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

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.