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. (2nd September 2021)

• Record Type: Journal Article
• Authors: Xiong, Juan; Zhou, Peng‐Jun; Jiang, Hao‐Wen; Huang, Ting; He, Yu‐Hang; Zhao, Ze‐Yu; Zang, Yi; Choo, Yeun‐Mun; Wang, Xiaojuan; Chittiboyina, Amar G.; Pandey, Pankaj; Hamann, Mark T.; Li, Jia; Hu, Jin‐Feng
• Is Part Of: Angewandte Chemie. Volume 133:Number 41(2021)
• Page Start: 22444
• Page End: 22449
• Publication Date: 2021-09-02
• Subjects: forrestiacids -- lipogenesis inhibitors -- natural products -- structure elucidation -- terpenoids; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202109082
• Languages: English
• ISSNs: 0044-8249

Abstract

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 (IC50 s <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. Abstract : Forrestiacids A (1 ) and B (2 ), comprising a rearranged spiro‐lanostane unit fused with an abietene by a Diels–Alder cycloaddition, represent a novel class of pentaterpenoids obtained from Pseudotsuga forrestii . Chemical computations demonstrate to be an effective strategy in the structure elucidation of complex molecules. Both 1 and 2 showed potent ACL inhibitory effects, and 1 even significantly attenuated the de novo lipogenesis in HepG2 cells.