Ring A-stereoisomers of 1-hydroxyvitamin D3 and their relative binding affinities for the intestinal 1α,25-dihydroxyvitamin D3 receptor protein |
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Authors: | H.E. Paaren W.S. Mellon H.K. Schnoes H.F. DeLuca |
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Affiliation: | Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 420 Henry Mall, Madison, Wisconsin 53706 USA |
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Abstract: | A set of eight 1-hydroxyvitamin D3 compounds comprising the four possible (5Z)-1,3-diol stereoisomers and the corresponding (5E)-double bond isomers, has been prepared in order to assess the effect of 1,3-diol stereochemistry and 5,6-double bond geometry on binding affinity for the intestinal 1,25-(OH)2D3-receptor protein. The compounds were synthesized from either vitamin D3 or 3-epivitamin D3 via 3,5-cyclovitamin D intermediates. Competitive receptor binding assays establish that all changes from the natural ring A-configuration (1S, 3R, 5Z) lead to decreased binding affinity, and confirm the importance of the 1-hydroxy function since the conversion of stereochemistry at that center from 1α(S) to 1β(R) has the most pronounced effect on binding affinity (attenuation by more than three orders of magnitude). Other modifications (i.e., conversion at C-3, or cis to trans isomerization of the 5,6-double bond) decrease binding affinity by more moderate (ca. 10-fold) but cumulative factors. |
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