Aphadilactones A–D, Four Diterpenoid Dimers with DGAT Inhibitory and Antimalarial Activities from a Meliaceae Plant

• Published in: Journal of organic chemistry 2014-01, Vol.79 (2), p.599-607
• Main Authors: Liu, Jia, He, Xiu-Feng, Wang, Gai-Hong, Merino, Emilio F, Yang, Sheng-Ping, Zhu, Rong-Xiu, Gan, Li-She, Zhang, Hua, Cassera, Maria B, Wang, He-Yao, Kingston, David G. I, Yue, Jian-Min
• Format: Article
• Language: English
• Subjects: Antimalarials - chemistry; Antimalarials - isolation & purification; Antimalarials - pharmacology; Diacylglycerol O-Acyltransferase - antagonists & inhibitors; Diacylglycerol O-Acyltransferase - metabolism; Dimerization; Diterpenes - chemistry; Diterpenes - isolation & purification; Diterpenes - pharmacology; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Humans; Meliaceae - chemistry; Molecular Conformation; Parasitic Sensitivity Tests; Plasmodium falciparum - drug effects; Recombinant Proteins - metabolism; Structure-Activity Relationship
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo402340h

Aphadilactones A–D (1–4), four diastereoisomers possessing an unprecedented carbon skeleton, were isolated from the Meliaceae plant Aphanamixis grandifolia. Their challenging structures and absolute configurations were determined by a combination of spectroscopic data, chemical degradation, fragment synthesis, experimental CD spectra, and ECD calculations. Aphadilactone C (3) with the 5S,11S,5′S,11′S configuration showed potent and selective inhibition against the diacylglycerol O-acyltransferase-1 (DGAT-1) enzyme (IC50 = 0.46 ± 0.09 μM, selectivity index > 217) and is the strongest natural DGAT-1 inhibitor discovered to date. In addition, compounds 1–4 showed significant antimalarial activities with IC50 values of 190 ± 60, 1350 ± 150, 170 ± 10, and 120 ± 50 nM, respectively.