Aphadilactones A-D, four diterpenoid dimers with DGAT inhibitory and antimalarial activities from a Meliaceae plant

Abstract

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.