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 i nclude: (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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK016595-21
Application #
2137012
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1977-04-01
Project End
1996-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
21
Fiscal Year
1995
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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