VITAMIN D--CHEMICAL AND RELATED STUDIES

这项调查的目标将继续是开发一个 在分子水平上详细了解作用机制 维生素D。通过设计、化学合成和生物 新类似物的评估、维生素 D 的适当结构评估 新类似物的代谢物和生物学评价，适当 维生素 D 代谢物和类似物的结构评估，两者都作为 游离配体并与宿主蛋白结合，以及结构功能元 分析我们自己的数据和文献数据，这是长期目标 是定义一个更精确和实用的治疗疾病的方案 与维生素 D 相关的内分泌紊乱有关的状态。 来自一个 从生物医学的角度来看，现在有很多病理学的例子 药物形式的维生素 D（一种类似物）会破坏正常状态 或代谢物）被认为是一种潜在有用的治疗形式， 例如它们在治疗各种癌症（乳腺癌、结肠癌和前列腺癌）中的用途 癌症和白血病）、骨骼和肾脏疾病（骨质疏松症、肾病 骨营养不良）、皮肤病（牛皮癣）、神经系统疾病 （阿尔茨海默病）、与免疫系统相关的问题（移植物） 排斥反应和几种自身免疫性疾病）以及艾滋病）。 的设计 类似物选择性地与靶组织相互作用然后激活靶组织， 大概通过受体介导的机制，是一个持续的目标 药物化学。 结构决定功能——就是这个底层 该提案所依据的论文。 本次活动的具体目标 提案包括； 目标 1，涉及化学合成和核 蛋白质结合的磁共振（NMR）光谱研究， 多种 C-13 标记的维生素 D 代谢物 [维生素 D3 (D3)； 25- 羟基维生素 D3 (25-D3)；和 1α,25-二羟基维生素 D3 (1,25-D3)] 作为 评估配体是 6-s-cis 还是 6-s-trans 构象的方法 参与蛋白质结合；目标 2，涉及设计和 6-s-cis 和 1,25-D3 相关类似物的化学合成和评价 和其他代谢物；目标 A-3，解决设计问题， 25-抑制剂的化学合成和生化评价 羟基维生素 D3-1α-羟化酶 (25-D3-1-OHase)，关键酶 参与 25-D 代谢活化为其最终产物的最后一步 激素活性形式、1,25-D3 以及维生素 D 代谢的其他方面； 目标 4，涉及选定的激动剂和拮抗剂的研究 维生素D受体；目标 5，预计将导致 立体选择性化学合成维生素D方法的发展 和相关的多烯。

The goal of this investigation will continue to be the development of a detailed understanding at the molecular level of the mechanism of action of vitamin D. Through the design, chemical synthesis and biological evaluation of new analogs, appropriate structural evaluation of vitamin D metabolites and biological evaluation of new analogs, appropriate structural evaluation of vitamin D metabolites and analogs, both as the free ligand and bound to host proteins, and structure-function meta analyses of our own data together with literature data,a the long term goal is to define a more precise and practical protocol for treating disease states associated with vitamin D-related endocrine disorders. From a biomedical standpoint, there are now many examples of pathological disruption of the normal state in which a drug form of vitamin D (an analog or metabolite) is proposed to be a potentially useful form of treatment, e.g. their use in treating various cancers (breast, colon and prostate cancers as well as leukemia), bone and kidney diseases (osteoporosis, renal osteodystrophy), skin diseases (psoriasis), neurological disorders (Alzheimer's disease), problems associated with the immune system (graft rejection and several autoimmune diseases) and also AIDS). The design of analogs to selectively interact with and then activate target tissues, presumably via a receptor mediated mechanism, is a continuing goal of medicinal chemistry. Structure determines function--it is this underlying thesis upon which this proposal is based. The specific aims of this proposal include; Aim 1, which concerns the chemical synthesis and nuclear magnetic resonance (NMR) spectroscopic investigations of protein bound, multiple C-13 labeled vitamin D metabolites [vitamin D3 (D3); 25- hydroxyvitamin D3 (25-D3); and 1alpha,25-dihydroxyvitamin D3 (1,25-D3)] as a means of assessing whether 6-s-cis or 6-s-trans conformations of ligand are involved in protein binding; Aim 2, which pertains tot he design and chemical synthesis and evaluation of 6-s-cis and related analogs of 1,25-D3 and other metabolites; Aim A-3, which addresses the problem of the design, chemical synthesis and biochemical evaluation of inhibitors of 25- hydroxyvitamin D3-1alpha-hydroxylase (25-D3-1-OHase), the key enzyme involved in the final step ina the metabolic activation of 25-D into its hormonally active form, 1,25-D3, and other aspects of vitamin D metabolism; Aim 4, which concerns studies of selected agonists and antagonists of vitamin D receptors; and Aim 5, which is expected to lead to the development of stereoselective chemical methods for synthesizing vitamin D and related polyenes.