title: Bioactivity-guided isolation of antiproliferative diterpenoids from Euphorbia kansui.
abstract: Cytotoxic assay guided multistep separation on the dichloromethane extract of the roots of Euphorbia kansui resulted in the isolation of 10 ingenol-type diterpenoids (1-4 and 7-12), of which, 5-O-(2'E,4'E-decadienoyl)-20-O-acetylingenol (1) is a new compound, and two are jatrophane-type diterpenoids (13-14). Interconversion of two pairs of positional ester isomers (1-4) in aqueous alcoholic solution was observed, the transesterification mechanism of which was speculated and confirmed by acylation of 3 and 4 to 6 and 5, respectively. All the isolates and the two acyl derivatives (5 and 6) were evaluated in vitro for their cytotoxicities in Bel-7402, Bel-7402/5FU, BGC-823 and SGC-7901 cell lines. The 12 ingenol-type diterpenoids exhibited weak to moderate cytotoxicities, whereas the two jatrophane-type diterpenoids displayed no antiproliferative effects, which, however, may increase the antitumour efficacy of those ingenol-type diterpenoids. The structure--activity relationships were investigated by principal component analysis (PCA) of the pIC₅₀ (-logIC₅₀) values of the compounds tested and their calculated molecular descriptors. The pIC₅₀ values were highly correlated with most descriptors, especially the highest occupied molecular orbital energy (E(HOMO)), absolute hardness (η) and positively charged solvent accessible surface areas (P-ASA). As the values of E(HOMO) increase, η and P-ASA decrease, and the antiproliferative effects of these compounds increase.
authors.affiliation: Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
authors.forename: Hong-Ying
authors.initials: HY
authors.lastname: Wang
authors.forename: Jun-Song
authors.initials: JS
authors.lastname: Wang
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Wei
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Yang
authors.forename: Ling-Yi
authors.initials: LY
authors.lastname: Kong
mesh_terms: D000215:Acylation; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D001681:Biological Assay / Q000379:methods; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D028481:Euphorbia / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D018517:Plant Roots / Q000737:chemistry*; D025341:Principal Component Analysis; D012997:Solvents; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D012997:Solvents; C008125:ingenol