VITAMIN D--CHEMICAL AND RELATED STUDIES

这项研究的一个基本前提是， 三烯的理论研究将为我们的研究提供重要的投入。 了解维生素D的生化作用模式。 后者 这反过来又会导致对这一问题采取更准确和更实际的办法， 与维生素D相关的代谢相关的疾病状态的治疗 紊乱 化学合成的发展将有助于准备 各种代谢物以及新的类似物，通过结构- 功能分析提供了有关作用机制的信息， 维生素D. 了解化学过程的特点， 维生素D或模型三烯从一个机械和理论 这一观点也有助于更好地理解 维生素D的行为的化学/生化机制，并提供一个 更有效地设计类似物的论坛。 具体目标包括： (1)[1，5] -和[1，7]-σ迁移氢位移的基础研究（其中 建议：（a）定量评估立体化学需求， [1，5]-和[1，7]-H通过取代基效应的组合发生位移， 基质结构变化和动力学同位素效应研究;（B） 研究在课程中控制横向双键几何形状的因素 这些氢转移;和（c）进行我们的探索性研究， 乙烯基丙二烯类金属有机配合物的热行为;（2）研究 维生素D类似物（其中建议：（a）化学和 生物学评价前维生素代谢物和类似物及其 转化为相应的维生素;（B）设计、合成和 生物学评价1 α-羟化酶抑制剂;和（c）合成 光亲和标记的维生素D类似物，并开发结构- 维生素D代谢物的功能关系，通过新的研究 类似物，特别是具有修饰的CD环的那些;和（3）合成的 与维生素D类似物和代谢物（其中合成的 将制定方法，以更有效地执行上述各项 具体目标，这些将包括多烯亚砜的发展 和基于丙二烯基锂的方法来全部或部分合成 维生素D代谢物或类似物）。

A basic premise of this study is that synthetic, mechanistic and theoretical studies of trienes will provide significant input in our understanding of the biochemical mode-of-action of vitamin D. The latter in turn should lead to a more precise and practical approach to the treatment of disease states associated with vitamin D-related metabolic disorders. The chemical synthesis developments will assist in preparing various metabolites as well as new analogs, which through structure- function analyses provide information concerning the mechanism of action of vitamin D. An understanding of chemical processes characteristic of vitamin D or model trienes from both a mechanistic and theoretical standpoint should also lead to a better understanding of the chemical/biochemical mechanism of the behavior of vitamin D and provide a forum for more effectively designing analogs. The specific aims include: (1) basic studies of [1,5] - and [1,7]-sigmatropic hydrogen shifts (wherein it is proposed to: (a) evaluate quantitatively the stereochemical demands of [1,5]- and [1,7]-H shifts through a combination of substituent effect, substrate structural variation and kinetic isotope effect studies; (b) study factors which govern lateral double bond geometries during the course of these hydrogen shifts; and (c) carry our exploratory studies of the thermal behavior of organometallic complexes of vinylallenes; (2) studies of vitamin D analogs (wherein it is proposed to : (a) chemically and biologically evaluate previtamin metabolites and analogs and their conversion to the corresponding vitamins; (b) design, synthesize and biologically evaluate inhibitors of 1alpha-hydroxylase; and (c) synthesize photoaffinity labeled analogs of vitamin D and also develop structure- function relationships for vitamin D, metabolites via studies of new analogs, particularly those with modified CD rings; and (3) synthetic studies related to vitamin D analogs and metabolites (wherein synthetic methods will be developed to more effectively implement the preceding specific aim and these will include the development of polyene sulfoxide and allenyllithium based approaches to the total or partial synthesis of vitamin D metabolites or analogs).