Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela, Avda das Ciencias s/n, 15782 Santiago de Compostela, Spain.
Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela, Avda das Ciencias s/n, 15782 Santiago de Compostela, Spain.
Bioorg Chem. 2021 Jun;111:104878. doi: 10.1016/j.bioorg.2021.104878. Epub 2021 Mar 30.
The hypercalcemic effects of the hormone 1α,25-dihydroxyvitamin D (calcitriol) and most of known vitamin D metabolites and analogs call for the development of non secosteroidal vitamin D receptor (VDR) ligands as new selective and noncalcemic agonists for treatment of hyperproliferative diseases. We report on the in silico design and stereoselective synthesis of six lithocholic acid derivatives as well as on the calcemic activity of a potent LCA derivative and its crystallographic structure in complex with zVDR LBD. The low calcemic activity of this compound in comparison with the native hormone makes it of potential therapeutic value. Structure-function relationships provide the basis for the development of even more potent and selective lithocholic acid-based VDR ligands.
1α,25-二羟维生素 D（骨化三醇）和大多数已知的维生素 D 代谢物和类似物的高钙血症作用要求开发非甾体维生素 D 受体（VDR）配体作为治疗过度增殖性疾病的新型选择性和非钙调激活性激动剂。我们报告了六种石胆酸衍生物的计算设计和立体选择性合成，以及一种有效的 LCA 衍生物的钙调活性及其与 zVDR LBD 的晶体结构。与天然激素相比，该化合物的低钙调活性使其具有潜在的治疗价值。结构-功能关系为开发更有效和选择性的基于石胆酸的 VDR 配体提供了基础。
