个人简介

Post-Doctoral Auburn University 1996; Ph.D. Auburn University 1996; B.A. University of South Florida 1992

研究领域

Organic Drug Design/Synthesis

Medicinal/Synthetic Bioorganic/Organic Chemistry and Drug Design: The Seley-Radtke research group is focused on the discovery, design and synthesis of nucleoside/nucleotide and heterocyclic enzyme inhibitors with chemotherapeutic emphasis in the areas of anticancer, antiviral, antibiotic, and antiparasitic targets. Primary goals include development of potent inhibitors to shut down disease replication pathways through a combination of cross-disciplinary synthetic, biological screening, mechanistic, and structure-based drug design techniques. One of the primary projects under investigation involves the design and synthesis of flexible nucleoside (“fleximers”) and nucleobases (“flex-bases) inhibitors as a powerful technique to overcome the development of resistance to currently used therapeutics. This approach represents somewhat of a paradigm shift due to the ability of the fleximers and flex-bases to retain full potency when faced with “escape mutations” in biologically critical enzymatic systems. The inherent flexibility of the inhibitors allows them to conformationally adjust to steric and electronic clashes encountered in the binding site, and to engage secondary amino acids not previously involved in the enzyme’s mechanism of action. Potent activity has been uncovered in various viruses including corona viruses such as SARS and MERS-CoV, as well as HIV, HCV and others. In that regard, use of the flex-bases to inhibit the HIV nucleocapsid protein NCp7 is also being pursued. NCp7 is of high interest due to its multifunctional role in HIV replication. A second project focuses on the use of nucleosides and nucleobases as anticancer agents. For example, the potent activity exhibited by gemcitabine, Ara-C and other related FDA-approved anticancer analogues, has led to numerous structural modifications designed to increase target specificity and potency. Following upon the recent observation that several nucleobase analogues including thiophene-expanded purines, as well as pyrrolo – and thienopyrimidines designed in our laboratories have exhibited selective and highly potent levels of activity against several key cancers including lung, colon, leukemia, renal, and breast cancers (among others), we have initiated a program to elucidate their mechanism of action, as well as to further study their highly promising activity in vitro and in vivo. Most recently, these compounds caused a 50% decrease in tumor growth in preliminary mouse models for melanoma. Additional mechanistic and animal studies are currently underway. Other projects include synthesis of carbocyclic fleximers as potential Ebola and Marburg drugs by inhibiting methylation of the viral mRNA necessary for proper transcription, as well as to inhibit RNA polymerase, while another employs a strategic use of prodrugs to increase oral bioavailability for a series of tricyclic nucleosides shown to be active against hepatitis C virus (HCV). This latter approach also allows the nucleosides to bypass the first rate-limiting kinase-mediated phosphorylation in the requisite intercellular conversion to their biologically active triphosphate form. Current efforts include applying this approach to other viruses and cancers. All of the projects being pursued in the Seley-Radtke laboratories employ structure activity relationship (SAR) algorithms for the biological enhancement of lead compounds. Intimately related to the goals of the drug design projects, synthetic organic research focus includes the discovery of unique strategies to solve design challenges using state of the art techniques, including protection/deprotection motifs, enzymatic resolution of enantiomeric mixtures, functional group manipulation, and template directed organometallics for the construction of modified heterocycles, carbohydrates and carbocyclic moieties. In addition, a cross-disciplinary chemical biology approach employs enzymatic assays to survey the effectiveness of the potential drug candidates, as well as to investigate polymerase fidelity with modified nucleotide analogues that possess unique structural advantages for enhanced molecular recognition.

近期论文

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Babkov, D. A.; Valuev-Elliston, V. T.; Paramonova, M. P.; Ozerov, A. A.; Ivanov, A. V.; Chizhov, A. O.; Khandazhinskaya, A. L.; Kochetkov, S. N.; Balzarini, J.; Dalemans, D.; Pannecouque, C.; *Seley-Radtke, K. L.; Novikov, M. S. “Scaffold hopping: exploration of acetanilide-containing uracil analogues as potential NNRTIs”, 2015, in press, Bioorganic Medicinal Chemistry. *corresponding author Zimmermann, S. C.; O’Neill, E.; Ebiloma, G. U.; Wallace, L. J. M.; De Koning, H. P.; Seley-Radtke, K. L. “Design and synthesis of a series of truncated neplanocin fleximers” Molecules 2014, 19, 21200-21214. Temburnikar, K.; Zimmermann, S. C.; Kim. N.; Ross, C.; Gelbmann, C.; Salomon, C.; Wilson, G.; Balzarini, J.; Seley-Radtke, K. L. “Antiproliferative activity of halogenated thieno[3,2-d]pyrimidines”, Bioorg Med Chem 2014, 22, 2113-2122. Matyugina, E. S.; Valuev-Elliston, V. T.; Gaisman, A.; Novikov, M. S.; Chizhov, A. O.; Kochetkov, S. N.; Seley-Radtke, K. L.; Khandazinskaya, A. L. “Structure-Activity Evaluation of New Uracil-Containing Non-Nucleoside Inhibitors of HIV Reverse Transcriptase” MedChemComm, 2013, 4, 1443-1451. Temburnikar, K.; Brace, K.; Seley-Radtke, K. L.”Synthesis of 2′-deoxy-9-deaza-C-nucleosides using Heck methodology”, J Org Chem, 2013, 78, 7305-7311. Novikov, M. S.; Babkov, D. A.; Paramonova, M. P.; Ozerov, A. A.; Khandazhinskaya, A. L.; Andrei, G.; Snoeck, R.; Balzarini, J.; Seley-Radtke, K. L. “Synthesis and anti-HCMV activity of 1-[w-(phenoxy)pentyl]uracil derivatives and analogues thereof” Bioorg Med Chem 2013, 21, 4151-4157. Matyugina, E. S.; Valuev-Elliston, V.; Babkov, D.; Novikov, M.; Ivanov, A.; Kutchetkov, S.; Balzarini, J.; Seley-Radtke, K. L.; Khandazhinskaya, A. L. “5′-nor carbocyclic nucleosides: surprising nonnucleoside inhibitors of HIV-1 reverse transcriptase”, MedChemComm, 2013, 4, 741-748. Zimmermann, S. C.; Sadler, J. M.; O’ Daniel, P. I.; Kim, N.T.; Seley-Radtke, K. L. ” “Reverse” Carbocyclic Fleximers. Synthesis of a New Class of Adenosine Deaminase Inhibitors” Nucleosides, Nucleotides & Nucleic Acids, 2013, 32, 137-154. Novikov, M. S., Paramonova; M. P., Babkov, D. A., Valuev-Elliston, V. T., Gavryushov, S. A. Ivanov, A. V., Kochetkov, S. N., Pannecouque, C., Andrei, G., Snoeck, R., Balzarini, J., Seley-Radtke, K. L. “N1, N3-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase”, Bioorg Med Chem, 2013, 21, 1150-1158. Novikov, M. S.; Babkova, D. A.; Paramonova, M. P.; Chizov, A. O., Seley-Radtke, K. L. “A highly facile approach to the synthesis of novel 2-(3-benzyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-N-phenylacetamides”, Tetrahedron Letters, 2013, 54, 576-578. Wauchope, O. R.; Velasquez, M.; Seley-Radtke, K. L. “Synthetic routes to a series of proximal and distal 2′-deoxy nucleoside analogues.” Synthesis, 2012, 3496-3504. Wauchope, O. R.; Johnson, C.; Krishnamurthy, P.; Andrei, G.; Snoeck, R.; Balzarini, J.; Seley-Radtke, K. L. “Synthesis and biological evaluation of a series of thiophene-expanded purine 2′-deoxy nucleoside analogues.” Bioorg Med Chem, 2012 20, 3009-3015. Temburnikar, K.; Zhang, Z.; Seley-Radtke, K. L.: “Modified Synthesis of 3′-OTBDPS-Protected Furanoid Glycal”, Nucleosides, Nucleotides and Nucleic Acids, 2012 31, 319-327. Manvilla, B. A.; Wauchope, O.; Seley-Radtke, K. L., Drohat, A. C.; “NMR Studies Reveal an Unexpected Binding Site for a Redox Inhibitor of AP Endonuclease 1″, Biochemistry 2011 50,10540-9. Novikov, M.S.; Ivanova, O. N.; Ivanov, A.V.; Ozerov, A.A.; Valuev-Elliston, V. T.; Temburnikar, K.; Gurskaya, G. V.; Kochetkov, S. N.; Pannecouque, C.; Balzarini, J.; Seley-Radtke, K.L.; “1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents” Bioorg Med Chem 2011, 19, 5794-5802. Zimmermann, S. C.; Sadler, J. M.; Andrei, G.; Snoeck, R.; Balzarini, J.; Seley-Radtke, K. L. “Carbocyclic 5′-Nor “Reverse” Fleximers. Design, Synthesis and Preliminary Biological Activity”, MedChemComm 2011, 2, 650 – 654. Novikov, M.S.; Buckheit, R.; Temburnikar, K.; Khandazhinskaya, A. L.; Ivanov, A.V; Seley-Radtke, K.L.; “1-Benzyl derivatives of 5-(arylamino)uracils as potential anti-HIV-1 and EBV agents” Bioorg Med Chem 2010, 18, 8310-14. Wauchope, O. R.; Tomney, M. J.; Pepper, J. L.; Korba, B. E.; Seley-Radtke, K. L. 2′-C-Modified tricyclic nucleosides as potential anti-HCV therapeutics, Org Lett 2010, 12, 4466-4469. Matyugina, E. S.; Seley-Radtke, K. L.; Andronova, V. L.; Galegov, G. A.; Khandazhinskaya, A. L. Synthesis and antiviral evaluation against vaccinia virus of new N1-oxide analogues of 5’-noraristeromycin, Russian J Bioorg Chem 2010, 36, 730-733; Original Russian Text: Bioorganicheskaya Khimiya, 2010, 797–801. Tomney, M.; Korba, B.; Zimmermann, S.; Seley-Radtke, K. L. “Synthesis of a Series of 2’-Modified Tricyclic Nucleosides as Potential Anti-HCV Agents” Antiviral Res. 2010, 86, A68.