Bioorganic and Medicinal Chemistry Letters
Bioorganic and Medicinal Chemistry Letters
4 years ago

Synthesis and evaluation of vitamin D3 analogues with C-11 modifications as inhibitors of Hedgehog signaling

Synthesis and evaluation of vitamin D3 analogues with C-11 modifications as inhibitors of Hedgehog signaling
Previous structure-activity relationship studies have provided potent and selective analogues of vitamin D3 as inhibitors of the Hedgehog (Hh) signaling pathway. These analogues contain both modified A- and seco-B ring motifs, and have been evaluated for anticancer therapeutic potential. To continue our studies on this scaffold, a new series of compounds were synthesized to explore additional interactions and spatial constraints. These compounds incorporate functional groups of varying size and hydrophobicity at the C-11 position. While large hydrophobic moieties (9c–e) resulted in significant loss of Hh inhibition, smaller or more flexible moieties (9a, 11) maintain anti-Hh activity. These results call for additional and continued studies to identify the binding pocket to better understand these structure-activity relationships.

Publisher URL: www.sciencedirect.com/science

DOI: S0960894X17307667

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