title: Structures, chemotaxonomic significance, cytotoxic and Na(+),K(+)-ATPase inhibitory activities of new cardenolides from Asclepias curassavica.
abstract: Five new cardenolide lactates (1–5) and one new dioxane double linked cardenolide glycoside (17) along with 15 known compounds (6–16 and 18–21) were isolated from the ornamental milkweed Asclepias curassavica. Their structures were elucidated by extensive spectroscopic methods (IR, UV, MS, 1D- and 2D-NMR). The molecular structures and absolute configurations of 1–3 and 17 were further confirmed by single-crystal X-ray diffraction analysis. Simultaneous isolation of dioxane double linked cardenolide glycosides (17–21) and cardenolide lactates (1–5) provided unique chemotaxonomic markers for this genus. Compounds 1–21 were evaluated for the inhibitory activities against DU145 prostate cancer cells. The dioxane double linked cardenolide glycosides showed the most potent cytotoxic effect followed by normal cardenolides and cardenolide lactates, while the C21 steroids were non-cytotoxic. Enzymatic assay established a correlation between the cytotoxic effects in DU145 cancer cells and the Ki for the inhibition of Na(+),K(+)-ATPase. Molecular docking analysis revealed relatively strong H-bond interactions between the bottom of the binding cavity and compounds 18 or 20, and explained why the dioxane double linked cardenolide glycosides possessed higher inhibitory potency on Na(+),K(+)-ATPase than the cardenolide lactate.
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China. trwjiang@jnu.edu.cn.
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Zhang
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Tian
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Tan
authors.forename: Tse-Yu
authors.initials: TY
authors.lastname: Chung
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Sun
authors.forename: Xue
authors.initials: X
authors.lastname: Xia
authors.forename: Wen-Cai
authors.initials: WC
authors.lastname: Ye
authors.forename: David A
authors.initials: DA
authors.lastname: Middleton
authors.forename: Natalya
authors.initials: N
authors.lastname: Fedosova
authors.forename: Mikael
authors.initials: M
authors.lastname: Esmann
authors.forename: Jason T C
authors.initials: JT
authors.lastname: Tzen
authors.forename: Ren-Wang
authors.initials: RW
authors.lastname: Jiang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D031108:Asclepias / Q000737:chemistry*; D002298:Cardenolides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002298:Cardenolides; D004791:Enzyme Inhibitors; D000254:Sodium-Potassium-Exchanging ATPase