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
Document Type
Article
Publication Date
10-4-2021
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 bicyclo2.2.2]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 (IC(50)s mu M) 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.
Keywords
Forrestiacids, Lipogenesis inhibitors, Natural products, Structure elucidation, Terpenoids
Divisions
Science
Funders
National Natural Science Foundation of China (NSFC)[21937002]
Publication Title
Angewandte Chemie-International Edition
Volume
60
Issue
41
Publisher
Wiley
Publisher Location
POSTFACH 101161, 69451 WEINHEIM, GERMANY