Biological Activities of Active Vitamin D A-Ring Analogues

Abstract

The active vitamin D hormone, 1α,25-dihydroxyvitamin D_3 (1α,25(OH)_2D_3) exerts a variety of biological responses through the vitamin D_3 endocrine system. The endocrine system includes not only regulations of extracellular Ca metabolism in intestine, kidney and bone, but also modifications of immune responses, proliferation and differentiation of normal/malignant cells, and functions of many endocrine cells. In the vitamin D_3 endocrine system, plasma vitamin D-binding protein (DBP) and unclear vitamin D receptor (VDR) play key roles in the actions of 1 α,25(OH)_2D_3. Therefore, it will be important to evaluate structure/function relationship of active vitamin D analogues through their binding affinity for DBP and VDR in order to understand not only the detailed net work of the vitamin D_3 endocrine system, but also the concept for the development of new drugs for treatment of osteoporosis, renal osteodystrophy and cancers. In the recent years, structural modifications of 1α,25(OH)_2D_3, especially with regard to the side chain and the A ring of the molecule generate a wide variety of analogues with highly selective and/or active biological functions. We have synthesized the side chain analogue (22-oxa-1α,25(OH)_2D_3: OCT) and the A ring analogue (2β-hydroxypropoxy-1α,25(OH)_2D_3: ED-71) of 1α,25(OH)_2D_3 and their 1β-isomers and evaluated their biological activities and pharmacokinetic properties in vitamin D-deficient rats. 1β-isomers showed higher pharmacokinetic properties and lower biolgical activities compared to the respective 1α-isomers. To examine the stereoselective effect of the 1α- or 1β-hydroxyl group, the biological activities of the 1α,25(OH)_2D_3 analogues with substitutions on carbon-2 were examined. The substitutions of either 3-hydroxybutyl group or 3-hydroxypropoxyl group into the A ring increased their binding affinity for DBP and decreased the binding affinity for VDR as observed in the 1β-isomers, suggesting that the orientation of 1-hydroxyl group itself is not directly involved in the changes of the affinity for DBP and VDR. It is suggested that the conformation of the A-ring rather than the orientation (α or β) of 1-hydroxyl group may be a critical factor influencing the binding affinity for DBP and VDR, presumably pharmacokinetic properties and biological activities of the 1α,25(OH)_2D_3 analogues.