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Katherine Seley-Radtke

SeleyRadkteweb
Contact Information
Office: CHEM 405C
Phone: 410-455-8684
Radtke CV

Professor

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

Professional Interests

Current Fields of Interest: Medicinal/Synthetic Bioorganic/Organic Chemistry and Drug Design: 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 focus for the Seley-Radtke laboratories 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 virus, SARS, MERS-CoV, HIV, HCV, HBV and others. Related to this, use of the flex bases to inhibit the HIV nucleocapsid protein NCp7 is also under investigation. This target 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 designed in our laboratories have exhibited selective and highly potent (nanomolar) levels of activity against several key cancers including melanomas, 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 flexible nucleosides 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 bioavailablity 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.
Selected Publications

  1. Temburnikar, K.; Brace, Seley-Radtke, K. L.’Synthesis of 2′-deoxy-9-deaza-C-nucleosides using Heck methodology’, J Org Chem201378, 7305-7311.
  2. Matyugina, E. S.; Valuev-Elliston, V. T.; Gaysman, 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’ MedChemComm2013, 4, 1443 – 1451.
  3. 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 201321, 4151-4157.
  4. 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’, MedChemComm20134, 741-748.
  5. Zimmermann, S. C.; Sadler, J. M.; O’ Daniel, P. I.; Kim, Nathaniel 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.
  6. 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 Chem2013, 21, 1150-1158.
  7. 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 Letters201354576-578.
  8. Wauchope, O. R.; Velasquez, M.; Seley-Radtke, K. L. ‘Synthetic routes to a series of proximal and distal 2′-deoxy nucleoside analogues.’ Synthesis2012, 3496-3504.
  9. 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 Chem2012 20, 3009-3015.
  10. 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.
  11. 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.
  12. 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 201119, 5794-5802.
  13. 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 20112, 650 – 654.
  14. 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.
  15. 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 201012, 4466-4469.
  16. 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 201036, 730-733; Original Russian Text: Bioorganicheskaya Khimiya2010, 797–801.
  17. 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. 201086, A68.
  18. Sadler, J. M.; Mosley, S. L.; Dorgan, K. M.; Zhou, Z. S.; Seley-Radtke, K. L. ‘Synthetic Strategies Toward Carbocyclic Purine-Pyrimidine Hybrid Nucleoside Inhibitors’ Bioorg. Med. Chem., 200917, 5520-5525.
  19. Ivanov, A.; Tunitskaya, V.; Smirnova, O.; Buckheit, R.; Seley-Radtke, K. L.; Ivanov, A.; Novikov, M. “Synthesis and Antiviral Activity of Substituted Uracils” Antiviral Res200982, A58.
  20. Seley-Radtke, K. L.; Sunkara, N. K. ‘Carbocyclic Thymidine Analogues as Potential Antiviral Agents’Nucleosides, Nucleotides, Nucleic Acids  200928, 633-641.
  21. O’Daniel, P. I.; Jefferson, M.; Wiest, O.; Seley-Radtke, K. L. ‘Computational Studies of Expanded Heterocyclic Nucleosides in DNA’ J Biomol Struct Dyn20083, 283-292. (Cover)
  22. Zhang, Z.; Wauchope, O. R.; Seley-Radtke, K. L.  ‘Design, Synthesis and Mechanistic Studies of a Series of Expanded Xanthosine Nucleosides’ Tetrahedron 200864, 10791-10797.
  23. Sadler, J. M.; Ojewoye, O.; Seley-Radtke, K. L. ”Reverse Fleximers.’ Introduction of a series of 5-substituted Carbocyclic uridine analogues’ Nucleic Acids Symp Ser. 200852, 571-572.
  24. Seley-Radtke, K. L.; Zhang, Z.; Wauchope, O. R.; Zimmermann, S. C.; Ivanov, A.; Korba, B. ‘Hetero-expanded Purine Nucleosides. Design, Synthesis and Preliminary Biological Activity’ Nucleic Acids Symp Ser.200852, 635-636.
  25. Mosley, S. L.; Bakke, B. A.; Sadler, J. M.; Dorgan, K.; Zhou, Z. S.; Seley-Radtke, K. L.  ‘Carbocyclic Pyrimidine Nucleosides as Inhibitors of S-Adenosylhomocysteine Hydrolase’, Bioorganic Med. Chem2006 14, 7967-7971.
  26. Sunkara, N. K.; Mosley, S. L.; Seley-Radtke, K. L. ‘A Carbocyclic 7-Deaza Purine-Pyrimidine Hybrid Nucleoside’ Collect. Czech. Chem. Commun., 200671, 1161-1168.
  27. Quirk, S.; Seley-Radtke, K.L. ‘Purification, crystallization, & preliminary X-ray characterization of human GTP fucose pyrophosphorylase’ Acta Cryst2006F62, 392-394.
  28. Quirk, S.; Seley, K. L. ‘Identification of catalytic amino acids in the human GTP fucose pyrophosphorylase active site’ Biochem. 2005,44, 13172-13178.
  29. Quirk, S.; Seley, K. L. ‘Substrate discrimination by human GTP-fucose pyrophosphorylase’ Biochem2005,44, 10854-10863.
  30. Seley, K. L.; Salim, S.; Zhang, L.; O’Daniel, P. I. “Molecular Chameleons’. Design and Synthesis of A New Series of Flexible Nucleosides’ J. Org. Chem200570, 1612-1619.
  31. Seley, K. L.; Salim, S.; Zhang, L.;’Molecular Chameleons’. Design and Synthesis of C-4-Substituted Imidazole Fleximers Org, Lett20057, 63-66.
  32. Schwimmer,  L. J.; Rohatgi, P.; Azizi, B.; Seley, K. L.; Doyle, D. F. ‘Creation and Discovery of Ligand-Receptor Pairs for Small Molecule Control of Transcription’ Proc. Nat. Acad. Sci2004101, 14707-14712.
  33. Polak, M.; Seley, K. L.; Plavec, J. ‘Conformational Properties of Novel Shaped Nucleosides – Fleximers’ J. Am. Chem. Soc. 2004126, 8159-8166.
  34. Wallace, L. J. M.; Candlish, D.; Hagos, A.; Seley, K. L.; de Koning, H. P. ‘Selective Transport of a New Class of Purine Antimetabolites by the Protozoan Parasite Trypanosoma Brucei‘ Nucleosides, Nucleotides, Nucleic Acids  200423, 1441-1444.
  35. Seley, K. L.; Mosley, S. L.; Xing, F. ‘Carbocyclic Isoadenosine Analogues of Neplanocin A’ Org. Letters, 2003,5, 4401-4403.
  36. Seley, K. L.; O’Daniel, P. I.; Salim, S. ‘Design and Synthesis of a Series of Chlorinated 3-Deazaadenine Derivatives’ Nucleosides, Nucleotides, Nucleic Acids200322, 2133-2144.
  37. Seley, K. L.; Quirk, S.; Salim, S.; Zhang, L.; Hagos, A. ‘Unexpected Inhibition of S-Adenosyl-L-homocysteine Hydrolase by a Guanosine Nucleoside’ Bioorg. Med. Chem. Lett. 200313, 1985-1988.
  38. Seley, K. L.; Zhang, L.; Hagos, A.; Quirk, S. ”Fleximers’. Design and Synthesis of A New Class of Novel Shape-Modified Nucleosides’ J. Org. Chem., 200267, 3365-3373.
  39. Seley, K. L.; Zhang, L. Hagos, A. ”Fleximers’. Design and Synthesis of Two Novel Split Nucleosides’ Org. Letters20013, 3209-3210.
  40. Barnard, D. L.; Stowell, V. D.; Seley, K. L.; Hegde, V. R.; Das, S. R.; Rajappan, V. P.; Schneller, S. W.; Smee, D. F.; Sidwell, R. W. ‘Inhibition of Measles Virus Replication by 5′-Nor Carbocyclic Adenosine Analogues’ Antiviral Chem. Chemoth.  200112, 241-250.
  41. Seley, K. L.; Januszczyk, P.; Hagos, A.; Zhang, L.; Dransfield, D.T. ‘Synthesis and Antitumor Activity of Thieno-Separated Tricyclic Purines’ J. Med. Chem.200043, 4877-4883.
  42. Barnard, D. L.; Stowell, V. D.; Seley, K. L.; Hegde, V. R.; Das, S. R.; Rajappan, V. P.; Schneller, S. W. and Sidwell, R. W. ‘Inhibition of Measles Virus Replication by 5′-Nor Carbocyclic Nucleoside Analogs’ Antiviral Res.2000, 46, 102.
  43. Hegde, V. R.; Seley, K. L.; Schneller, S. W. Carbocyclic 5′-Norcytidine (5′-Norcarbodine)’ J. Heterocycl. Chem.200037, 1361-1362.
  44. Hegde, V. R.; Seley, K. L.; Schneller, S. W. ‘Carbocyclic 5′-Noruridine’ Nucleosides Nucleotides  200019, 269-273.
  45. Hegde, V. R.; Seley, K. L.; Chen, X.; Schneller, S. W. ‘The Synthesis of Carbocyclic 5′-Nor Thymidine and an Isomer as Oligonucleotide Monomers’ Nucleosides Nucleotides199918, 1905-1910.
  46. Seley, K. L.; Schneller, S. W. ‘7-Deaza-5′-noraristeromycin Derivatives Resembling L-Toyocomycin and L-Sangivamycin’ J. Heterocycl. Chem.  199936, 287-288.
  47. Hegde, V. R.; Seley, K. L.; Schneller, S. W.; Elder, T. J. J. ‘5’-Amino-5′-deoxy-5′-noraristeromycin and Related Analogues’ J. Org. Chem. 199863, 7092-7094.
  48. Seley, K. L.; Schneller, S. W. Korba, B. ‘Does the Anti-HBV Activity of (+)-5′-Noraristeromycin Exist in its 4′-Epimer and 4′-Deoxygenated Derivatives?’ J. Med. Chem.  199841, 2168-2170.
  49. Seley, K. L.; Schneller, S. W.; Korba, B.; de Clercq, E.; Rattendi, D.; Lane, S.; Bacchi, C. J. ‘The Importance of the 4′-Hydroxyl Hydrogen for the Anti-trypanosomal and Antiviral Properties of (+)-5′-Noraristeromycin’Bioorg. Med. Chem. 19986, 797-802.
  50. Wu, J.; Schneller, S. W.; Seley, K. L.; de Clercq, E. ‘Carbocyclic 7-Deazaguanine Oxetanocin Analogues’Heterocycles  199847, 757-765.
  51. Wu, J.; Schneller, S. W.; Seley, K. L.; Snoeck, R.; Andrei, G.; Balzarini, J.; de Clercq, E. ‘Carbocyclic Oxetanocins Lacking the C-3′ Methylene’ J. Med. Chem199740, 1401-1406.
  52. Seley, K. L.; Schneller, S. W. Korba, B. ‘A 5′-Noraristeromycin Enantiomer with Activity Towards Hepatitis B Virus’ Nucleosides Nucleotides 199716, 2095-2099.
  53. Seley, K. L.; Schneller, S. W.; de Clercq, E. ‘A Methylated Derivative of 5′-Noraristeromycin’ J. Org. Chem. 199762, 5645-5646.
  54. Seley, K. L.; Schneller, S. W.; Rattendi, D.; Lane, S.; Bacchi, C. J. ‘Synthesis and Anti-Trypanosomal Activity of a Series of 7-Deaza-5′-noraristeromycin Derivatives Varied in the Cyclopentyl Ring’ Antimicrob. Agents Chemother.  199741, 1658-1661.
  55. Seley, K. L.; Schneller, S. W.; Rattendi, D.; Lane, S.; Bacchi, C. J. ‘Synthesis and Anti-trypanosomal Activity of Various 8-Aza-7-deaza-5′-noraristeromycin Derivatives’ J. Med. Chem.  199740, 625-629.
  56. Seley, K. L.; Schneller, S. W.; Rattendi, D.; Bacchi, C. J. ‘(+)-7-Deaza-5′-noraristeromycin as an Anti-Trypanosomal Agent’ J. Med. Chem.  199740, 622-624.
  57. Seley, K. L.; Mosley, S. L. ‘Purine Analogues and Their Role in Methylation and Cancer Chemotherapy’ inDNA Methylation and Cancer Therapy, Moshe Szyf, Ed. Landes Bioscience,  Georgetown, TX, 2004, Chapter 13, pp 178-186.
  58. Seley, K. L. ‘Tricyclic Nucleosides Revisited’ in Recent Advances in Nucleosides: Chemistry and Chemotherapy, pg. 299-326, C.K. Chu, Ed. Elsevier Science, 2002
  59. Schneller, S. W.; Seley, K. L.; Hegde, V. R.; Rajappan, V. P. ‘5’-Norcarbanucleosides in L-Like Configurations’ in Recent Advances in Nucleosides: Chemistry and Chemotherapy, pg. 291-297; C.K. Chu, Ed. Elsevier Science, 2002.
  60. Seley, K. L. ‘CoFactor’ IDrugs20014, 99-101.
  61. Seley, K. L. ‘Tezacitabine’ Current Opin. Investigational Drugs   20001, 135-140.
  62. Seley, K. L. ‘MDL 101,731′ Investigational Drugs, Current Drugs Ltd, 1997.

 

Honors and Awards

Scientific Advisory Committee & Session Chair,
ACS Medicinal Chemistry Division
2013-present
National ACS Medicinal Chemistry Symposium, Charleston, SC, May 18-21, 2014
Member, Award Nomination & Selection Committee
ACS Medicinal Chemistry Division
2013-present
Member, Board of Directors
International Society of Antiviral Research
May 2013
Session Chair, 26th ICAR, San Francisco
International Society of Antiviral Research
2013
Jefferson Science Fellow
National Academies of Science, U.S. Dept of State, Carnegie Corporation, MacArthur Foundation
2006-present
AIDS Discovery & Development of Therapeutics (ADDT) study section
National Institues of Health
2010-present
Secretary
International Society of Nucleosides, Nucleotides & Nucleic Acids (IS3NA)
2007-2012
Vice President
International Society of Nucleosides, Nucleotides & Nucleic Acids (IS3NA)
2013-2014
President Elect
International Society of Nucleosides, Nucleotides & Nucleic Acids (IS3NA)
2015-2016
Long Range Plannning Committee
American Chemical Society – Medicinal Chemistry Division
2010-2012
Session Chair, 244th National ACS meeting, Philadelphia, PA
American Chemical Society – Medicinal Chemistry Division
2012
Session Chair, 243rd National ACS meeting, San Diego, CA
American Chemical Society – Medicinal Chemistry Division
2012
Outstanding Faculty Fellow
UMBC Honors College student body
2011
Session Chair
4th European Workshop in Drug Synthesis, Siena, Italy
2012
Associate Editor
Current Protocols in Chemical Biology
2011- present
Chair, Poster Award Committee
International Society of Antiviral Research
2012-present
Chair, Membership Committee
International Society of Nucleosides, Nucleotides & Nucleic Acids (IS3NA)
2005-present
Jefferson Science Fellow Selection Panel
National Academies of Science, U.S. Dept of State
2008-present
Session Chair
8th European Workshop in Drug Design, Siena, Italy
2011
Scientific Advisory Board
Deszyme Inc.
NIGMS Biomedical Research Training A/B study sections
National Institues of Health
2005-2010
Session Chair
19th International Roundtable on Nucleosides, Nucleotides & Nucleic Acids, Lyon, France
2010
Editorial Board
Research and Reports in Medicinal Chemistry
Editorial Board
Clinical Medicine Insights, Therapeutics
Distinguished Faculty
The National Society of Collegiate Scholars
2006
Session Chair
International Roundtable on Nucleosides, Nucleotides and Nucleic Acids, Minneapolis, MN
2004
ACS PROGRESS Lectureship in Chemical Sciences Award
American Chemical Society
2003
Session Chair
Gordon Research Conference, Purines, Pyrimidines & Related Substances, Newport, RI
2003
Class Of 1940 W. Howard Ector Outstanding Teacher
Georgia Institute of Technology
2002
Outstanding Faculty Award
Cardinal Key Honor Society, Auburn University
1998
Outstanding Dissertation Award, Auburn University
Sigma Xi
1997
Carolyn Taylor Carr Award
Auburn University
1997
American Assoc. of University Women Scholarship
AAUW
1992
Hugh Culverhouse Award
University of South Florida
1992

Funding

A flexible approach to avoid viral escape mutations
$275,000
National Institutes of Health
Prodrug strategies for HCV nucleoside lead development
$275,000
National Institutes of Health
Graduate Training at the Chemistry Biology Interface
$677,000
National Institutes of Health
Fused Pyrimidine (IsoA) Nucleosides: Design, Synthesis and Biological Investigations
$1,401,075
National Institutes of Health, NCI
2002-2007
Investigation of a series of carbocyclic hybrid purine/pyrimidine nucleosides as potential dual inhibitors of S-adenosylhomocysteine hydrolase and DNA methyltransferase.
Unnatural Base Pairs as DNA Bioprobes
$940,800
National Institutes of Health
2004-2008
Synthesis, biological and biophysical investigation of DNA structure and function utilizing series of unnatural DNA base pairs. Expanded purine and extended pyrimidine heterobase scaffolds are employed.
Research Supplements for Underrepresented Minorities, “Unnatural Base Pairs as DNA Probes”
$198,303
National Institutes of Health
2004-2006
Research Supplements for Underrepresented Minorities, “Fused Pyrimidine (IsoA) Nucleosides”
$183,445
National Institutes of Health
2002-2006
“Fused Pyrimidine (IsoA) Nucleosides: Design, Synthesis and Biological Investigations”
$739,000
American Cancer Society
2002-2007
Drug and Gene Therapy Development
$1,099,548
GAANN
2002-2006
Antivirals for Orthopoxviral Infections
$260,000
5. US Department of Defense/Defense Threat Reduction Agency
2001-2006
Fleximers. New Molecular Tools for Drug Design
$11,000
Molecular Design Institute
2002-2003
College of Science Faculty Development Award
$7500
Georgia Institute of Technology
2002
Chlorinated Adenosine Derivatives as Regulators of Colorectal Cell Growth
$60,000
Georgia Tech/Medical College of Georgia
2000-2002
Modified Nucleoside “Fleximers” as Biological Probes
$24,700
Emory/Georgia Tech Biomedical Technology Collaborative Research
1998-2000

Courses Taught

  • CHEM 299: Training in Experimental Chemistry (Cooperative Education)
  • CHEM 351: Organic Chemistry I
  • CHEM 351L: Organic Chemistry Laboratory I
  • CHEM 352: Organic Chemistry II
  • CHEM 352L: Organic Chemistry Laboratory II
  • CHEM 399: Tutorial Projects in Chemistry
  • CHEM 450: Chemistry of Heterocyclic Compounds
  • CHEM 453: Organic Chemistry of Nucleic Acids
  • CHEM 455: Introduction to Biomedicinal Chemistry
  • CHEM 490: Special Topics in Chemistry – Organic Synthetic Methology
  • CHEM 499: Undergraduate Research
  • CHEM 600: Advanced Laboratory Projects
  • CHEM 602: Introduction to Laboratory Research
  • CHEM 650: Chemistry of Heterocyclic Compounds
  • CHEM 653: Organic Chemistry of Nucleic Acids
  • CHEM 654: Organic Synthetic Methodology
  • CHEM 655: Introduction to Biomedicinal Chemistry
  • CHEM 713: Biochemistry/Chemistry Seminar
  • CHEM 715: Issues at the Chemistry/Biology Interface
  • CHEM 898: Pre-Candidacy Doctoral Research
  • CHEM 899: Doctoral Dissertation Research

 

Research Description

 

Seley-Radtke Research Group

Current Fields of Interest: Medicinal/Synthetic Bioorganic/Organic Chemistry and Drug Design: Discovery, design and synthesis of nucleoside/nucleotide and heterocyclic enzyme inhibitors with chemotherapeutic emphasis in the areas of anticancer, antiviral, antibiotic, antifungal and antiparasitic targets. Goals include development of potent inhibitors to shut down disease replication pathways through a combination of cross-disciplinary synthetic, biological screening, mechanistic, computational and structure-based drug design techniques.

The primary focus of the Seley-Radtke laboratories 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 has caused a paradigm shift in the medicinal chemistry community 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.

A second project involves the strategic use of prodrugs to increase oral bioavailability for a series of tricyclic nucleosides shown to be active against hepatitis C virus (HCV). This 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 such as the HIV and herpes viruses. A third project employs carbocyclic nucleoside inhibitors as potential antiparasitic drugs by inhibiting methylation of the ‘cap four’ structure of parasite mRNA required for proper transcription and translation. All of the projects being pursued in the Seley-Radtke laboratories employ structure activity relationship (SAR) algorithms for the biological enhancement of lead compounds.

A third 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 potent and selective 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.

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. Cross-disciplinary chemical biology research involves use of enzymatic assays to survey the effectiveness of the potential drug candidates, as well as investigations into polymerase fidelity with modified nucleotide analogues that possess unique structural advantages for enhanced recognition.