PhD, chemistry (synthetic/medicinal chemistry), University of Montana, Missoula, Mont.
Bachelor of Science, chemistry, Central Washington University, Ellensburg, Wash.
Fellowships & Additional Training
Post Doctoral Research: Shafizadeh Rocky Mountain Center for Wood and Carbohydrate Chemistry: The University of Montana, Missoula, Mont. 2005-2007
Post Doctoral Research: Human BioMolecular Research Institute, San Diego, Calif. 2002-2005
Denton is the instructor of record for PharDSci 547 (drug discovery and development) and PharmSci 576 (biophysical methods). He also contributes to the chemical biology section of PharDSci 508 (pharmaceutics).
Synthetic Medicinal Chemistry, Neuroscience, Drug Metabolism and Disposition, and Pharmacokinetics.
Phosphonate analogues of brain sulfur amino acids and metabolites as aids in the study of neurodegenerative diseases and autophagy; Phosphonate analogues of a-ketoacids as probes of the individual steps of the mitochondrial TCA cycle and the relationship to cancer cells; Inhibitors of Cytochrome P-450 2A6 as lead candidates in the development of smoking cessation agents; the use of carboxyethyl succinyl phosphonate (CESP) as a mechanistic probe of the mitochondrial α-ketoglutarate dehydrogenase complex and its relationship to neurodegenerative diseases; Development of stable isotope analogues of medicinally relevant compounds for use in analytical chemistry; Development of small molecules as probes of the binding sites of the cys-loop receptor family.
Our group also has a component directed towards carbohydrate and polymer chemistry for the development of novel antibacterial agents, cell Targeted, non-Viral drug and gene delivery agents and biodegradable gels, plastics and glues.
- Novel antibacterial agents: Polymeric quaternary ammonium compounds have a unique set of properties for the selective destruction of bacteria with the unique mode of action that avoids the possibility of the bacteria becoming resistant to the antibiotic. The chemistry used in the design and preparation of the polymeric antibiotics affords a large opportunity for chemical functionalization and optimization. The polymers can be biodegradable, non-biodegradable, water soluble, impervious to water and selective for certain strains of bacteria over others, as well as many more features.
- Cell Targeted, Non-Viral Drug and Gene Delivery Agents: We have developed a series of polycationic macromolecules with the ability to condense plasmid DNA with the ability of transfecting mammalian cells. The materials are unique in that once they are taken into the cell and release their cargo they are slated for destruction within the cell and, specifically designed, to release a monomeric unit that has been demonstrated to have chemotherapeutic value against some carcinogens. The chemical structure of the polymers also affords the chemist a number of “handles” to append the backbone to selectively target the polymer-payload polyplexes to specific cells via cell surface receptors.
- Biodegradable Gels, Plastics and Glues: Although this may not sound oriented towards pharmaceutical sciences, it most certainly is. The monomeric units for the materials in question are directly prepared from corn sugar, connected together with peptide bonds and have been shown to release bioavailable nutrients upon their breakdown. These materials are being developed for use in biomedical applications such as adhesives for wound dressings, tissue engineering and other regenerative medicine.
We also develop Phosphonate analogues of -Ketoacids as Mechanistic Probes of -Ketoacid Dehydrogenase Complexes and Aminotransferases. This project focuses on the preparation of phosphonate analogues of the a-ketoacids. Our group has experience in the preparation and utilization of phosphonates in a number of applications ranging from the inhibition of the -ketoglutarate dehydrogenase complex, the branched chain dehydrogenase complex and branched chain amino acid transaminases.
Development of stable isotope analogues of medicinally relevant compounds for use in analytical chemistry. Using our experience in synthetic organic chemistry, we have made and are in the process of making more stable isotope isoforms of small molecules of therapeutic interest. Besides having our own research programs, we are always open and available to help out in the preparation of any small molecule or macromolecule, which may prove beneficial to our companions in science.
- Arthur J. L. Cooper, PhD, New York Medical College
- Thomas Jeitner, PhD, New York Medical College
- Dimitrios Tsikas, PhD, Hannover Medical School, Hannover, Germany
- Paul Whiteaker, PhD, Barrow Neurological Institute
- Gary Gibson, PhD, Weill Cornell Medicine
- Kenneth Hensley, PhD, Arkansas College of Osteopathic Medicine
- Hui Feng, M.D., PhD, Boston University School of Medicine
- Carlos B. Mantilla, M.D., PhD, Mayo Clinic
- Martyn A. Sharpe, PhD, Houston Methodist
- Steven J. Fliesler, PhD, University at Buffalo, Jacobs School of Medicine and Biomedical Sciences
- Jason Gerstner, PhD, WSU, Elson S. Floyd College of Medicine
Chen, H., Xu, H., Potash, S, Starkov, A., Belousov, V. V., Bilan, D. S., Denton, T. T. and Gibson, G. E. Mild metabolic perturbations alter succinylation of mitochondrial proteins. J Neurosci Res. 2017, Jun 20. doi: 10.1002/jnr.24103. [Epub ahead of print]
Chen, H., Denton, T. T., Xu, H., Calingasan, N., Beal, M. F., Gibson, G. E. Reductions in the mitochondrial enzyme α-ketoglutarate dehydrogenase complex in neurodegenerative disease – beneficial or detrimental? J. Neurochem. 2016, 139(5), 24
Hariharan, V. A., Denton, T. T., Paraszcszak, S., McEvoy, K., Jeitner, T. M., Krasnikov, B. F., Cooper, A. J. The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites. Biology (Basel). 2017, 6(2), 823-838
Anderson, N. M, Li, D., Peng, H. L., Laroche, F. J., Mansour, M. R., Gjini, E., Aioub, M., Helman, D. J., Roderick, J. E., Cheng, T., Harrold, I., Samaha, Y., Meng, L., Amsterdam, A., Neuberg, D. S., Denton, T. T., Sanda, T., Kelliher, M. A., Singh, A., Look, A. T., Feng, H. The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis. Leukemia 2016, 30(6), 1365-1374
Banerjee, K, Munshi, S., Hui, F., Chen, H-L., Chu, C. T., Yang, J., Cho, S., Kagna, V. E., Denton, T. T., Tyurina, Y. Y., Jiang, J. F., Gibson, G. E. Mild mitochondrial metabolic deficits by α-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: Potential role in the pathobiology of Alzheimer’s disease. Neurochemistry International. 2016, 96, 32-45.
Cooper A. J., Shurubor, Y. I., Dorai, T., Pinto, J. T., Isakova, E. P., Deryabina, Y. I., Denton, T. T., Krasnikov, B. F. ω-Amidase: an underappreciated, but important enzyme in L-glutamine and L-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases. Amino Acids. 2016, 48(1), 1-20.
Gibson, G. E., Xu, H., Chen, H. L., Chen, W., Denton, T. T., Zhang, S. Alpha-ketoglutarate dehydrogenase complex-dependent succinylation of proteins in neurons and neuronal cell lines. J. Neurochem. 2015, 134(1), 86-96
Hensley, K., Denton, T. T. Alternative functions of the brain transsulfuration pathway represent an underappreciated aspect of brain redox biochemistry with significant potential for therapeutic engagement. Free Radic Biol Med. 2015, 78, 123-134.
Tsikas D, Denton TT, Cooper AJ. Comment on Absorption of Aminoethyl Cysteine Ketimine Decarboxylated Dimer in Mice: Effect on Plasma Antioxidant Potential. J. Agric. Food Chem. 2013, 61 (25), 6122–6124.
Baker MJ, Denton TT, Herr C. An explanation for why it is difficult to form slush nitrogen from liquid nitrogen used previously for this purpose. Cryobiology 2012, 66 (1), 43-46.
Tsikas D, Evans CE, Denton TT, Mitschke A, Gutzki FM, Pinto JT, Khomenko T, Szabo S, Cooper AJ. Stable isotope gas chromatography-tandem mass spectrometry determination of aminoethylcysteine ketimine decarboxylated dimer in biological samples. Anal. Biochem. 2012, 430(1), 4-15.
Gibson GE, Chen HL, Xu H, Qiu L, Xu Z, Denton TT, Shi Q. Deficits in the mitochondrial enzyme α-ketoglutarate dehydrogenase lead to Alzheimer’s disease-like calcium dysregulation. Neurobiol Aging. 2012, 33(6), 1121.e13-24.
Denton TT, Hardcastle KI, Dowd MK, Kiely DE. Characterization of D-glucaric acid using NMR, X-ray crystal structure, and MM3 molecular modeling analyses. Carbohydr Res. 2011, 346(16), 2551-2557.
Shimizu M, Denton TT, Kozono M, Cashman JR, Leeder JS, Yamazaki H. Developmental variations in metabolic capacity of flavin-containing mono-oxygenase 3 in childhood. Br. J. Clin. Pharmacol. 2011, 71(4), 585-91.