VITAMINS A AND D: CHEMICAL AND RELATED STUDIES

建议从综合性、机械性和理论性三个方面进行研究。 多烯化学的几个方面，因为它们与化学和 维生素A(维甲酸)和维生素D(钙化醇)的生物学。除了他们的角色 在视觉和盐生细菌的能量传递过程中， 维甲酸在某些皮肤病的治疗中很有价值。 疾病，如维生素D，在细胞分化和增殖中 与癌症化学预防有关。1α，25-二羟基维生素D3(1α， 25-(OH)2-D3)，维生素D的激素活性形式，也是强烈的 感兴趣的疾病统计数据(例如，骨质疏松症) 钙代谢异常。这项研究的长期目标是 是在生物化学的分子水平上发展一种理解 这些多烯在穿越内分泌迷宫时的作用模式。是这样的 对这些生物活性物质的作用机理有详细的了解 多烯有望导致一种更精确和更实用的方法 维生素A和维生素D相关代谢紊乱的治疗。这个 目标包括：系统的、机械的和综合的调查 乙烯基烯和烯烃的热(1，5)-σ向移位 与维生素A和维生素D有关的环丙基烯类化合物和模型体系； 热反面(1，7)-Sigma向移位的详细研究 通过同位素标记和结构变化研究，以及 评价结果与生物学指标的关系 维生素D3前体和维生素D3生物合成的意义 一种战略上唯一的Seco-C-环策略的发展 维生素D类似物和代谢物的全合成.烯丙烷的研究 与手性非对映选择性合成有关的阴离子和双阴离子 烯烃，合成维生素A和维生素D的有用的合成中间体； 开发热法合成维生素A和维生素D类似物 乙烯基烯和其他多烯的异构化；在维甲酸中， 视觉色素类似物及模型体系的研究 合适底物诱导细胞的构效关系研究 分化和增殖；在骨化醇领域，研究 1α，25-(OH)2-D3在雏鸡肠道的激动剂和拮抗剂 受体水平、该受体的纯化及设计 参与维生素D代谢的酶的抑制剂，特别是在 肾脏水平。

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.