title: In vitro platelet-activating factor receptor binding inhibitory activity of pinusolide derivatives: a structure-activity study.
abstract: Pinusolide, a labdane-type diterpene lactone isolated from Biota orientalis, was found to be a potent platelet-activating factor (PAF) receptor binding antagonist. To investigate the structure-activity relationship and find derivatives with improved pharmacological profiles, 17 pinusolide derivatives were prepared and tested for their ability to inhibit the PAF receptor binding. The results demonstrated that the carboxymethyl ester group at C-19, the integrity of the alpha,beta-unsaturated butenolide ring, and the exocyclic olefinic function of pinusolide are all necessary for its maximum PAF receptor binding inhibitory activity. Among the derivatives, the 17-nor-8-oxo derivative 8 was found to be as potent as pinusolide. The results also suggested that several derivatives warrant further pharmaceutical and pharmacological studies due to their improved water solubility (8 and 11) and apparent lack of susceptibility to Michael-type nucleophilic addition (13 and 18).
authors.affiliation: Natural Products Research Institute, Seoul National University, 28, Yeongun-dong, Jongro-ku, Seoul 110-460, Korea.
authors.forename: B H
authors.initials: BH
authors.lastname: Han
authors.forename: H O
authors.initials: HO
authors.lastname: Yang
authors.forename: Y H
authors.initials: YH
authors.lastname: Kang
authors.forename: D Y
authors.initials: DY
authors.lastname: Suh
authors.forename: H J
authors.initials: HJ
authors.lastname: Go
authors.forename: W J
authors.initials: WJ
authors.lastname: Song
authors.forename: Y C
authors.initials: YC
authors.lastname: Kim
authors.forename: M K
authors.initials: MK
authors.lastname: Park
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D010972:Platelet Activating Factor / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013329:Structure-Activity Relationship
chemical_list: D004224:Diterpenes; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C101973:pinusolide