There is continuing and emerging new interest in the development of vitamin D analogs resulting from the recognition that analogs of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3] may be therapeutically useful. Side chain analogs of this steroid hormone are of particular interest because a family of lead structures have recently emerged for possible use in the treatment of certain types of cancers and skin diseases. Because of the chaotic array of side chain structures which exhibit useful therapeutic indices for these purposes, a more systematic approach towards developing intelligible structure-function information needs development. Accordingly, a method has been devised to analyze analogs as to their side chain topology based on identifying specific occupancy volumes through conformational analysis. Dot maps have been constructed as an indication of the volume in space which the side chain of 1 alpha,25-(OH)2-D3 or analogs is permitted to occupy. Volume exclusion analyses based on comparison of structural and biological data for 1 alpha,25-(OH)2-D3 and analogs are anticipated to lead to a more cogent model for drug design. A cautionary note on the limitations of this approach is discussed.
A homologous series of side-chain analogues of 25-hydroxyvitamin D3 (25-hydroxycholecalciferol) in which the length of the side chain is modified while maintaining its characteristic tertiary hydroxyl moiety has been synthesized. The following five analogues have been prepared and characterized: pentanor-25-OH-D3 (2a), trinor-25-OH-D3 (2b), dinor-25-OH-D3 (2c), nor-25-OH-D3 (2d), and homo-25-OH-D3 T2e). Biological assays in vivo of intestinal calcium absorption and bone calcium mobilization in the chick of the five analogues revealed that the homo analogue 2e exhibited a significant biological response relative to the -D (vitamin D3) control. Compared to the natural vitamin D3, 2e is as active in its ability to mobilize bone calcium and is about half as effective in stimulating intestinal calcium transport. The remaining analogues (2a-d) exhibited no significant activity in either assay, although the nor analogue 2d was previously observed to exhibit antimetabolite activity.
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