Forrestiacids A and B, Pentaterpene Inhibitors of ACL and Lipogenesis: Extending the Limits of Computational NMR Methods in the Structure Assignment of Complex Natural Products

Abstract

Forrestiacids A (1) and B (2) are a novel class of [4+2] type pentaterpenoids derived from a rearranged lanostane moiety (dienophile) and an abietane unit (diene). These unprecedented molecules were isolated using guidance by molecular ion networking (MoIN) from Pseudotsuga forrestii, an endangered member of the Asian Douglas Fir Family. The intermolecular hetero‐Diels–Alder adducts feature an unusual bicyclo[2.2.2]octene ring system. Their structures were elucidated by spectroscopic analysis, GIAO NMR calculations and DP4+ probability analyses, electronic circular dichroism calculations, and X‐ray diffraction analysis. This unique addition to the pentaterpene family represents the largest and the most complex molecule successfully assigned using computational approaches to predict accurately chemical shift values. Compounds 1 and 2 exhibited potent inhibitory activities (IC50s <5 μM) of ATP‐citrate lyase (ACL), a new drug target for the treatment of glycolipid metabolic disorders including hyperlipidemia. Validating this activity 1 effectively attenuated the de novo lipogenesis in HepG2 cells. These findings provide a new chemical class for developing potential therapeutic agents for ACL‐related diseases with strong links to traditional medicines.

Investigation of the Biosynthetic Mechanism of Bipentaromycin Featuring an Unprecedented Cyclic Head-to-Tail Dimeric Scaffold

“…Besides, enriched carbon signals for bipentaromycin E (5) were observed at 20 different carbons in [2-13 C]-sodium acetate feeding experiment, including C2, C4, C6, C8, C12, C14, C16, C18, C20, C22, C2′, C4′, C6′, C8′, C12′, C14′, C16′, C18′, C20′, and C22′ (Figure S13). Further analysis of the 13 C NMR spectrum of [1,[2][3][4][5][6][7][8][9][10][11][12][13] C 2 ]-sodium acetate labeled 3 showed that all carbon resonances except Me-13 were enriched (Figure S13). All except C2, C9, C2′, and C9′ were coupled to one other carbon, in which carbons derived from the same sodium acetate unit shared the same J CC values (Table S7).…”

A facile turn‐on chemiluminescence probe for sensitive imaging on aminopeptidase N activity

“…In total, 11 compounds (C1–C11) were kindly offered by the research group of Professor Hu, which were newly separated from traditional Chinese medicine ( Pseudotsuga forrestii ). [ 29 ] Here, we explored their potential activity to inhibit APN activity based on our new CL strategy. As show in Figure 3b, four compounds showed an obvious inhibitory ability for APN, especially C7 and C8 with the highest inhibitory activity, which indicated they were the potential drug candidates for abnormally elevated APN‐related diseases.…”

Beshanzuamide A, an unprecedented prenylated indole alkaloid produced by Aspergillus sp. Y-2 from the critically endangered conifer Abies beshanzuensis

“…These prenylated indole alkaloids were also found to be inactive (IC 50 s > 20 μM) in the bioassays against PTP1B, ATP-citrate lyase (ACL), and acetyl-CoA carboxylate 1 (ACC1), which are potential drug targets associated with the glycolipid metabolic disorders. 3,9…”

“…In recent years, relevant research on the REPs endemic to China have been launched by our group. 3 However, in many cases, it is not easy to investigate endangered species due to the difficulties in collecting the rare plant materials. Fortunately, a large number of endophytic fungi, bacteria and actinomycetes contained in each plant species may be able to synthesize related plant metabolites.…”