Date of Completion

1-22-2018

Embargo Period

7-21-2018

Keywords

VD3, Hedgehog Signaling, Oxysterols, BCC, VDR

Major Advisor

M. Kyle Hadden

Associate Advisor

Dennis Wright

Associate Advisor

Andrew Wiemer

Associate Advisor

Brian Aneskievich

Associate Advisor

Mark Peczuh

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The Hedgehog (Hh) pathway is a development pathway with therapeutic potential as a target for treatment of cancers and degenerative disorders. Multiple agonists of Hh signaling have been investigated to treat degenerative disorders, oxysterols (OHCs) have been the most well studied. A series of OHC analogues were synthesized with modifications at the C-20 position to further study binding. Combined with modeling studies, inverting the C-20 stereochemistry was determined to switch the activity of the analogues from agonist to antagonists. Additional studies suggested that inversion rigidified the alkyl side chain to increase interactions leading to the activity change. Among the scaffolds under investigation as anti-cancer chemotherapeutics and antagonists of Hh signaling is vitamin D3 (VD3). Previous structure-activity relationship studies contained both modified A- and seco-B ring motifs, and provided potent and selective analogues for Hh signaling. To continue studies on this scaffold, new series of compounds were synthesized to explore additional interactions and spatial constraints. While large hydrophobic moieties at the C-11 position resulted in significant loss of Hh inhibition, smaller or more flexible moieties maintained anti-Hh activity. Hydroxylation at the C-25 position significantly increased VDR activation while also increasing anti-Hh potency for most analogues. Masking the hydroxyl group as a methyl ether could regain selectivity for Hh signaling with minor losses in anti-Hh activity. Mechanism of action studies have been contradictory, but suggest the vitamin D receptor (VDR) plays a role in inhibiting Hh signaling. These results call for additional and continued studies to identify the binding target and pocket to better understand these structure-activity relationships.

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