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Research Summary

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.

Current research in the group is divided among several general areas:

(1) 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.

(2) 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.

(3) 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 that is produced as a second messenger in response to extracellular stimuli such as insulin, epidermal growth factor, and platelet derived growth factor. Hydrogen peroxide 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.

Selected Publications

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

DNA strand damage analysis provides evidence that the tumor cell-specific cytotoxin tirapazamine produces hydroxyl radical and acts as a surrogate for molecular oxygen Chowdhury, C.; Junnotula, V.; Daniels, J. S.; Greenberg, M. M.; Gates, K. S. J. Am. Chem. Soc. 2007, 129, 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, 1315-1320.

The paper above was among the top 10 most downloaded articles July-Sept 2007.

Chemical reactions of DNA damage and degradation (click here to access an order form for this book) Gates, K. S. Reviews of Reactive Intermediate Chemistry, Platz, M.; Moss, R. A.; Jones, M. Jr., Eds. John Wiley & Sons, New York. 2007, pp. 333-378.

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.; Monge, A.; Dutta, S.; Sarkar, U.; Gates, K. S. J. Med. Chem. 2007, X, 5485-5492.

Entering the leinamycin rearrangement via 2-(trimethylsilyl)ethyl sulfoxides Keerthi, K.; Gates, K. S. Org. Biomol. Chem. 2007, 5, 1595-1600.

Redox Regulation of Protein Tyrosine Phosphatase 1B (PTP1B) by Peroxymonophosphate (=O3POOH) LaButti, J.; Chowdhury, G.; Reilly, T. J.; Gates, K. S. J. Am. Chem. Soc. 2007, 129(17), 5321-5322.

The paper above was recommended on the "Faculty of 1000 Biology website".

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.

Stabilities and Spin Distributions of Benzannulated Benzyl Radicals Sui, Y.; Glaser, R.; Sarkar, U.; Gates, K. S. J. Chem. Theory and Comput. 2007, 3(3), 1091-1099.

Crystal Structures of 3-Methyl-1,2,4-benzotriazine 1-oxide and 2-oxide Junnotula, V.; Sarkar, U.; Barnes, C. L.; Thallapally, R. V.; 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 the Mechanism of Oxidative DNA Damage by Fecapentaene-12 Szekely, J.; Gates, K. S. Chem. Res. Toxicol. 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 paper above was mentioned 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 JACS article above was highlighted in the "Editor's Choice" section of Science Magazine. Science 2005, 309 (July 29), 671-672. ...and in Chemical and Engineering News. Chem. Eng. 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, 46, 3921-3924.

A Fluorimetric Assay for the Depurination of an N7-Alkylguanine Residue from Duplex DNA. Shipova, K.; Gates, K. S. Bioorganic Med. Chem. Lett. 2005, 46, 2111-2113.

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

Enzyme-Activated, Hypoxia-Selective DNA Damage by 3-Amino-2-quinoxalinecarbonitrile 1,4-Dioxide. Chowdhury, G.; Kotandeniya, D.; Daniels, J. S.; Barnes, C. L.; Zang, H.; Gates, K. S. Chem. Res. Toxicol. 2004, 17, 1399-1405.

Biologically Relevant Chemical Reactions of N7-Alkylguanine Residues in DNA. Gates, K. S.; Nooner, T; Dutta, S. Chem. Res. Toxicol. 2004, 17, 839-856.

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

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.; Didaroglu, M.; Gates, K. S. J. Am. Chem. Soc. 2003, 125, 11607-11615

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

Small Molecules that Mimic the Alkylating Properties of the Natural Product Leinamycin. Chatterji, T.; Kizil, M.; Keerthi, K.; Chowdhury, G.; Posposil, J.; Gates, K. S. J. Am. Chem. Soc. 2003, 125, 4996-4997.

The JACS article above was highlighted in the Editor's Choice section of Science Magazine. 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, 9054-9067.

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. Bioorganic 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.; Fredin, Z. P.; Pickard, L.; Guerrero, E. L.; Kessler, M.; Chowdhury, G.; Kotandeniya, D.; Gates, K. S.Photochemistry and Photobiology 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(78), 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 Medicinal Chemistry 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 Medicinal Chemistry Letters 2001, 11, 1511-1515.

Thiol-Independent DNA Alkylation by Leinamycin. Breydo, L.; Mitra, K.; Zang, H.; Gates, K. S. Journal of the American Chemical Society 2001, 123, 2060-2061.

The JACS article above was highlighted in the Science Concentrates section of Chemical and Engineering News. C&ENews 2001, March 5, 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. Journal of Organic Chemistry 2001, 66, 107-114.

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

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

Thiol-Dependent DNA Cleavage by 3H-1,2-Benzodithiol-3-one 1,1-Dioxide.Breydo, L.; Gates, K. S.Bioorganic and Medicinal Chemistry Letters . 2000, 10, 885-889.

Covalent Modification of DNA by Natural Products. Gates, K. S. In Comprehensive Natural Products Chemistry, Volume 7: DNA and Aspects of Molecular Biology, Kool, E. T., Ed.; Pergamon: Oxford,1999; pp 491-552.

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. Journal of Chemical Crystallography. 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. Chemical Research in Toxicology. 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.

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

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, 1254-1257.

DNA Cleavage by 7-Methylbenzopentathiepin: A Simple Analog of the Antitumor Antibiotic Varacin. Chatterji, T.; Gates, K. S. Bioorganic Medicinal Chemistry Letters 1998, 8, 535-538.

Photochemical DNA Cleavage by the Antitumor Agent 3-Amino-1,2,4-benzotriazine 1,4-dioxide (Tirapazamine, WIN 59075, SR4233). Daniels, J. S.; Chatterji, T.; MacGillivray, L. R.; Gates, K. S. J. Org. Chem. 1998, 63(26), 10027-10030.

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, 63(26), 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.Journal of the American Chemical Society 1997, 119, 11691-11692. (Abstracted in Chemical and Engineering News 1997, Dec. 8, 23)

The JACS article above was highlighted in the "Hot Off the Press" section of Nat. Prod. Reports 1998, 15(1), iii-iv.

The JACS article above was highlighted in the "Science Concentrates" section of Chemical and Engineering News. C&ENews 1997, Dec 8, 23.

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. Chemical Research in Toxicology 1997, 10, 296-301.

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

DNA Cleavage by Antitumor Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (SR4233): Evidence for Involvement of Hydroxyl Radical. Daniels, J.S.; Gates, K.S., Journal of the American Chemical Society 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. (Reviewed in: Chemical and Engineering News 1996, Feb. 26, 38.)

The Biochemistry article above was discussed in Chemical and Engineering News. C&ENews 1996, Feb 6, 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. Journal of Organic Chemistry 1995, 60, 3964-66.

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


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