| Research Abstract |
To clarify the stereochemical structure of the active form of vitamin D responsible for binding to the receptor (VDR), we analyzed the conformation of vitamin D by molecular mechanics method, designed and synthesized analogs of vitamin D whose conformations are restricted, and tested their affinity for VDR.
1) The analysis of the side chain conformation of 1,25 (OH) _2D_3 (1) and its 20-epi analog (2), showed that the side chains of these compounds occupies different spatial regions that are further separated in two areas.
2) Four analogs whose side chain are restricted to occupy each of these four spatial regions were designed and synthesized : They are four diastereomers at C (20) and C (22) of 22-methylated 1,25 (OH) _2D_3 (3,4,5, and 6).
3) The affinities of these four analogs for VDR and vitamin D binding protein (DBP) were examined. The 20R,22S-and 20S,22R-analogs 4 and 5 showed significant binding affinity for VDR.It should be noted that especially the potency of 5 was nearly 20 times higher than 1. The results indicate these spatial regions responsible for binding of 1 and 2 to VDR.For DBP only 4 showed significant affinity.
4) Analogs of 1,25 (OH) _2D_3 (1) which have a substituent at C (1) were synthesized to investigate the conformation and activity relationship of the A-ring. Introduction of only a methyl group at 1B-position of 1 reduced the affinity to VDR to 1/50 indicating the importance of the 1alpha-hydroxyl group.
5) We found for the first time a new photochemical isomerization of provitamin D which is caused by a substituent at C (1).
6) The method for synthesizing 19-Fluorovitamin D analogs via vitamin D-SO_2 adduct was developed.
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