Fortunefuroic Acid J from Keteleeria Hainanensis and its Dual Inhibitory Effects on ATP-Citrate Lyase and Acetyl-CoA Carboxylase

Chem Biodivers. 2024 Dec;21(12):e202401520. doi: 10.1002/cbdv.202401520. Epub 2024 Oct 26.

Abstract

A previously undescribed triterpenoid (fortunefuroic acid J, 1) was isolated from the endangered conifer Keteleeria hainanensis, along with 20 other known terpenoids. Compound 1 is characterized by an unusual 3,4-seco-9βH-lanost-3-oic acid motif, featuring a rare furoic acid moiety in its lateral chain. The structure elucidation of this compound was achieved through a combination of spectroscopic and computational methods. The C-15 epimers of 15-methoxypinusolidic acid (15R-8 and 15S-9) were successfully separated and identified for the first time. Compound 1 demonstrated dual inhibitory effects against ATP-citrate lyase (ACL, IC50: 0.92 μM) and acetyl-CoA carboxylase 1 (ACC1, IC50: 10.76 μM). Compounds 2 and 11 exclusively inhibited ACL, exhibiting IC50 values of 2.64 and 6.35 μM, respectively. Compound 1 is classified among the fortunefuroic acid-type compounds, previously isolated from K. fortunei, distinguished by the presence of a rare furoic acid moiety in their lateral chain. The chemotaxonomic significance of the 9βH-lanost-26-oic acids in Keteleeria was briefly discussed. These findings highlight the importance of conserving plant species diversity, thereby enhancing the exploration of structurally diverse compounds and potential avenues for developing new therapeutics targeting ACL/ACC1-associated diseases.

Keywords: ATP-citrate lyase; Acetyl-CoA carboxylase 1; Fortunefuroic acid; Keteleeria hainanensis; Natural products; Pinaceae; Terpenoids.

MeSH terms

  • ATP Citrate (pro-S)-Lyase* / antagonists & inhibitors
  • ATP Citrate (pro-S)-Lyase* / metabolism
  • Acetyl-CoA Carboxylase* / antagonists & inhibitors
  • Acetyl-CoA Carboxylase* / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / isolation & purification
  • Enzyme Inhibitors* / pharmacology
  • Molecular Docking Simulation
  • Structure-Activity Relationship
  • Triterpenes* / chemistry
  • Triterpenes* / isolation & purification
  • Triterpenes* / pharmacology

Substances

  • ATP Citrate (pro-S)-Lyase
  • Acetyl-CoA Carboxylase
  • Enzyme Inhibitors
  • Triterpenes