Structurally Diverse Triterpene-26-oic Acids as Potential Dual ACL and ACC1 Inhibitors from the Vulnerable Conifer Keteleeria fortunei

A preliminaryphytochemical investigation on the 90%MeOH extractfrom the twigs and needles of the vulnerable conifer Keteleeriafortunei led to the isolation and characterization of 17structurally diverse triterpen-26-oic acids, including nine previouslyundescribed ones (fortunefuroic acids A-I, 1-9) featuring a rare furoic acid moiety in the lateral chain.Among them, 1-5 are uncommon 9 beta H-lanostane-type triterpenoic acids. Friedo-rearranged triterpenoids 6 and 7 feature a unique 17,14-friedo-lanostaneskeleton, whereas 9 possesses a rare 17,13-friedo-cycloartane-typeframework. Their structures and absolute configurations were elucidatedby extensive spectroscopic (e.g., detailed 2D NMR) and computational(NMR/ECD) calculations and the modified Mosher's method. Inaddition, the absolute structure of compound 1 was ascertainedby single-crystal X-ray diffraction analyses. Fortunefuroic acidsB (2), G (7), and I (9), alongwith isomangiferolic acid (12) and 3 alpha,27-dihydroxycycloart-24E-en-26-oic acid (14), exhibited dual inhibitoryeffects against the adenosine triphosphate (ATP)-citrate lyase (ACL,IC50s: 5.7-11.4 mu M) and acetyl-CoA carboxylase1 (ACC1, IC50s: 7.5-10.5 mu M), both of whichare key enzymes for glycolipid metabolism. The interactions of thebioactive triterpenoids with both enzymes were examined by moleculardocking studies. The above findings reveal the important role of protectingplant species diversity in support of chemical diversity and potentialsources of new therapeutics for ACL-/ACC1-associated diseases.