Characterization of five 19-nor-analogs of 1α,25(OH) 2-Vitamin D 3 with 20-cyclopropyl-modified side-chains: implications for ligand binding and calcemic properties

Abstract

The steroid hormone 1α,25(OH) 2-Vitamin D 3 [1α,25(OH) 2D 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, 1α,25(OH) 2D 3, can stimulate transcription of a wide variety of genes. The synthesis of 1α,25(OH) 2D 3 analogs allows the study of structure–function relationships between ligand and the VDR. 1α,25(OH) 2D 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 1α,25(OH) 2D 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-1α,25(OH) 2D 3] possesses a respectable binding affinity for the VDR and exhibits a high transcriptional activity (EC 50 ∼10 pM), 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.