Kent S. Gates

Kent_Gates_photo_2014
Professor and Associate Chair for Graduate Studies
Phone: 
573-882-6763
Office: 
325.1 Chemistry
Research Emphasis: 

Bioorganic Chemistry, Medicinal Chemistry, Chemical Biology, Chemical Toxicology, Organic Chemistry, Nucleic Acid Chemistry, and Mechanisms of Enzyme Inactivation

Education: 

BS, University of Kansas, 1985
PhD, Northwestern University, 1990

Professional Experience: 

Schlundt Professor of Chemistry, 2005-present
Professor of Chemistry, 2001-present
Associate Professor of Chemistry, 1998-2001
Assistant Professor of Chemistry, 1993-1998
NIH Postdoctoral Fellow, California Institute of Technology (Dervan), 1990-1992

Professional Activities
Elected as a Fellow of the American Association for the Advancement of Science (AAAS), 2012
Elected as a Fellow of the American Chemical Society (ACS), 2016
Gold Chalk Award, MU Graduate Professional Council, 2015
Fuldner Faculty Fellow, MU College of Arts and Sciences, 2013 and 2014
Excellence in Education Award, MU Division of Student Affairs, 2014
Editorial Advisory Board, Chemical Research in Toxicology, 2000-2010
Editorial Advisory Board, Current Medicinal Chemistry-Anti-Cancer Agents, 2005-present
Editorial Advisory Board, Sulfur Chemistry, 2004-present
Editorial Advisory Board, Analytical Chemistry Insights, 2006-present
Program Chair for the Division of Chemical Toxicology of the ACS, 2006-2008
Co-founder and co-organizer of Nucleic Acid Topics Summit Conference, Telluride, CO 2008
Member, Cancer Etiology Study Section of the National Institutes of Health, 2001-2005
Ad hoc Member, Drug Discovery and Molecular Pharmacology Study Section of the NIH, 2008
Ad hoc Member, Bioorganic Natural Products Study Section of the NIH, 1998
Member, American Chemical Society (ACS)
Member, American Association for the Advancement of Science (AAAS)
Member, American Association for Cancer Research (AACR)

Research: 

The group employs the tools of synthetic organic chemistry, physical organic chemistry, biochemistry, biophysics, and molecular biology to study the molecular mechanisms of drug action.  Students in the lab enjoy using a wide array of cutting-edge techniques to elucidate the products and mechanisms of the reactions that occur between biologically-active small molecules and their macromolecular targets in the cell.

DNA-Damaging Natural Products as a Source of New Anticancer Drugs
DNA serves as the molecular blueprint that directs all cellular operations.  Accordingly, chemical modification of cellular DNA can have profound biological consequences.  For example, many clinically-used anticancer drugs derive activity by causing DNA damage that kills rapidly dividing cancer cells.  Accordingly, the development of new anticancer drugs will be advanced by the discovery of new fundamental mechanisms for the molecular recognition and chemical modification of DNA.  Indeed such efforts are important to a variety of fields including medicinal chemistry, toxicology, and biotechnology.

Historically, structurally unusual natural products that possess potent biological activity have shown the potential to reveal mechanisms of DNA modification that are chemically unexpected and remarkably efficient.  In addition, because of their potent bioactivity, natural products represent a rich source of pharmaceuticals.  In fact, it has recently been estimated that more than 60% of the anti-infective and anticancer agents in current use or in advanced clinical trials are derived from natural products.

We are investigating the chemistry and biology of natural products that damage DNA by unusual chemical mechanisms.  Below we show the structures of some natural products and their synthetic analogues that are currently under investigation in the lab.  Some of these compounds generate radicals that lead to oxidative DNA damage, while others generate electrophilic species that alkylate DNA (for an overview of these DNA-damage pathways, please see the Reviews of Reactive Intermediate Chemistry chapter on the group’s website).  In recent years, we have placed special emphasis on studies of leinamycin (Scheme below), a Streptomyces-derived natural product that gains exceptionally potent antitumor activity through its ability to simultaneously generate both DNA-damaging radicals and electrophiles by completely novel chemical pathways.  In general, our studies with these natural products continue to reveal fantastically efficient chemical mechanisms for DNA damage that are beyond our wildest imaginings.

Hypoxia-Selective Antitumor Agents
Solid tumors differ from most normal human tissue, in that they contain significant populations of oxygen-poor (hypoxic) cells.  For this reason, medicinal chemists have long sought agents that selectively generate cell-killing reactive intermediates under hypoxic conditions.  The compound 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) is the most promising hypoxia-selective antitumor agent discovered to date.  The compound is currently undergoing a variety of phase I, II, and III clinical trials for the treatment of human cancers.  The anticancer activity of this drug stems from its ability to selectively cause DNA damage in hypoxic tumor cells.

Upon entering cells, tirapazamine is enzymatically reduced to its radical form.  In normally-oxygenated cells this radical undergoes relatively harmless back-oxidation to the starting drug.  On the other hand, under hypoxic conditions (in tumor cells), the radical intermediate goes on to cause cell-killing DNA damage.  The chemical mechanisms responsible for DNA-damage by tirapazamine are the subject of intense, ongoing studies in our group and others because understanding the mechanisms of clinically promising anticancer agents can lead to more effective therapeutic strategies and to the design of new, more potent analogues.

We are currently investigating the mechanisms of DNA damage by heterocyclic N-oxides and working to define the structure-activity relationships within this promising new class of drugs.  This includes the study of naturally-occurring heterocyclic N-oxides such as myxin, iodinin, and carboxyquinoxaline di-N-oxide.  Our work aims to test the hypothesis that bioreductively-activated N-oxides undergo homolytic fragmentation to release the well-known DNA-damaging agent hydroxyl radical.  In addition, we are investigating the ability of tirapazamine and its metabolites to undergo secondary reactions with the initially-generated DNA radicals in a manner that mimics molecular oxygen to generate toxic DNA strand breaks and base labile lesions.  Finally, we are employing heterocyclic N-oxides as a platform for the design of tumor-cell-selective alkylating agents, kinase inhibitors, and agents for fluorescent imaging of hypoxic cells in living organisms.

research image

Discovery of Small Molecules that Regulate the Cellular Activity of Protein Tyrosine Phosphatases
Protein tyrosine phosphatases (PTPs) are cysteine-dependent enzymes that catalyze the hydrolytic removal of phosphate groups from tyrosine residues in proteins.  PTPs, in concert with protein tyrosine kinases, play a central role in cell signaling by regulating the phosphorylation status and, in turn, the functional properties, of target proteins in various signal transduction pathways.

The cellular activity of some PTPs is regulated by endogenous hydrogen peroxide (H2O2) that is produced as a second messenger in response to extracellular stimuli such as insulin, epidermal growth factor, and platelet derived growth factor.  H2O2 inactivates PTPs via oxidation of the active site cysteine thiol residue to a sulfenic acid.  In some cases, the cysteine sulfenic acid undergoes subsequent conversion to an active site sulfenyl amide or disulfide.  Oxidative inactivation of PTPs inside cells is slowly reversed by reaction of the inactivated enzyme with biological thiols.

PTP inactivators are of widespread interest in medicinal chemistry and cell biology because of their potential to regulate or dysregulate important cellular signaling pathways.  For example, PTP1B is a validated target for the treatment of type 2 diabetes.  PTP1B is the major negative regulator of insulin signaling and inhibition of this enzyme prevents dephosphorylation of the insulin receptor and insulin receptor substrates, thus potentiating the action of insulin.  We are currently investigating the fundamental chemical and enzymatic reactions underlying the redox regulation of PTPs.  In addition, we are characterizing endogenous, dietary, and synthetic chemicals that modulate cellular PTP activity.

Select Publications: 

Effective molarity in a nucleic acid-controlled reaction. Catalano, M. J.; Price, N. E.; and Gates, K. S. Bioorg. Med. Chem. Lett. 2016, 26, 2627-2630.

Sulfone-stabilized carbanions for the reversible covalent capture of a posttranslationally-generated cysteine oxoform found in protein tyrosine phosphatase 1B (PTP1B). Parsons, Z. D.; Ruddraraju, K. V. and Gates, K. S. Bioorg. Med. Chem. 2016, 24, 2631-2640.

Simple syntheses of DNA duplexes containing interstrand DNA-DNA cross-links between an N4-aminocytidine residue and an abasic site. Varela, J. G. and Gates, K. S. Curr. Protoc. Nucleic Acid Chem. 2016, 65, 5.16.1-5.16.15

Crystal structure of a nucleoside model of the interstrand cross-link formed by the reaction of 2’-deoxyguanosine and an abasic site in duplex DNA. Catalano, M. J.; Ruddraraju, K.V. and Gates, K. S. Acta Cryst. E. 2016, E72, 624-627.

Chemical structure and properties of interstrand cross-links formed by reaction of guanine residues with abasic sites in duplex DNA. Catalano, M. J.; Liu, S.; Anderson, N.; Yang, Z.; Johnson, K. M.; Price, N. E.; Wang. Y. and Gates, K. S. J. Am. Chem. Soc. 2015, 137, 3933-3945.

Characterization of interstrand DNA-DNA cross-links using the alpha-hemolysin protein nanopore. Zhang, X.; Price, N. E.; Fang, X.; Yang, Z.; Gu, L.-Q. and Gates, K. S. ACS Nano 2015, 9, 11812-11819.

Reactions of 1,3-diketones with a dipeptide isothiazolidin-3-one: Toward agents that covalently capture oxidized protein tyrosine phosphatase 1B. Ruddraraju, K. V.; Parsons, Z. D.; Llufrio, E. M.; Frost, N. L. and Gates, K. S. J. Org. Chem. 2015, 80, 12015-12026.

Mimicking ribosomal unfolding of an RNA pseudoknot in a protein channel. Zhang, X.; Xu, X.; Yang, Z.; Burcke, A. J.; Chen, S.-J.; Gates, K. S.; Gu, L.-Q. J. Am. Chem. Soc. 2015, 137, 15742-15752.

A simple, high-yield synthesis of DNA duplexes containing a covalent, thermally cleavable interstrand cross-link at a defined location. Varela, J. G.; Gates, K. S. Angew. Chem. Int. Ed. Eng. 2015, 54, 7666-7669. (Designated as a hot paper in journal issue #26

The paper above received a write-up in: Nat. Chem. 2015, 7, 537.

Characterization of interstrand DNA-DNA cross-links derived from abasic sites using bacteriophage phi29 DNA polymerase. Yang, Z.; Price, N. E.; Johnson, K. M.; Gates, K. S. Biochemistry 2015, 54 4259-4266.

Diethylaminobenzaldehyde Is a Covalent, Irreversible Inactivator of ALDH7A1. Luo, M.; Gates, K. S.; Henzl, M. T. and Tanner, J. J. ACS Chem. Biol. 2015, 10, 693-697.

Inactivation of protein tyrosine phosphatases by dietary isothiocyanates. Lewis, S. M.; Li, Y.; Catalano, M.; Laciak, A. R.; Singh, H.; Seiner, D. R.; Reilly, T. J.; Tanner, J. J.; Gates, K. S. Bioorg. Med. Chem. Lett. 2015, 25, 4549-4552.

Chemical and structural characterization of cross-links formed between abasic sites and adenine residues in duplex DNA. Price, N. E.; Catalano, M. J.; Liu, S.; Wang, Y. and Gates, K. S. Nucleic Acids Res. 2015, 43, 3434-3441.

Crystal structure of methyl (S )-2-{(R )-4-[(tert-butoxycarbonyl)amino]-3-oxo-1,2-thiazolidin-2-yl}-3-methylbutanoate: a chemical model for oxidized protein tyrosine phosphatase 1B (PTP1B). Ruddraraju, K. V.; Hillebrand, R.; Barnes, C. L. and Gates, K. S. Acta Cryst. E. 2015, E71, 741-743.

Generation of Reactive Oxygen Species Mediated by 1-Hydroxyphenazine, a Virulence Factor of Pseudomonas aeruginosa. Sinha, S.; Shen, X.; Gallazzi, F.; Li, Q.; Zmijewski, J. W.; Lancaster, J. R. Jr.; and Gates, K. S. Chem. Res. Toxicol. 2015, 28, 175-181.

Near-silence of isothiocyanate carbon in 13C-NMR spectra: a case study of allyl isothiocyanate. Glaser, R.; Hillebrand, R.; Wycoff, W.; Camasta, C.; Gates, K. S. J. Org. Chem. 2015, 80, 4360-4369.

Crystal structure of 5-{4-[(2-{2-[2-(2-ammonioethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-4-methoxy-[1,1-biphenyl]-3-yl}-3-oxo-1,2,5-thiadiazolidin-2-ide 1,1-dioxide: a potential inhibitor of the enzyme protein tyrosine phosphatase 1B. Ruddraraju, K. V.; Hillebrand, R.; Barnes, C. L.; Gates, K. S. Acta. Cryst. E 2015, E71, 336-338.

Covalent adduct formation between the antihypertensive drug hydralazine and abasic sites in double- and single-stranded DNA. Melton, D.; Lewis, C.; Price, N. E. and Gates, K. S. Chem. Res. Toxicol. 2014, 27, 2113-2118.

Interstrand DNA-DNA cross-link formation between adenine residues and abasic sites in duplex DNA. Price, N.; Johnson, K. M.; Wang, J.; Fekry, M. I.; Wang, Y.; and Gates, K. S. J. Am. Chem. Soc. 2014, 136, 3483-3490. (doi.org/10.1021/ja410969x)

The article above was one of four spotlighted in the issue of JACS where it appeared (J. Am. Chem. Soc. 2014, 136, 3321) and also was one of seven articles, from all areas of science, highlighted in the Editor`s Choice section of the March 7th issue of Science Magazine (Science 2014, 343, 1058-1059).

Single Molecule Investigation of Ag(I) Interactions with Single Cytosine-, Methylcytosine- and Hydroxymethylcytosine-Cytosine Mismatches in a Nanopore. Yong Wang, Bin-Quan Luan, Zhiyu Yang, Xinyue Zhang, Brandon Ritzo, Kent Gates, and Li-Qun Gu Sci. Reports (www.nature.com/scientificreports) 2014, 4(5883), 1-8 (DOI: 10.1038/srep05883)

DNA double whammy. Gates, K. S. Nat. Chem. 2014, 6, 464-465.

Toward hypoxia-selective DNA-alkylating agents built by grafting nitrogen mustards onto the bioreductively-activated, hypoxia-selective DNA-oxidizing agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine). Kevin M. Johnson, Zachary D. Parsons, Charles L. Barnes, and Kent S. Gates J. Org. Chem. 2014, 79, 7520-7531.

Isotopic labeling experiments that elucidate the mechanism of DNA strand cleavage by the hypoxia-selctive antitumor agent 1,2,4-benzotriazine 1,4-di-N-oxide. Shen, X. Rajapakse, A.; Galazzi, F.; Junnotula, V.; Fuchs-Knotts, T.; Glaser, R.; and Gates, K. S. Chem. Res. Toxicol. 2014, 27, 111-118.

Redox regulation of protein tyrosine phosphatases: methods for kinetic analysis of covalent enzyme inactivation. Parsons, Z. D.; Gates, K. S. Methods Enzymol. 2013, 528, 129-154.

Thiol-dependent recovery of activity from oxidized protein tyrosine phosphatases (PTPs). Parsons, Z. D.; Gates, K. S. Biochemistry 2013, 52, 6412-6423.

Fapy lesions and DNA mutations. Gates, K. S. Nat. Chem. Biol. 2013, 9, 412-413.

Rajapakse, A.; Linder, C.; Morrison, R. D.; Sarkar, U.; Leigh, N. D.; Barnes, C. L.; Daniels, J. S.; Gates, K. S. Enzymatic conversion of 6-nitroquinoline to the fluorophore 6-aminoquinoline selectively under hypoxic conditions. Chem. Res. Toxicol. 2013, 26, 555-563.

On the Formation and Properties of Interstrand DNA-DNA Cross-links Forged by Reaction of an Abasic Site With the Opposing Guanine Residue of 5’-CAp Sequences in Duplex DNA. Johnson, K. M.; Price, N. E.; Wang, J.; Fekry, M. I.; Dutta, S.; Seiner, D. R.; Wang, Y.; Gates, K. S. J. Am. Chem. Soc. 2013, 135, 1015-1025.

Synthesis and characterization of a small analogue of the anticancer natural product leinamycin. Keerthi, K.; Rajapakse, A.; Gates, K. S. Submitted to Bioorg. Med. Chem. 2013, 21, 235-241.

Transferring oxygen isotopes to 1,2,4-benzotriazine 1-oxides forming the corresponding 1,4,-dioxides using the HOF•CH3CN complex. Gatenyo, J.; Johnson, K.; Rajapakse, A.; Gates, K. S.; Rozen, S. Tetrahedron 2012, 68(43), 8942-8944.

Cellular responses to the DNA-damaging natural compound leinamycin. Sinha, P.; Shin, Y.; Hays, A. M.; Gates, K. S.; Sun, D. J. Cancer Sci. Ther. 2012, S8 (open access journal) S8:003. doi:10.4172/1948-5956.S8-003.

DNA cleavage induced by antitumor antibiotic leinamycin and its biological consequences. Viswesh, V.; Hayes, A. M.; Gates, K. S.; Sun, D. Bioorg. Med. Chem. Lett. 2012, 22, 4413-4421.

Generation of DNA-damaging reactive oxygen species via the autoxidation of hydrogen sulfide under physiologically-relevant conditions: chemistry relevant to both the genotoxic and cell signaling properties of H2S. Hoffman, M.; Rajapakse, A.; Shen, X.; Gates, K. S. Chem. Res. Toxicol. 2012, 25, 1609-1615.

Hypoxia-selective, enzymatic conversion of 6-nitroquinoline into a fluorescent helicene: pyrido[3,2-f]quinolino[6,5-c]cinnoline 3-oxide. Rajapakse, A; Gates, K. S. J. Org. Chem. 2012, 77, 3531-3537.

The macrocycle of leinamycin imparts hydrolytic stability to the thiol-sensing 1,2-dithiolan-3-one 1-oxide unit of the natural product. Sivaramakrishnan, S.; Breydo, L.; Sun, D.; Gates, K. S. Bioorg. Med. Chem. Lett. 2012, 22, 3791-3794.

On the reaction mechanism of tirapazamine reduction chemistry: unimolecular N-OH homolysis, stepwise dehydration, or triazine ring-opening. Yin, J.; Glaser, R.; Gates, K. S. Chem. Res. Toxicol. 2012, 25, 634-645.

Electron and spin-density analysis of tirapazamine reduction chemistry. Yin,, J.; Glaser, R.; Gates, K. S. Chem. Res. Toxicol. 2012, 25, 620-633.

Hypoxia-selective, enzymatic conversion of 6-nitroquinoline into a fluorescent helicene: pyrido[3,2-f]quinolino[6,5-c]cinnoline 3-oxide. Rajapakse, A.; Gates, K. S. Submitted to J. Org. Chem. 2012, 77, 3531-3537.

DNA strand cleavage by the phenazine di-N-oxide natural product myxin under both aerobic and anaerobic conditions. Chowdhury, G.; Sarkar, U.; Pullen, S.; William R. Wilson, W. R.; Rajapakse, A.; Fuchs-Knotts, T. and Gates, K. S. Chem. Res. Toxicol. 2012, 25, 195-206.

Non-covalent DNA binding drives DNA alkylation by leinamycin: evidence that the Z,E-5-(thiazol-4-yl)-penta-2,4-dienone moiety of the natural product serves as an atypical DNA intercalator. Fekry, M. I.; Szekely, J.; Dutta, S.; Breydo, L.; Zang, H.; Gates, K. S. J. Am. Chem. Soc. 2011, 132, 17641-17651.

The biological buffer, bicarbonate/CO2, potentiates H2O2-mediated inactivation of protein tyrosine phosphatases. Zhou, H.; Singh, H.; Parsons, Z. D.; Lewis, S. M.; Bhattacharya, S.; Seiner, D. R.; LaButti, J. N.; Reilly, J. N.; Tanner, J. J.; Gates, K. S. J. Am. Chem. Soc. 2011, 132, 15803-15805.

Redox regulation of protein tyrosine phosphatases: Structural and chemical aspects. Tanner, J. J.; Parsons, Z. D.; Cummings, A. H.; Zhou, H.; Gates, K. S. Antioxidants Redox Signaling 2011, 15(1), 77-97.

Synthesis and Crystal Structure of the Azoxydichinyl Helicene, Pyrido[3,2-f]quinolino[6,5-c]cinnoline 5-Oxide Monohydrate. Rajapakse, A.; Barnes, C. L.; Gates, K. S. J. Chem. Cryst. 2011, 41, 1712-1716.

Kinetic Consequences of Replacing the Internucleotide Phosphorus Atoms in DNA with Arsenic. Fekry, Mostafa I.; Tipton, Peter A.; Gates, Kent S. ACS Chem. Biol. 2011, 6, 127-130.

Thiol-Activated DNA Damage By α-Bromo-2-cyclopentenone. Fekry, M. I.; Price, N.; Zang, H.; Huang, C.; Harmata, M.; Brown, P.; Daniels, J. S.; Gates, K. S. Chem. Res. Toxicol. 2011, 24, 217-228.

Synthesis, Crystal Structure, and Rotational Energy Profile of 3-Cyclopropyl-1,2,4-benzotriazine 1,4-Di-N-oxide. Sarkar, U.; Glaser, R. E.; Parsons, Z. D.; Barnes, C. L.; Gates, K. S. J. Chem. Crystallog. 2010, 40, 624-629.

DNA strand cleaving properties and hypoxia-selective cytotoxicity of 7- chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide. Junnotula, R.; Rajapakse, A.; Arbillaga, L; Lopez de Cerain, A.;  Solano, B.; Villar, R.; Monge, A.; Gates, K. S. Bioorganic Med. Chem.   2010, 18, 3125-3132.

Inactivation of protein tyrosine phosphatases by oltipraz and other cancer chemopreventive 1,2-dithiole-3-thiones. Bhattacharya, S.; Zhou, H.; Seiner, D. R.; Gates, K. S. Bioorganic Med. Chem. 2010, 18, 5945-5949.

Characterization of DNA damage induced by a natural product antitumor antibiotic leinamycin in human cancer cells. Viswesh, V.; Gates, K. S.; Sun, D. Chem. Res. Toxicol. 2010, 23, 99-107.

Protection of a single-cysteine redox switch from oxidative destruction: on the functional role of sulfenyl amide formation in the redox-regulated enzyme PTP1B. Sivaramakrishnan, S.; Cummings, A. H.; Gates, K. S. Bioorganic Med. Chem. Lett. 2010, 20, 444-447.

An overview of chemical processes that damage cellular DNA:  spontaneous hydrolysis, alkylation, and reactions with radicals. Gates, K. S. Chem. Res. Toxicol. 2009, 22, 1747-1760.  This review was featured on the cover of the November 2009 issue of Chemical Research in Toxicology.

Kent S. Gates, Guest Editor, Thematic Collection on Chemistry and Biology of DNA Damage. Chem. Res. Toxicol. Virtual Issue. 2009, http://pubs.acs.org/page/crtoec/thematic/dna-damage.html

DNA-catalyzed hydrolysis of DNA phosphodiesters. Fekry, M. I.; Gates, K. S. Nature Chem. Biol. 2009, 5, 710-711.

Initiation of DNA strand cleavage by 1,2,4-benzotriazine 1,4-dioxides antitumor agents: Mechanistic insight from studies of 3-methyl-1,2,4- benzotriazine 1,4-dioxide. Junnotula, V.; Sarkar, U.; Sinha, S.; Gates, K. S. J. Am. Chem. Soc. 2009, 130, 1015-1024.

Biologically relevant chemical properties of peroxymonophosphate (=O3POOH). LaButti, J. N.; Gates, K. S. Bioorganic Med. Chem. Lett.  2009, 19, 218-221.

Oxidative inactivation of PTP1B by organic peroxides. Bhattacharya, S.; LaButti, J. N.; Seiner, D. R.; Gates, K. S. Bioorganic Med. Chem.  Lett. 2008, 18, 5856-5859.

Evidence for a Morin type intramolecular cyclization of an alkene with a phenylsulfenic acid group in neutral aqueous solution. Keerthi, K.; Sivaramakrishnan, S.; Gates, K. S. Chem. Res. Toxicol. 2008, 21(7), 1368-1374.

Electronic structures and spin topologies of gamma-picolinium radicals. A study of the homolysis of N-methyl-gamma-picolinium and of benzo-, dibenzo-, and naphthoannulated analogs. Glaser, R.; Sui, Y.; Sarkar, U.; Gates, K. S.J. Phys. Chem. A 2008, 112(21), 4800-4814. This paper was featured on the cover of J. Phys Chem A.

Possible mechanisms underlying the antitumor activity of S-deoxyleinamycin. Sivaramakrishnan, S.; Gates, K. S. Bioorganic Med. Chem. Lett. 2008, 18,3076-3080.

Synthesis and Biological Evaluation of New 2-Arylcarbonyl-3-trifluoromethylquinoxaline 1,4-Di-N-oxide Derivatives and Their Reduced Analogues. Solano, B.; Junnotula, V.; Marin, A.; Villar, R.; Burguete, A.; Vicente, E.; Perez-Silanes, S.; Aldana, I.; Monge, A.; Dutta, S.; Sarkar, U.; Gates, K. S. J. Med. Chem. 2007, 50(22), 5485-5492.

DNA Strand Damage Analysis Provides Evidence That the Tumor Cell-Specific Cytotoxin Tirapazamine Produces Hydroxyl Radical and Acts as a Surrogate for O2. Chowdhury, G.; Junnotula, V.; Daniels, J. S.; Greenberg, M. M.; Gates, K. S. J. Am. Chem. Soc. 2007, 129(42), 12870-12877.

Kinetics and Mechanism of Protein Tyrosine Phosphatase 1B Inactivation by Acrolein. Seiner, D. R.; LaButti, J. N.; Gates, K. S. Chem. Res. Toxicol. 2007, 20(9), 1315-1320.

Redox Regulation of Protein Tyrosine Phosphatase 1B (PTP1B) by Peroxymonophosphate (=O3POOH). LaButti, J. N.; Chowdhury, G.; Reilly, T. J.; Gates, K. S.  J. Am. Chem. Soc. 2007, 129(17), 5320-5321.

The Chemical Reactions of DNA Damage and Degradation. Kent S. Gates In: Reviews of Reactive Intermediate Chemistry, Platz, M.; Moss, R. A.; Jones, M. Jr., Eds.  John Wiley & Sons, New York.  2007, pp 333-378.

Entering the Leinamycin Rearrangement Reaction Via 2-(Trimethylsilyl)ethyl Sulfoxides. Keerthi, K.; Gates, K. S. Org. Biomol. Chem. 2007, 5(10), 1595-1600.

Interstrand Cross-Links Generated by Abasic Sites in Duplex DNA. Dutta, S.; Chowdhury, G.; Gates, K. S. J. Am. Chem. Soc. 2007, 129(7), 1852-1853.

Crystal structures of 3-methyl-1,2,4-benzotriazine 1-oxide and 2-oxide. Junnotula, V.; Sarkar, U.; Barnes, C. L.; Thallapally, P. K.; Gates, K. S. J. Chem. Cryst. 2006, 36(9),  557-561.

Getting Under Wraps:  Alkylating DNA in the Nucleosome. Gates, K. S. Nature Chem. Biol. 2006, 2(2), 64-66.

Noncovalent DNA Binding and Oxidative DNA Damage by Fecapentaene-12. Szekley, J.; and Gates, K. S. Chem. Res. Toxicology 2006, 19(1), 117-121.

DNA Damage by Fasicularin. Dutta, S; Abe, H.; Aoyagi, S.; Kibayashi, C.; Gates, K. S. J. Am. Chem. Soc. 2005, 127, 15004-15005.

The article above was discussed in the “Hot Off the Press” section of: Nat. Prod. Rep. 2006, 23(1), 11-14.

A Chemical Model for Redox Regulation of Protein Tyrosine Phosphatase 1B (PTP1B) Activity. Sivaramakrishnan, S.; Keerthi, K.; Gates, K. S. J. Am. Chem. Soc. 2005, 127, 10830-10831.

The article above was highlighted in the “Editor’s Choice” section of Science 2005, 309(July 29), 671-672… and in Chemical and Engineering News 2005, August 1, page 31.

Generation of Reactive Oxygen Species by a Persulfide (BnSSH). Chatterji, T.; Keerthi, K.; Gates, K. S. Bioorganic Med. Chem. Lett. 2005, 15, 3921-3924.

A Fluorimetric Assay for the Spontaneous Release of an N7-Alkylguanine Residue from Duplex DNA. Shipova, K.; Gates, K. S. Bioorganic Med. Chem. Lett. 2005, 15, 2111-2113.

Enzyme-Activated, Hypoxia-Selective DNA Damage by 3-Amino-2-quinoxalinecarbonitrile 1,4-Dioxide. Chowdhury, G.; Kotandenaya, D.; Barnes, C. L.; Gates, K. S. Chem. Res. Toxicol. 2004, 17(11), 1400-1405.

Biologically Relevant Chemical Properties of N7-Alkylguanine Residues in DNA (Review Article).  Gates, K. S.; Nooner, T.; Dutta, S. Chem. Res. Toxicol. 2004, 17(7), 839-856.

Chemical Properties of the Leinamycin-Guanine Adduct in DNA.  Nooner, T.; Dutta, S.; Gates, K. S. Chem. Res. Toxicol. 2004, 17(7), 942-949.

Synthesis and DNA-Binding Properties of Thiazole Derivatives Related to Leinamycin.  Breydo, L; Zang, H.; Gates, K. S. Tetrahedron Lett. 2004, 45, 5711-5716.

Sequence Specificity of DNA Alkylation by the Antitumor Natural Product Leinamycin.  Zang, H.; Gates, K. S. Chem. Res. Toxicol. 2003, 16, 1539-1546.

DNA Base Damage by the Antitumor Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine).  Birincioglu, M.; Jaruga, P.; Chowdhury, G.; Rodriguez, H.; Dizdaroglu, M.; Gates, K. S. J. Am. Chem. Soc. 2003, 125(38), 11607-11615.

A Mass Spectrometry Study of Tirapazamine and Its Metabolites: Insights Into the Mechanism of Metabolic Transformations and Characterization of Reaction Intermediates.  Zagorevskii, D.; Song, M.; Breneman, C.; Yuan, Y.; Fuchs, T.; Gates, K. S.; Greenlief, C. M. J. Am. Soc. for Mass Spec. 2003, 14(8), 881-892.

Small Molecules That Mimic the Thiol-Triggered Alkylating Properties Seen in the Natural Product Leinamycin.  Chatterji, T.; Kizil, M.; Keerthi, K.; Chowdhury, G.; Pospisil, T.; Gates, K. S. J. Am. Chem. Soc. 2003, 125(17), 4996-4997.

The article above was highlighted in the “Editor’s Choice” section of Science 2003, 300(May 2), 703-705.

Reaction of Thiols with 7-Methylbenzopentathiepin.  Chatterji, T.; Gates, K. S. Bioorg. Med. Chem. Lett., 2003, 13, 1349-1352.

Activation of Leinamycin by Thiols:  A Theoretical Study.  Breydo, L.; Gates, K. S. J. Org. Chem. 2002, 67, 9054-9060.

Oxidative DNA Base Damage by the Antitumor Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine).  Kotandeniya, D.; Ganley, B.; Gates, K. S. Bioorg. Med. Chem. Lett. 2002, 12, 2325-2329.

E,E- and Z,E-Thiazol-5-yl-penta-2,4-dienones.  Breydo, L.; Barnes, C. L.; Gates, K. S. Acta Cryst. C, 2002, C58, o447-o449.

Photochemical Electron Transfer Reactions of Tirapazamine.  Poole, J. S.; Hadad, C. M.; Platz, M. S.; Fredin, Z. P.; Pickard, L.; Guerrero, E. L.; Kessler, M.; Chowdhury, G.; Kotandeniya, D.; Gates, K. S. Photochem. Photobiol. 2002, 75(4), 339-345.

Crystal Structure of 3-Amino-5-methyl-1,2,4-benzotriazine 1-Oxide: Evidence for Formation of a Covalent Attachment Between a Carbon-Centered Radical and the Antitumor Agent Tirapazamine.  Fuchs, T.; Barnes, C. L.; Gates, K. S. J. Chem. Crystallog. 2001, 31(7/8), 387-391.

Redox-Activated, Hypoxia-Selective DNA Cleavage by Quinoxaline 1,4-Dioxide.  Ganley, B.; Chowdhury, G.; Bhansali, J.; Daniels, J. S.; Gates, K. S. Bioorganic Med. Chem. 2001, 9, 2395-2401.

DNA Alkylation by Leinamycin Can Be Triggered by Cyanide and Phosphines.  Zang, H.; Breydo, L.; Mitra, K. Dannaldson, J.; Gates, K. S. Bioorganic Med. Chem. Lett. 2001, 11, 1511-1515.

Thiol-Independent DNA Alkylation by Leinamycin.  Breydo, L.; Mitra, K.; Zang, H.; Gates, K. S. J. Am. Chem. Soc. 2001, 123, 2060-2061.

The article above was highlighted in the Science Concentrates section of Chemical and Engineering News 2001, March 5, page 35.

3-Amino-1,2,4-benzotriazine 4-Oxide:  A New Product Arising from Bioreductive Metabolism of the Antitumor Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine).  Fuchs, T.; Chowdhary, G.; Barnes, C. L.; Gates, K. S. J. Org. Chem. 2001, 66, 107-114.

DNA Binding and Alkylation by the "Left Half" of Azinomycin B.  Zang, H.; Gates, K. S.  Biochemistry 2000, 39, 14968-14975.

Mechanisms of DNA Damage by Leinamycin.  Gates, K. S. Chem. Res. Toxicol. 2000, 13, 953-956.

Thiol-Dependent DNA Cleavage by 3H-1,2-Benzodithiol-3-one 1,1-Dioxide.  Breydo, L.; Gates, K. S. Bioorganic Med. Chem. Lett. 2000, 10, 885-889.

Covalent Modification of DNA by Natural Products.  Kent S. Gates  In: Comprehensive Natural Products Chemistry, Volume 7, Chapter 14.  Barton, D., Nakanishi, K., Meth-Cohn, O. Eds.; Kool, E. T., Volume Ed.  Pergamon Press, Oxford.  1999; pp 491-552  (For a review of this book, see: J. Nat. Prod. 2000, 63(2), 291-291)

Crystal Structure of Methyl trans-3-[(2-(methoxycarbonyl)phenyl)sulfinyl] Acrylate:  A Product Resulting from Trapping of a Sulfenic Acid by Methyl Propiolate.  Mitra, K.; Barnes, C. L.; Gates, K. S. J. Chem. Crystallogr. 1999, 29(10), 1133-1136.

Photosensitization of Guanine-Specific DNA Damage by a Cyano-Substituted Quinoxaline Di-N-Oxide.  Fuchs, T.; Gates, K. S.; Hwang, J.-T.; Greenberg, M. M. Chem. Res. Toxicol. 1999, 12(12), 1190-1194.

Reaction of the Hypoxia-Selective Antitumor Agent Tirapazamine with a C1'-Radical in Single-Stranded and Double-Stranded DNA:  The Drug and Its Metabolites Can Serve As Surrogates for Molecular Oxygen in Radical-Mediated DNA-Damage Reactions.  Hwang, J.-T.; Greenberg, M. M.; Fuchs, T.; Gates, K. S. Biochemistry 1999, 38(43), 14248-14255.

Chemistry of Thiol-Dependent DNA Damage by the Antitumor Antibiotic Leinamycin.  Mitra, K.; Gates, K. S. Recent Res. Devel. Organic Chem. 1999, 3, 311-317.

Direct Evidence for Bimodal DNA Damage Induced by Tirapazamine.  Daniels, J. S., Gates, K. S., Tronche, C., Greenberg, M. M. Chem. Res. Toxicol. 1998, 11(11), 1254-1257.

Total Synthesis and DNA-Cleaving Properties of Thiarubrine C.  Wang, Y.; Koreeda, M.; Chatterji, T.; Gates, K. S.  J. Org. Chem. 1998, 63(24), 8644-8645.

Photochemical DNA Cleavage by the Antitumor Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine, SR4233).  Daniels, J. S.; MacGillivray, L. R.; Gates, K. S.  J. Org. Chem. 1998, 63, 10027-10030.

Crystal Structure of 3H-1,2-Benzodithiol-3-one 1-Oxide.  Behroozi, S.J.; Barnes C.L.; Gates, K.S., J. Chem. Crystallog. 1998, 28(9), 689-691.

DNA Cleavage by 7-Methylbenzopentathiepin:  A Simple Analog of the Antitumor Antibiotic Varacin.  Chatterji, T.; Gates, K. S.  Bioorg. Med. Chem. Lett. 1998, 8, 535-538.

Synthesis and Structure of Functionalized Derivatives of the Cleft-Shaped Molecule Dithiosalicylide.  Mitra, K.; Pohl, M.; Barnes, C. L.; Gates, K. S., J. Org. Chem. 1997, 62, 9361-9364.

Oxidative DNA Cleavage by Leinamycin and Simple 1,2-Dithiolan-3-one 1-Oxides: Evidence for Thiol-Dependent Conversion of Molecular Oxygen to DNA-Cleaving Oxygen Radicals Mediated by Polysulfides.  Mitra, K.; Kim, W.; Gates, K. S., J. Am. Chem. Soc. 1997, 119, 11691-11692.

The article above was highlighted in the Science Concentrates section of Chemical and Engineering News 1997, Dec. 8, page 23… and in the “Hot of the Press” section of Nat. Prod. Rep. 1998, 15(1), iii-iv.

Evidence for Thiol-Dependent Production of Oxygen Radicals by 4-Methyl-5-pyrazinyl-3H-1,2-Dithiole-3-thione: Possible Relevance to the Anticarcinogenic Properties of 1,2-Dithiole-3-thiones.  Kim, W.; Gates, K. S. Chem. Res. Toxicol. 1997, 10, 296-301.

Reactions of 3H-1,2-Benzodithiol-3-one 1-Oxide with Amines and Anilines.  Kim, W.; Dannaldson, J.; Gates, K. S., Tetrahedron Lett. 1996, 37, 5337-5340.

DNA Cleavage by the Antitumor Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (SR4233):  Evidence for Involvement of Hydroxyl Radical.  Daniels, J.S; Gates, K.S., J. Am. Chem. Soc. 1996, 118, 3380-3385.

1,2-Dithiolan-3-one 1-Oxides: Thiol-Activated DNA-Cleaving Agents Structurally Related to Antitumor Antibiotic Leinamycin.  Behroozi, S.J.; Kim, W.; Dannaldson, J.; Gates, K.S. Biochemistry 1996, 35, 1768-1774.

The article above was discussed in: Chemical and Engineering News 1996, Feb. 26, 38.)

The Reaction of n-Propanethiol With 3H-1,2-Benzodithiol-3-one 1-Oxide and 5,5-Dimethyl-1,2-dithiolan-3-one 1-Oxide: Studies Related to the Reaction of Antitumor Antibiotic Leinamycin With DNA.  Behroozi, S.B.; Kim, W.; Gates, K.S. J. Org. Chem. 1995, 60, 3964-3966.

Novel Syntheses of Dithiosalicylide.  Mitra, K.; Gates, K.S. Tetrahedron Lett. 1995, 36, 1391-1394.

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