title: Inhibitors of 25-hydroxyvitamin D3-1alpha-hydroxylase: thiavitamin D analogs and biological evaluation.
abstract: Six A-ring analogs of 1alpha,25-dihydroxyvitamin D3 (1, 1alpha,25-(OH)2-D3) 3-deoxy-3-thia-1alpha,25-(OH)2-D3 (3), 3-deoxy-3-thia-1alpha,25-(OH)2-D3-3alpha-oxide (6), 3-deoxy-3-thia-1alpha,25-(OH)2-D3-3beta-oxide (7) and the 5,6-trans counterparts 5, 8, and 9, respectively--were tested for their ability to inhibit 25-hydroxy-D3-1alpha-hydroxylase (1-OH-ase) in vitro in mitochondria isolated from kidneys of vitamin D deficient chicks. The six analogs were also evaluated in terms of their ability to bind to the chicken intestinal nuclear receptor (VDR) in comparison to the natural hormone 1alpha,25-(OH)2-D3. Analog 7 is not only the best inhibitor of the 1-OH-ase but it also binds effectively to the chick intestinal receptor. It is established that vitamin D analogs must have a 1alpha oxygen group for effective inhibition of the 1-OH-ase. This functional group is also needed for effective binding to the chick intestinal VDR.
authors.affiliation: Department of Chemistry, University of California, Riverside 92521, U.S.A.
authors.forename: K R
authors.initials: KR
authors.lastname: Muralidharan
authors.forename: M
authors.initials: M
authors.lastname: Rowland-Goldsmith
authors.forename: A S
authors.initials: AS
authors.lastname: Lee
authors.forename: G
authors.initials: G
authors.lastname: Park
authors.forename: A W
authors.initials: AW
authors.lastname: Norman
authors.forename: H L
authors.initials: HL
authors.lastname: Henry
authors.forename: W H
authors.initials: WH
authors.lastname: Okamura
mesh_terms: D000818:Animals; D002645:Chickens; D053493:Cholestanetriol 26-Monooxygenase; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology*; D008928:Mitochondria / Q000201:enzymology*; D015394:Molecular Structure; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014808:Vitamin D Deficiency / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D014807:Vitamin D; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase