title: Synthesis and Evaluation of Osteogenic Oxysterols as Hedgehog Pathway Activators.
abstract: Oxysterols (OHCs) are metabolic byproducts of cholesterol that are known to function as agonists of the Hedgehog (Hh) signaling pathway. Previously, we reported 23(S)-hydroxycholesterol [23(S)-OHC, 4] as a potent activator of Hh signaling with the ability to functionally differentiate mouse embryonic fibroblasts to an osteogenic fate. To obtain 23(S)-OHC in quantities suitable for in vivo evaluation, we developed a revised synthetic route that decreases the number of steps and chromatographic purifications, and which also enhances the stereoselective nature of the synthesis. This new route also allows access to the C21 methyl group of the OHC scaffold, and several new analogues with varying stereochemistry at this location were evaluated for their ability to up-regulate the Hh pathway.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT, 06269-3092, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Maschinot
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT, 06269-3092, USA.
authors.forename: Audrey R
authors.initials: AR
authors.lastname: Corman
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT, 06269-3092, USA.
authors.forename: Albert M
authors.initials: AM
authors.lastname: DeBerardinis
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT, 06269-3092, USA. kyle.hadden@uconn.edu.
authors.forename: M Kyle
authors.initials: MK
authors.lastname: Hadden
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D008968:Molecular Conformation; D000072376:Oxysterols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D053823:Hedgehog Proteins; D000072376:Oxysterols
keywords: Hedgehog; oxysterols; signal transduction; stereochemistry; structure-activity relationships