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.
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