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

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posted on 17.01.2014, 00:00 by Jia Liu, Xiu-Feng He, Gai-Hong Wang, Emilio F. Merino, Sheng-Ping Yang, Rong-Xiu Zhu, Li-She Gan, Hua Zhang, Maria B. Cassera, He-Yao Wang, David G. I. Kingston, Jian-Min Yue
Aphadilactones A–D (14), 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 14 showed significant antimalarial activities with IC50 values of 190 ± 60, 1350 ± 150, 170 ± 10, and 120 ± 50 nM, respectively.