VITAMIN D: CHEMICAL AND RELATED STUDIES

本研究的一个基本前提是综合、机械和

A basic premise of this study is that synthetic, mechanistic and theoretical studies of trienes will provide significant input in our understanding of the biochemical mode-of-action of vitamin D. The latter in turn should lead to a more precise and practical approach to the treatment of disease states associated with vitamin D-related metabolic disorders. The chemical synthesis developments will assist in preparing various metabolites as well as new analogs, which through structure- function analyses provide information concerning the mechanism of action of vitamin D. An understanding of chemical processes characteristic of vitamin D or model trienes from both a mechanistic and theoretical standpoint should also lead to a better understanding of the chemical/biochemical mechanism of the behavior of vitamin D and provide a forum for more effectively designing analogs. The specific aims include: (1) basic studies of [1,5] - and [1,7]-sigmatropic hydrogen shifts (wherein it is proposed to: (a) evaluate quantitatively the stereochemical demands of [1,5]- and [1,7]-H shifts through a combination of substituent effect, substrate structural variation and kinetic isotope effect studies; (b) study factors which govern lateral double bond geometries during the course of these hydrogen shifts; and (c) carry our exploratory studies of the thermal behavior of organometallic complexes of vinylallenes; (2) studies of vitamin D analogs (wherein it is proposed to : (a) chemically and biologically evaluate previtamin metabolites and analogs and their conversion to the corresponding vitamins; (b) design, synthesize and biologically evaluate inhibitors of 1alpha-hydroxylase; and (c) synthesize photoaffinity labeled analogs of vitamin D and also develop structure- function relationships for vitamin D, metabolites via studies of new analogs, particularly those with modified CD rings; and (3) synthetic studies related to vitamin D analogs and metabolites (wherein synthetic methods will be developed to more effectively implement the preceding specific aim and these will include the development of polyene sulfoxide and allenyllithium based approaches to the total or partial synthesis of vitamin D metabolites or analogs).