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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK016595-23
Application #
2391301
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1977-04-01
Project End
2001-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
23
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Chemistry
Type
Schools of Earth Sciences/Natur
DUNS #
City
Riverside
State
CA
Country
United States
Zip Code
92521
Okamura, William H; Zhu, Gui-Dong; Hill, David K et al. (2002) Synthesis and NMR studies of (13)C-labeled vitamin D metabolites. J Org Chem 67:1637-50
Hayashi, Rena; Fernandez, Susana; Okamura, William H (2002) An 8pi electron electrocyclization leading to a 9,19-methano-bridged analogue of 1 alpha,25-dihydroxyvitamin D3. Org Lett 4:851-4
Norman, Anthony W; Okamura, William H; Bishop, June E et al. (2002) Update on biological actions of 1alpha,25(OH)2-vitamin D3 (rapid effects) and 24R,25(OH)2-vitamin D3. Mol Cell Endocrinol 197:1-13
Okamura, W H; Do, S; Kim, H et al. (2001) Conformationally restricted mimics of vitamin D rotamers. Steroids 66:239-47
Norman, A W; Manchand, P S; Uskokovic, M R et al. (2000) Characterization of a novel analogue of 1alpha,25(OH)(2)-vitamin D(3) with two side chains: interaction with its nuclear receptor and cellular actions. J Med Chem 43:2719-30
Norman, A W; Song, X; Zanello, L et al. (1999) Rapid and genomic biological responses are mediated by different shapes of the agonist steroid hormone, 1alpha,25(OH)2vitamin D3. Steroids 64:120-8
Song, X; Bishop, J E; Okamura, W H et al. (1998) Stimulation of phosphorylation of mitogen-activated protein kinase by 1alpha,25-dihydroxyvitamin D3 in promyelocytic NB4 leukemia cells: a structure-function study. Endocrinology 139:457-65
Norman, A W; Okamura, W H; Hammond, M W et al. (1997) Comparison of 6-s-cis- and 6-s-trans-locked analogs of 1alpha,25-dihydroxyvitamin D3 indicates that the 6-s-cis conformation is preferred for rapid nongenomic biological responses and that neither 6-s-cis- nor 6-s-trans-locked analogs are preferred for ge Mol Endocrinol 11:1518-31
Muralidharan, K R; Rowland-Goldsmith, M; Lee, A S et al. (1997) Inhibitors of 25-hydroxyvitamin D3-1alpha-hydroxylase: thiavitamin D analogs and biological evaluation. J Steroid Biochem Mol Biol 62:73-8
Norman, A W; Bishop, J E; Collins, E D et al. (1996) Differing shapes of 1 alpha,25-dihydroxyvitamin D3 function as ligands for the D-binding protein, nuclear receptor and membrane receptor: a status report. J Steroid Biochem Mol Biol 56:13-22

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