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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antimalarials / chemistry
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Antimalarials / isolation & purification
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Antimalarials / pharmacology*
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Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
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Diacylglycerol O-Acyltransferase / metabolism
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Dimerization
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Diterpenes / chemistry
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Diterpenes / isolation & purification
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Diterpenes / pharmacology*
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / isolation & purification
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Enzyme Inhibitors / pharmacology*
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Humans
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Meliaceae / chemistry*
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Molecular Conformation
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Parasitic Sensitivity Tests
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Plasmodium falciparum / drug effects*
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
Substances
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Antimalarials
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Diterpenes
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Enzyme Inhibitors
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Recombinant Proteins
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DGAT1 protein, human
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DGAT2 protein, human
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Diacylglycerol O-Acyltransferase