Inhibitors of 25-hydroxyvitamin D3-1alpha-hydroxylase: thiavitamin D analogs and biological evaluation.
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.
Muralidharan
K R
KR
Department of Chemistry, University of California, Riverside 92521, U.S.A.
Rowland-Goldsmith
M
M
Lee
A S
AS
Park
G
G
Norman
A W
AW
Henry
H L
HL
Okamura
W H
WH
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*
D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D014807:Vitamin D; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase