title: Design and synthesis of pyrrolidine-containing sphingomimetics.
abstract: Based on the structures of natural sphingolipids, we designed heterocyclic sphingoid base mimetics in which the conformational restriction is introduced by incorporation of a pyrrolidine moiety between the 2-amino group and the C-4 carbon atom of the sphingoid base. Our synthesis features a regioselective nucleophilic ring opening of a cyclic sulfate with cyanide and subsequent manipulation of the cyanide group. During the course of synthesis, Staudinger-type reductive cyclization of 1,3-azido carboxylic acid and 1,4-azido alcohol offers a direct route to the five-membered pyrrolidone and pyrrolidine products. The preliminary biological evaluation indicates that the designed pyrrolidine analog is biologically active and its cytotoxic effect is associated with the induction of apoptosis.
authors.affiliation: College of Pharmacy, Seoul National University, San 56-1, Shilim, Kwanak, Seoul 151-742, Korea.
authors.forename: Seokwoo
authors.initials: S
authors.lastname: Lee
authors.forename: Sukjin
authors.initials: S
authors.lastname: Lee
authors.forename: Hyen Joo
authors.initials: HJ
authors.lastname: Park
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
mesh_terms: D000438:Alcohols / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001386:Azides / Q000737:chemistry; D032701:Biomimetics; D002264:Carboxylic Acids / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003486:Cyanides / Q000737:chemistry; D003500:Cyclization; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013107:Sphingolipids / Q000138:chemical synthesis / Q000494:pharmacology; D013237:Stereoisomerism; D013431:Sulfates / Q000737:chemistry
chemical_list: D000438:Alcohols; D001386:Azides; D002264:Carboxylic Acids; D003486:Cyanides; D011759:Pyrrolidines; D011760:Pyrrolidinones; D013107:Sphingolipids; D013431:Sulfates