title: Total synthesis, assignment of the absolute stereochemistry, and structure-activity relationship studies of subglutinols A and B.
abstract: Immunosuppressive drugs are used to prevent rejection of transplanted organs and treat autoimmune diseases. Clinically approved immunosuppressive drugs possess undesirable side effects, including acute neurological toxicity, chronic nephrotoxicity, and osteoporosis. As a result, considerable efforts have been devoted to the identification of immunosuppressive natural products that lack cytotoxicity and undesirable side effects on bone structure. Subglutinols A (1 a) and B (1 b) are diterpene pyrones isolated from Fusarium subglutinans. Compounds 1 a and 1 b are equipotent in the mixed lymphocyte reaction assay and thymocyte proliferation assay (IC(50) = 0.1 microM). Owing to the lack of toxicity, 1 a and 1 b are expected to be promising new immunosuppressive drugs. Herein, we detail our efforts that have culminated in a stereoselective synthesis of 1 a and 1 b from the (S)-(+)-5-methyl-Wieland-Miescher ketone and determined their absolute stereochemistries. We also present initial biological data to show the great potential of 1 a as an immunosuppressive drug with dose-dependent osteogenic activity.
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27708, USA.
authors.forename: Hyoungsu
authors.initials: H
authors.lastname: Kim
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Baker
authors.forename: Yongho
authors.initials: Y
authors.lastname: Park
authors.forename: Hyung-Bae
authors.initials: HB
authors.lastname: Park
authors.forename: Patrick D
authors.initials: PD
authors.lastname: DeArmond
authors.forename: Seong Hwan
authors.initials: SH
authors.lastname: Kim
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fitzgerald
authors.forename: Dong-Sup
authors.initials: DS
authors.lastname: Lee
authors.forename: Jiyong
authors.initials: J
authors.lastname: Hong
mesh_terms: D000818:Animals; D002460:Cell Line; D003300:Copper / Q000737:chemistry; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005670:Fusarium / Q000737:chemistry; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004224:Diterpenes; D007166:Immunosuppressive Agents; D011753:Pyrones; C551806:subglutinol A; C551807:subglutinol B; D003300:Copper