VITAMIN D--CHEMICAL AND RELATED STUDIES

这项调查的目标将继续是发展一个 在分子水平上详细了解 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 代谢产物和新类似物的生物学评价，适当 维生素D代谢物和类似物的结构评价， 游离配体和结合宿主蛋白质，以及结构-功能Meta 分析我们自己的数据与文献数据，长期目标 是制定一个更精确和实用的治疗方案 与维生素D相关的内分泌失调。 从 从生物医学的角度来看，现在有许多病理性的例子， 破坏正常状态，其中维生素D的药物形式（类似物 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 癌症以及白血病）、骨和肾脏疾病（骨质疏松症、肾 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 排斥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， 可能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， 这一提议所依据的理论。 具体目标是 目标1，涉及化学合成和核 结合蛋白质的磁共振（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1 α，25-二羟基维生素D3（1，25-D3）]， 一种评估配体的6-s-顺式或6-s-反式构象的方法 参与蛋白质结合;目标2，涉及设计和 1，25-D3的6-S-顺式和相关类似物的化学合成和评价 和其他代谢物;目标A-3，它解决了设计的问题， 抑制剂的化学合成和生化评价 羟维生素D3- 1 α-羟化酶（25-D3-1-OHase），关键酶 参与25-D代谢活化的最后一步， 维生素D代谢的代谢活性形式，1，25-D3和其他方面; 目的4，其涉及选择的激动剂和拮抗剂的研究， 维生素D受体;以及Aim 5，预计将导致 立体选择性化学合成维生素D方法的研究进展 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.