Jetze Tepe
Associate Professor Office: 510 Chemistry
Phone: 517-355-9715 147 /
Websites: Research Group - Area
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Bioorganic Chemistry
(Research Description PDF - 1102 kb)Our research program provides an interdisciplinary blend of synthetic organic, bioorganic and proteomic/genomic research. Our goal is to develop new synthetic methodologies to provide rapid access to biologically significant natural products and evaluate their biological properties in a range of cell lines. Once activity has been established, detailed mechanistic studies are initiated using a wide range of genomic and proteomic tools such as gene chip arrays, ELISA's, reporter assays, DPAGE etc.
Synthesis: The development of small molecular weight scaffolds containing a high degree of diversity has become a leading focus in modern drug discovery. In contrast to target-oriented synthesis and combinatorial chemistry, the goal of diversity-oriented synthesis is to develop short (3-5 steps) pathways leading to a collection of small molecules with skeletal and stereochemical diversity with defined coordinations in space. Our skeletal diversity is focused on biologically important small heterocycles with two or more new stereocenters and three or more points of diversity. The highly functionalized scaffolds are applied to the total syntheses of several classes of natural products including the lactacystins, hymenialdisines, kottamides, oxazolomycins, fusarins, indolic-imidazolones and many others.
Bioorganic: Cancer is currently the leading cause of death in the U.S. Even though many chemotherapeutic drugs are available in the clinic, their anticancer efficacy is limited by the toxicity of these agents. Our research in this area is directed towards the development of new compounds that sensitize cancer cells towards anticancer drugs. We have developed a new class of compounds that drastically enhances the anticancer efficacy of clinically used chemotherapeutic drugs. Our lead compound, SP-x4-84, can be used as an additive to the drugs resulting in an enhancement of their antitumor efficacy by 10-100 fold in cells and animal models. Proteomic and genomic analysis of cell extracts revealed that this compound inhibits the gene expression of survival and cell cycle genes in response to chemotherapeutic treatment. Our current work is focused on the elucidation of the detailed mechanism and optimization of the scaffold.
Proteomics and Genomics: Protein phosphorylations are widely recognized as critical events in the regulation of division, gene expression and metabolism. Deregulation of these signal transduction cascades is implicated in cancer, type II diabetes, cystic fibrosis, Alzheimer's disease and many more diseases. Unfortunately, proteomic techniques relevant to the elucidation of signal transduction have been lacking in development in comparison to genomic technologies, which have unraveled the human genome. We have recently developed the first general and universal method for the isolation of phosphorylated peptides from protein digests. Our chemical based phosphoproteomic technique allows us to rapidly characterize phosphorylation state of proteins in cells in response to external stimuli such as drugs or toxins and compare these with its genomic profile using microarrays. Correlating the genomic and proteomic profile should provide unprecedented insight in cellular regulation, target validation and disease diagnosis.
Selected Publications
Synthesis of tert-Alkyl Amino Hydroxy Carboxylic Esters via an Intermolecular Ene-type Reaction of Oxazolones and Enol Ethers, R.A. Mosey, J.S. Fisk and J.J. Tepe, Organic Letters 2008,10, 825-828.Mechanistic Insights into the Multistage Gas-Phase Fragmentation Behavior of Phosphoserine- and Phosphothreonine-Containing Peptides, A. Palumbo, J.J. Tepe, G.E. Reid, J. Prot. Res. 2008, 7, 771-779.
The Diverse Chemistry of Azlactones, J.S. Fisk, R.A. Mosey and J.J. Tepe, Chemistry Society Reviews, 2007, 36, 1432-1440.
Enhancing the Efficacy of Chemotherapeutic Drugs by Small Molecule Inhibition of NF-kappaB and Checkpoint Kinases, V. Sharma, C. Hupp and J.J. Tepe, Current Medicinal Chemistry 2007, 14, 1061-1074.
Intermolecular Ene Reactions Utilizing Oxazolones and Enol Ethers, J.S. Fisk and J.J. Tepe, J. Am. Chem. Soc. 2007, 129, 3058-3059.
Enhancement of Chemotherapeutic Efficacy with Imidazoline Additive, V. Sharma, T.A. Lansdell and J.J. Tepe, J. Am. Chem. Soc. 2006, 128, 9137-9143.
