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Synthesis and Evaluation of Osteogenic Oxysterols as Hedgehog Pathway Activators
Author(s) -
Maschinot Chad A.,
Corman Audrey R.,
DeBerardinis Albert M.,
Hadden M. Kyle
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500550
Subject(s) - hedgehog signaling pathway , hedgehog , activator (genetics) , chemistry , in vivo , metabolic pathway , embryonic stem cell , function (biology) , signal transduction , biochemistry , microbiology and biotechnology , stereochemistry , enzyme , biology , receptor , genetics , gene
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.