title: Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors.
abstract: A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 μM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269-3092, United States.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Deberardinis
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Madden
authors.forename: Upasana
authors.initials: U
authors.lastname: Banerjee
authors.forename: Vibhavari
authors.initials: V
authors.lastname: Sail
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Raccuia
authors.forename: Daniel
authors.initials: D
authors.lastname: De Carlo
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lemieux
authors.forename: Adam
authors.initials: A
authors.lastname: Meares
authors.forename: M Kyle
authors.initials: MK
authors.lastname: Hadden
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D053823:Hedgehog Proteins; D002762:Cholecalciferol