VITAMIN D--CHEMICAL AND RELATED STUDIES

这项研究的一个基本前提是，综合的、机械的和 对三烯的理论研究将为我们的 对维生素D的生化作用模式的理解后者 进而应导致更精确和实用的方法来处理 维生素D相关代谢相关疾病状态的治疗 精神错乱。化学合成的进展将有助于制备 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其作用机制的信息 维他命D：了解维生素D的化学过程 来自机理和理论的维生素D或模型三烯 立场也应该有助于更好地理解 维生素D行为的化学/生化机制，并提供 更有效地设计类比的论坛。具体目标包括： (1)[1，5]-和[1，7]-Sigmatroic氢转移的基础研究(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移动， 底物结构变化和动力学同位素效应研究； 研究影响侧链双键几何构型的因素 ；及(C)进行有关氢转移的探索性研究。 乙烯基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 维他命前体代谢物及其类似物的生物学评价 转化为相应的维生素；(B)设计、合成和 1α-羟基酶抑制剂的生物学评价；和(C)合成 光亲和力标记的维生素D类似物，还开发了结构- 通过研究新的维生素D代谢物的功能关系 类似物，特别是那些具有修饰CD环的类似物；和(3)合成的 与维生素D类似物和代谢物相关的研究(其中合成 将开发方法以更有效地实现前面的 具体目标，其中将包括开发聚烯亚砜 和基于烯基锂的全部或部分合成方法 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).