PREPARATION OF VITAMIN D ANALOGS AND METABOLITES

拟议的研究涉及化学合成和生物学评价 新的维生素D3（胆钙化醇，D3）类似物和代谢物。 化学 开发研究包括：（a）乙烯基丙二烯法构建 l-羟基维生素D系统;（B）1 α， 25-二羟维生素D3（1 α，25-（OH）2-D3）;（c） 乙烯基丙二烯化学（（1，5）-σ迁移，手性金属-丙二烯， （d）（1，7）-σ迁移机理; (e)D3，25-羟基维生素的还原、氧化和光化学反应 D3（25-OH-D3）和1 α，25-（OH）2-D3。 使用乙烯基丙二烯或其它方法， 我们计划合成一些可能有用的类似物和代谢物 对于我们理解维生素D在分子水平上的作用方式， 内分泌系统。 合成的靶标包括：（a）A-环、侧链、C/D 1 α 25-（OH）2-D3、25-OH-D3和D3的环和三烯修饰的类似物;（B） 代谢物和/或催化剂。 这些类似物，可以被分类为 激动剂、拮抗剂或协同剂对于确定 结构、立体化学和构象要求 或最小的体外受体结合和体内生物活性。 的 合成激动剂将在鸡肠受体中进行体外评价 和假定的骨受体测定系统和研究将进行相关 结果与体内肠钙吸收和骨钙 动员数据。 尝试鉴定拮抗剂，特别是抗-l α，25-（OH）2-D 3因子在治疗癌症中的可能应用， 和增效剂将继续。 的结构鉴定和合成 将尝试最近发现的以及推定的新代谢物。 与10，19-二氢维生素相关的类似物将进一步检查其 在制备亲和层析系统中的可能应用， 用于开发D-代谢物的放射免疫分析。 质谱和其他 维生素D类固醇的光谱研究将继续进行。 立体结构和 将开始对大环内酯类抗生素filipin进行生物学研究。

The proposed research concerns the chemical synthesis and biological evaluation of new vitamin D3 (cholecalciferol, D3) analogs and metabolites. Chemical development studies include: (a) the vinylallene method for constructing the l-hydroxyvitamin D system; (b) the total synthesis of 1 alpha, 25-dihydroxyvitamin D3 (1 alpha, 25-(OH)2-D3); (c) fundamental studies of vinylallene chemistry ((1,5)-sigmatropic shifts, chiral metallo-allenes, dienallenes and cyclopropylallenes); (d) mechanism of (1,7)-sigmatropic shifts; (e) reduction, oxidation and photochemical reactions of D3, 25-hydroxy-vitamin D3 (25-OH-D3) and 1 alpha, 25-(OH)2-D3. Using the vinylallene or other methods, we plan to synthesize a number of analogs and metabolites which may be useful for our understanding the mode of action of vitamin D at the molecular level in its endocrine system. Synthetic targets include: (a) A-ring, side chain, C/D ring and triene modified analogs of 1 alpha 25-(OH)2-D3, 25-OH-D3, and D3; (b) metabolites and/or catabolites. These analogs, which can be classified as agonists, antagonists or synergists, are of importance for determining the structural, stereochemical and conformation requirements necessary for optimal or minimal in vitro receptor binding and in vivo biological activity. The synthetic agonists will be evaluated in vitro in the chick intestinal receptor and putative bone receptor assay systems and studies will be made to correlate the results with in vivo intestinal calcium absorption and bone calcium mobilization data. Attempts to identify antagonists, particularly an anti-l alpha, 25-(OH)2-D3 factor with possible application in the treatment of cancer, and synergists will continue. The structural elucidation and synthesis of recently discovered as well as putative new metabolites will be attempted. Analogs related to 10,19-dihydrovitamins will be further examined for their possible application in the preparation of affinity chromatography systems and for developing a radio-immunoassay for D-metabolites. Mass spectral and other spectroscopic studies of vitamin D steroids will continue. Stereostructural and biological studies of the macrolide antibiotic filipin will be initiated.