The Importance of Stereochemistry on the Actions of Vitamin D

Author(s): G. Chiellini, H. F. DeLuca.

Journal Name: Current Topics in Medicinal Chemistry

Volume 11 , Issue 7 , 2011

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Abstract:

The seco-steroid hormone 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is the most potent natural metabolite of vitamin D3 and regulates primarily calcium and phosphate homeostasis, but also as a regulator of specific differentiation and of the immune system. Most, if not all, of the biological actions of 1α,25(OH)2D3 are mediated through its specific receptor, the vitamin D receptor (VDR), which is a member of the nuclear receptor superfamily acting as a liganddependent transcription factor with coactivators. 1α,25(OH)2D3 has significant therapeutic potential in the treatment of osteoporosis, rickets, secondary hyperparathyroidism, psoriasis, and renal osteodystrophy. However, the use of 1α,25(OH)2D3 itself is limited because it induces significant hypercalcemia. Vitamin D is a highly flexible molecule and a very large number of analogs have been synthesized by industry and academia in an attempt to provide beneficial therapeutic agents with low calcemic activity. Chemical modifications of every portion of the vitamin D3 molecule (the A, C, and D rings, the 17β-aliphatic side chain, and the 5,6,7,8-diene moiety) have been reported, with the most of the interesting analogs resulting from a combination of several modifications. The three-dimensional structure of both rat and human VDR-LBD have provided significant information for our understanding of the structure-function relationship (SFR) of vitamin D and some synthetic analogs. In this review, we focus on the current understanding of the relationship between selected stereochemical modifications of key structural components (i.e. A-ring, CD-ring and Side-chain) of the 1α,25(OH)2D3 molecule and their effect on biological potency and selectivity. Based on current information, suggestions for the structure-based design of therapeutically valuable vitamin D analogs will conclude the review.

Keywords: Calcium homeostasis, 1,25-dihydroxyvitamin D analog, functions of vitamin D, stereochemistry, structure-activity relationship, tissue-selective activity, vitamin D metabolism, seco-steroid hormone, vitamin D receptor (VDR), of osteoporosis, rickets, renal osteodystrophy, structure-function relationship (SFR), vitamin D analogs, previtamin D3

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Article Details

VOLUME: 11
ISSUE: 7
Year: 2011
Page: [840 - 859]
Pages: 20
DOI: 10.2174/156802611795165016
Price: $58

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