VITAMINS A AND D: CHEMICAL AND RELATED STUDIES

建议从综合、机理和理论三个方面进行研究

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.