VITAMINS A AND D: CHEMICAL AND RELATED STUDIES

本文拟从合成、机理和理论三个方面进行研究。 多烯化学的方面，因为它们涉及化学和 维生素A（类维生素A）和维生素D（钙化醇）的生物学。 除了他们的角色 在视觉和盐生盐杆菌的能量转换过程中， 类维生素A在某些皮肤病的治疗中是有意义的 维生素D在细胞分化和增殖中的作用， 与癌症化学预防有关。 1 α，25-二羟基维生素D3（1 α， 25-（OH）2-D3），维生素D的代谢活性形式，也具有强烈的 在疾病统计方面的兴趣（例如，骨质疏松症）与 钙代谢异常。 这项研究的长期目标是 是在分子水平上理解生物化学 这些多烯的作用模式，因为他们穿越内分泌迷宫。 等 详细了解这些生物活性物质的作用机制， 多烯预计将导致更精确和实用的方法， 治疗维生素A和维生素D相关的代谢紊乱。 的 目的包括：系统的机制和综合研究， 乙烯基联烯的热（1，5）-σ迁移以及 与维生素A和D相关的环丙基丙二烯和模型系统; 详细研究了热反面（1，7）-σ位移 通过同位素标记和结构变异研究， 评价结果与生物学的关系 前维生素D3的意义和维生素D3的生物合成; 制定了一个战略性的独特的seco-C-ring战略， 维生素D类似物和代谢物的全合成; 阴离子和二价阴离子的非对映选择性合成手性 丙二烯，用于维生素A和D合成的有用的合成中间体; 开发通过热合成维生素A和D类似物的方法 乙烯基丙二烯和其它多烯的异构化;在类视色素Aresa中， 视觉色素类似物和模型系统的研究以及 诱导细胞适宜底物构效关系研究 分化和增殖;在钙化醇领域， 1 α，25-（OH）2-D3在鸡肠道的激动剂和拮抗剂 受体水平，该受体的纯化和设计 参与维生素D代谢的酶的抑制剂，特别是在 肾水平

It is proposed to investigate the synthetic, mechanistic and theoretical aspects of polyene chemistry as they relate to both the chemistry and biology of vitamins A (retinoids) and D (calciferols). Besides their role in vision and in the energy transduction process of Halobacterium halobium, the retinoids are of interest in the treatment of certain dermatological diseases and, like vitamin D, in cell differentiation and proliferation as related to cancer chemoprevention. 1Alpha, 25-Dihydroxyvitamin D3 (1Alpha, 25-(OH)2-D3), the hormonally active form of vitamin D, is also of intense interst in terms of disease stats (e.g., osteoporosis) associated with abnormalities in calcium metabolism. The long-range goal of this research is to develop an understanding at the molecular level of the biochemical mode-of-action of these polyenes as they traverse the endocrine maze. Such a detailed understanding of the mechanism of action of these bioactive polyenes is expected to lead to a more precise and practical approach to the treatment of vitamin A- and vitamin D-related metabolic disorders. The aims include: systematic mechanistic and synthetic investigations of thermal (1,5)-sigmatropic shifts of vinyl-allenes as well as cyclopropylallenes related to vitamins A and D and model systems; a detailed investigation of thermal, antarafacial (1,7)-sigmatropic shifts through isotopic labeling and structural variation studies and an evaluation of the relationship of the results to the biological significance of previtamin D3 and the biosynthesis of vitamin D3; the development of a strategicaly unique seco-C-ring strategy for the formal total sysnthesis of vitamin D analogues and metabolites; studies of allenic anions and dianions pertinent to the diastereoselective synthesis of chiral allenes, useful synthetic intermediates for vitamin A and D syntheses; develop the synthesis of analogues of vitamins A and D via thermal isomerizations of vinylallenes and other polyenes; in the retinoids aresa, studies of visual pigment analogues and model systems as well as structure-activity studies of appropriate substrates in inducing cell differentiation and proliferation; and, in the calciferol area, studies of agonists and antagonists of 1 alpha, 25-(OH)2-D3 at the chick intestinal receptor level, the purification of this receptor and the design of inhibitors of enzymes involved in vitamin D metabolism, particularly at the renal level.