A continuation of synthetic chemical work relating to the vitamin D2 metabolite series is proposed. Planned new efforts are based directly on progress made thus far which includes the development of synthetic routes to 25-hydroxyvitamin D2 and 1a, Alpha25-dihydroxyvitamin D2 and their corresponding 24R-methyl epimers. Hence, proposed continued work focuses on exploiting this method development effort by preparing larger amounts of these metabolites and their epimers, and by synthesizing the corresponding tritium-labeled forms. In addition, the preparation of certain sidechain analogs of the natural products (modified at C-24 and/or at the double-bond site) to explore the effect of distinct structural parameters on the expression of biological activity. Since available bioassay results have shown the synthetic 24R-epimer of (1alpha,25-(OH)2D2 to exhibit differential activity in intestine vs. bone, detailed biological assays (including bone histological measurements) and some metabolism work is planned to explore and explain this unique phenomenon. All other analogs synthesized will also be tested in rats and chicks, to obtain data on the potency of these compounds in stimulating intestinal calcium and phosphate transport, bone mineral mobilization, and bone mineralization. The activity of synthetic vitamin D2 compounds in promoting the differentiation human myeloid leukemia cells will also be investigated in human promyelocytic HL-60 cell cultures.
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| Ostrem, V K; Lau, W F; Lee, S H et al. (1987) Induction of monocytic differentiation of HL-60 cells by 1,25-dihydroxyvitamin D analogs. J Biol Chem 262:14164-71 |
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