the adipocyte differentiation dose-dependently. Moreover, hypersampsone P down-regulated the expressions of several key regulators for adipogenesis, including PPARγ and FABP4. The treatment of cells at the early stage of adipogenesis by hypersampsone P induced the greatest blunting of adipocyte differentiation and the effect might be involved in the LKB1-AMPK signaling pathway. Graphic Abstract

Hyperispirones A and B, spiro-bridged polycyclic polyprenylated acylphloroglucinols with anti-angiogenesis activity from Hypericum beanii

“…The single electron oxidation of i afforded a stabilized α-triketo radical at C-2, which could successively trigger the radical cyclization to provide rings B and C. 23,24 Deprotonation of the allylic C-7 of ii provided the C-7 carbanion, and the subsequent C-7-C-1 bond formation built the dual-bridged core (rings D and E) in iii. 14,25,26 Rings F and G were achieved by a series of intramolecular cyclization and oxidation biosynthetic reactions of the geranyl unit, leading to the final construction of the complex heptacyclo[18.3.1.0 1,20 .0 2,17 .0 3,15 .0 6,15 .0 8,13 ]tetracosane core of 1. 16,27 Angiogenesis is a hallmark of cancer cells that leads to tumor vascular proliferation and metastasis, and suppressing angiogenesis is an effective strategy for cancer therapy.…”

“…In conclusion, two architecturally complex PPAPs, hyperispirone A (1) with an unparalleled caged heptacyclo [18.3.1.0 1,20 .0 2,17 .0 3,15 .0 6,15 .0 8,13 ]tetracosane core, which to the best of our knowledge is the first PPAP possessing a heptacarbocyclic skeleton, and hyperispirone B (2) with an unusual 8-oxa-tetracyclo[7.4.2.0 1,9 ,0 3,7 ]cetane ring system were isolated and characterized from the aerial parts of H. beanii. The discovery of 1 and 2 simultaneously possessing spiro, bridged, and fused ring systems greatly extended the PPAP skeletons and contributed to the diversity of metabolites of H. beanii.…”

“…2,3 Due to their unique structural features and limited natural occurrence, PPAPs were considered as important chemotaxonomic markers and have attracted widespread attention from phytochemical, organic synthetic, biosynthetic and pharmacological endeavors. [4][5][6][7][8][9] To date, more than 600 PPAPs have been reported from the family Guttiferae. The most studied, hyperforin, featuring a bicyclo [3.3.1]nonane skeleton, has been widely investigated due to its anti-depressive, anti-bacterial, and anti-obesity activities.…”

“…[16][17][18][19][20][21][22] As a result of our continuing project, two unprecedented PPAPs that simultaneously harbor spiro, bridged, and fused ring systems, namely, hyperispirones A (1) and B (2), were isolated from the aerial parts of H. beanii. Structurally, hyperispirone A (1) possesses a caged heptacyclo [18.3.1.0 1,20 .0 2,17 .0 3,15 .0 6,15 .0 8,13 ]tetracosane ring system composed of a dual-bridged spiro core (rings C-F) fused with a tetrahydronaphthalene (rings A and B) and a cyclopentane (ring G), which to the best of our knowledge is the first PPAP possessing a hepta-carbocyclic skeleton, whereas hyperispirone B (2) features an unparalleled 8-oxa-tetracyclo[7.4.2.0 1,9 ,0 3,7 ]cetane ring system. Compounds 1 and 2 represent the first cases of PPAPs acting as potential anti-angiogenesis agents.…”

Total Synthesis of Hypersampsone M

“…We identified hypersampsone M ( 1 ), isolated from Hypericum sampsonii in 2014, to be a prototypical representative of this subclass, making it an excellent target for our initial investigations into this family of PPAPs . Many homoadamantane PPAPs have been known for decades and many more have provided glimpses into the promising bioactivity of this class, with several being implicated to have antitumor, anti-inflammatory/immunosuppressive, , hepatoprotective, and antiadipogenesis properties. Like other homoadamantane PPAPs, the phloroglucinol moiety in hypersampsone M ( 1 ) is clearly conserved (Figure , highlighted in blue), yet the unsymmetrical homoadamantane core and fused cyclopentane make it difficult to utilize an alkylative dearomatization strategy such as was cleverly applied to an adamantane PPAP by Porco and co-workers…”