Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
Arch Biochem Biophys. 2012 Jul 1;523(1):48-57. doi: 10.1016/j.abb.2011.11.010. Epub 2011 Nov 15.
The growing interest in1α,25(OH)(2)D(3), the hormonally active form of vitamin D(3), has prompted numerous efforts to synthesize vitamin D analogs as potential therapeutic agents, and some of these are already on the market and in clinical development. Although most vitamin D preparations developed thus far have focused on side-chain modifications, providing many useful analogues with high potency and selectivity, in recent years, modifications of the A-ring has attracted much attention because it can afford useful analogues exhibiting unique activity profiles as well. In this review we will focus on the current understanding of the relationship between selected modifications in the A-ring of the 1α,25(OH)(2)D(3) molecule, such as epimerization and/or substitution at C-1 and C-3, substitution at C-2, and removal of the 10,19-exocyclic methylene group, and their effect on biological potency and selectivity. Finally, suggestions for the structure-based design of therapeutically valuable A-ring vitamin D analogs will conclude the review.
人们对 1α,25(OH)(2)D(3）（维生素 D(3）的活性形式）的兴趣日益浓厚，这促使人们努力合成维生素 D 类似物作为潜在的治疗剂，其中一些已经上市并处于临床开发阶段。尽管迄今为止开发的大多数维生素 D 制剂都集中在侧链修饰上，提供了许多具有高效力和选择性的有用类似物，但近年来，A 环的修饰引起了广泛关注，因为它可以提供具有独特活性谱的有用类似物。在这篇综述中，我们将重点介绍对 1α,25(OH)(2)D(3）分子 A 环中某些修饰（如 C-1 和 C-3 的差向异构化和/或取代、C-2 的取代以及 10、19-环外亚甲基的去除）与生物效力和选择性之间关系的最新认识。最后，我们将对基于结构的治疗价值 A 环维生素 D 类似物的设计提出建议。
