title: 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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Xiu-Feng
authors.initials: XF
authors.lastname: He
authors.forename: Gai-Hong
authors.initials: GH
authors.lastname: Wang
authors.forename: Emilio F
authors.initials: EF
authors.lastname: Merino
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Yang
authors.forename: Rong-Xiu
authors.initials: RX
authors.lastname: Zhu
authors.forename: Li-She
authors.initials: LS
authors.lastname: Gan
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Maria B
authors.initials: MB
authors.lastname: Cassera
authors.forename: He-Yao
authors.initials: HY
authors.lastname: Wang
authors.forename: David G I
authors.initials: DG
authors.lastname: Kingston
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Yue
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019281:Dimerization; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D029582:Meliaceae / Q000737:chemistry*; D008968:Molecular Conformation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004224:Diterpenes; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C494881:DGAT1 protein, human; C494885:DGAT2 protein, human; D051048:Diacylglycerol O-Acyltransferase