title: Synthesis and evaluation of colletoic acid core derivatives.
abstract: Cortisol homeostasis has been linked to the pathogenesis of metabolic syndrome (MetS), since it stimulates hepatic gluconeogenesis and adipogenesis. MetS is classified as a constellation of health conditions that increase the risk of type 2 diabetes and cardiovascular disease. Intracellular cortisol levels are regulated by 11β-hydroxysteroid dehydrogenase (type 1 and type 2) in a tissue dependent manner. The type 1 enzyme (11β-HSD1) is widely expressed in glucocorticoid targeted tissues and is responsible for the conversion of cortisone to the active cortisol. Local reduction of cortisol regeneration presents a potential strategy for MetS treatment. Recently we disclosed the total synthesis of (+)-colletoic acid as a potent 11β-HSD1 inhibitor. Herein, we describe our improved processing chemistry for the synthesis of the colletoic acid core to access a diverse number of derivatives for evaluation against 11β-HSD1. The Evan's chiral auxiliary was utilized to construct the acyclic precursor 12 to afford the acorane core 9 using a modified Heck reaction in excellent chemical yields. The colletoic acid core derivatives showed modest activity against 11β-HSD1 and will serve for further biological evaluation.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Taotao
authors.initials: T
authors.lastname: Ling
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Lekh Nath
authors.initials: LN
authors.lastname: Gautam
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Griffith
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Sourav
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Lang
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Shadrick
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Anang
authors.initials: A
authors.lastname: Shelat
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lee
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA. Electronic address: Fatima.rivas@stjude.org.
authors.forename: Fatima
authors.initials: F
authors.lastname: Rivas
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D012717:Sesquiterpenes; C532324:colletoic acid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone
keywords: (+)-colletoic acid; 11β-HSD1; 11β-HSD2; Metabolic syndrome