Olivera Christopher J, Bula Craig M, Bishop June E, Adorini Luciano, Manchand Percy, Uskokovic Milan R, Norman Anthony W
Department of Biochemistry, University of California, Riverside, CA 92521, USA.
J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):99-106. doi: 10.1016/j.jsbmb.2004.04.001.
The steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) [1alpha,25(OH)(2)D(3)] exerts a wide variety of biological actions through one or more receptors/binding proteins. The nuclear Vitamin D receptor (VDR) when bound to its natural ligand, 1alpha,25(OH)(2)D(3), can stimulate transcription of a wide variety of genes. The synthesis of 1alpha,25(OH)(2)D(3) analogs allows the study of structure-function relationships between ligand and the VDR. 1alpha,25(OH)(2)D(3) is a conformationally flexible molecule; specifically the side-chain of the hormone can display a large variety of shapes for its receptor. Here, we describe and analyze the properties of 10 1alpha,25(OH)(2)D(3) analogs modified at the side-chain of which five lack carbon-19 (19-nor) but have a novel 20-cyclopropyl functionality. Analog NG [20,21-methylene-23-yne-26,27-F(6)-19-nor-1alpha,25(OH)(2)D(3)] possesses a respectable binding affinity for the VDR and exhibits a high transcriptional activity (EC(50) approximately 10pM), while retaining low induction of hypercalcemia in vivo in the mouse, making it a primary candidate for further analyses of its anti-proliferative and/or cell differentiating properties.
类固醇激素1α,25(OH)₂-维生素D₃[1α,25(OH)₂D₃]通过一种或多种受体/结合蛋白发挥多种生物学作用。核维生素D受体（VDR）与其天然配体1α,25(OH)₂D₃结合时，可刺激多种基因的转录。1α,25(OH)₂D₃类似物的合成有助于研究配体与VDR之间的结构-功能关系。1α,25(OH)₂D₃是一种构象灵活的分子；具体而言，该激素的侧链对于其受体可呈现多种形状。在此，我们描述并分析了10种在侧链处进行修饰的1α,25(OH)₂D₃类似物的性质，其中5种缺乏碳-19（19-去甲）但具有新型的20-环丙基官能团。类似物NG [20,21-亚甲基-23-炔-26,27-F₆-19-去甲-1α,25(OH)₂D₃]对VDR具有可观的结合亲和力，并表现出高转录活性（半数有效浓度约为10pM），同时在小鼠体内保持低血钙诱导作用，这使其成为进一步分析其抗增殖和/或细胞分化特性的主要候选物。
