25-羟基维生素D3-1α-羟化酶抑制剂：硫代维生素D类似物及其生物学评价

Inhibitors of 25-hydroxyvitamin D3-1alpha-hydroxylase: thiavitamin D analogs and biological evaluation.

作者信息

Muralidharan K R, Rowland-Goldsmith M, Lee A S, Park G, Norman A W, Henry H L, Okamura W H

机构信息

Department of Chemistry, University of California, Riverside 92521, U.S.A.

出版信息

J Steroid Biochem Mol Biol. 1997 May;62(1):73-8. doi: 10.1016/s0960-0760(97)00015-0.

DOI:10.1016/s0960-0760(97)00015-0

PMID:9366500

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.

摘要

测试了1α,25 - 二羟基维生素D3（1, 1α,25-(OH)2-D3）的六种A环类似物——3 - 脱氧 - 3 - 硫代 - 1α,25-(OH)2-D3（3）、3 - 脱氧 - 3 - 硫代 - 1α,25-(OH)2-D3 - 3α - 氧化物（6）、3 - 脱氧 - 3 - 硫代 - 1α,25-(OH)2-D3 - 3β - 氧化物（7）以及它们各自对应的5,6 - 反式类似物5、8和9——在体外对从维生素D缺乏雏鸡肾脏分离的线粒体中25 - 羟基 - D3 - 1α - 羟化酶（1 - OH - 酶）的抑制能力。与天然激素1α,25-(OH)2-D3相比，还评估了这六种类似物与鸡肠道核受体（VDR）结合的能力。类似物7不仅是1 - OH - 酶的最佳抑制剂，而且还能有效地与雏鸡肠道受体结合。已确定维生素D类似物必须具有1α氧基团才能有效抑制1 - OH - 酶。有效结合雏鸡肠道VDR也需要这个官能团。