We report advances in the synthesis of a clickable probe to further the understanding of the pathogenesis of Smith-Lemili-Optiz Syndrome (SLOS). SLOS is a genetic disorder that is caused by a deficiency in functional 3�-hydroxysterol-?7 reductase (DHCR7), an enzyme that converts 7-dehydrocholesterol (7DHC) to cholesterol in cholesterol biosynthesis. This causes the buildup of 7DHC, a compound that is prone to form toxic oxysterols upon reaction with oxygen. Nucleophilic amino acid residues of proteins are likely to react with these 7DHC oxysterols by Michael addition, resulting in covalent protein modifications. The probe will contain an alkyne on the terminal carbons of 7DHC ligand chain. Probe-protein adducts can be captured on streptavidin after click derivatization of alkynyl adducts with a photocleavable azido-biotin tag. This synthesis would develop an effective probe to isolate and identify the affected proteins of improper cholesterol metabolism.

Synthesis of a clickable probe for electrophiles formed in sterol biosynthesis

243rd National Meeting (2012)

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