Past Research Effort

Our principal research is in bioorganic chemistry complemented by extensive efforts in synthetic and mechanistic organic chemistry. We are particularly interested in the mechanism of hormone action and the molecular basis of drug design. We utilize biochemical and structural methods in addition to our efforts in the partial and total synthesis of biologically significant natural products.

More specifically, we are attempting to understand the precise topology of how steroid hormones such as 1a,25-dihydroxyvitamin D3 (1,25-D3) and other members of this superfamily of chemical messengers (cortisone, retinoids, thyroxine, etc.) bind to their respective receptor proteins, enzymes and other hosts. NMR investigations of synthetically derived, multiply 13C labeled 1,25-D3 bound to proteins and biological evaluation of conformationally locked synthetic analogs are expected to provide information regarding the shape of the ligand in protein active sites. This information should provide a clear molecular basis for steroid hormone drug design.

Recent studies have focused on Cholesterol, the most highly decorated small molecule in the biological sciences. We are attempting to understand how cholesterol binds to proteins by NMR investigations of 13C labeled substrates. The resulting structural information will provide information on how cholesterol is transported and how this steroid is associated with certain disease states such as atherosclerosis.

Recent Selected Publications

Okamura, W. H.; Zhu, G-D.; Hill, D. K.; Thomas, R. J.; Ringe, K.; Borchardt, D. B.; Norman, A. W.; Mueller, L. J. "Synthesis and NMR Studies of 13C-Labeled Vitamin D Metabolites," J. Org. Chem. 2002, 67, 1637-1650.

Hayashi, R.; Fernandez, S. M.; Okamura, W. H. "An 8p Electron Electrocyclization Leading to a 9,19-Methano Bridged Analogue of 1a,25-Dihydroxyvitamin D3," Org. Lett. 2002, 4, 851-854.

Okamura, W. H.; Do, S.; Kim, H.; Jeganathan, S.; Vu, T.; Zhu, G-D.; Norman, A. W. "Conformationally Restricted Mimics of Vitamin D Rotamers," Steroids 2001, 66, 239-247.

Reddy, G. S.; Muralidharan, K. R.; Okamura, W. H.; Tserng, K-Y.; McLane, J. A. "Metabolism of 1a,25-dihydroxyvitamin D3 and its C-3 epimer 1a,25-dihydroxy-3-epi-vitamin D3 in Neonatal Human Keratinocytes," Steroids 2001, 66, 441-450.

Hang, S.; Norman, A. W.; Okamura, W. H.; Sen, A.; Zemel, M. B. "1a,25-Dihydroxyvitamin D3 Modulates Human Adipocyte Metabolism via Nongenomic Actions," FASEB J. 2001, 15, 2751-2753.

Tan, E. S.; Tham, F. S.; Okamura, W. H. "Vitamin D1," Chem. Commun. 2000, 2345-2346.

Norman, A. W.; Manchand, P. S.; Uskokovic, M.; Okamura, W. H.; Takeuchi, J. A.; Bishop, J. E.; Hisatake, J-I.; Koeffler, H. P.; Peleg, S. "Characterization of a Novel Analog of 1a,25-(OH)2-Vitamin D3 with Two Side Chains: Interaction with its Nuclear Receptor," J. Medicinal Chem. 2000, 43, 2719-2730.

Overviews

Okamura, W. H.; Zhu, G.-D. "Chemistry and Design: Structural Biology of Vitamin D Action," in Vitamin D, D. Feldman; F. H. Glorieux; J. W. Pike, eds.; Academic Press: San Diego, 1997, pp. 939-971.

Okamura, W. H.; Midland, M. M.; Hill, D. K.; Ringe, K.; Takeuchi, J. A.; Vassar, V. C.; Vu, T. H.; Zhu, G.-D.; Norman, A. W.; Bouillon, R.; Farach-Carson, M. C. "Vitamin D Drug Design and Synthesis: Towards Understanding the 'Mutually Induced Fit' of Vitamin D Ligands and Various Proteins Which Bind Metabolites and Analogs," in Vitamin D: Chemistry, Biology and Clinical Applications of the Steroid Hormone, A. W. Norman; R. Bouillon, M. Thomasset, eds.; University of California, Riverside, 1997; pp. 11-18.

Okamura, W. H.; Midland, M. M.; Hammond, M. W.; Abd.Rahman, N.; Dormanen, M. C.; Nemere, I.; Norman, A. W. "Chemistry and Conformation of Vitamin D Molecules," J. Steroid Biochem. and Molec. Biol. 1995, 53, 603-613.

Zhu, G. -D.; Okamura, W. H. "Synthesis of Vitamin D (Calciferol)," Chemical Reviews 1995, 95, 1877-1952.