Synthetic Strategy and Biological Activity of A-ring Stereoisomers of 1,25- Dihydroxyvitamin D₃ and C2-Modified Analogues

Abstract

The hormonally active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1a), has a wide variety of biological activities and its major molecular target is considered to be the vitamin D receptor (VDR). The A-ring stereoisomers of 1a as well as its C2-modified analogues, which have different stereochemistry at the C1 and/or C3 hydroxy groups, are of interest since recent metabolic studies have shown that catabolism could occur through A-ring modification. In this review, a practical and versatile synthesis of the A-ring enyne precursors by the convergent method of Trost and coworkers, which is needed to construct all possible A-ring stereoisomers of 1,25-dihydroxyvitamin D3 (1a-d), and the C2-modified analogues (4a-d, 5a-d, 6a-d and 7a-d) is described. A strategy for the synthesis and evaluation of all possible A-ring stereoisomers of 1a and their A-ring modified analogues is important, and this will stimulate synthesis and biological studies into vitamin D.

The genetic determinants of circulating C3-epimers of 25-hydroxyvitamin D

“…In the body, vitamin D is obtained from food (D 2 and D 3 ), supplementation (D 2 and D 3 ), or from cutaneous synthesis (D 3 ), and is metabolized further through C25-, C1- and C24-hydroxylation pathways [8] , [9] , [10] . These processes produce various forms of vitamin D such as 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH) 2 D], 24,25-dihydroxyvitamin D [(24R,25(OH) 2 D] [11] , [12] , [13] , [14] . Importantly, vitamin D can be metabolized through an alternative pathway or C3-epimerization [15] , [16] .…”