个人简介

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 Editorial Advisory Board, Chemical Research in Toxicology, 2000-present 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 Editorial Board of Reviewers, Arkivoc-The Online Organic Chemistry Journal, 2008-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, Biooganic Natural Products Study Section of the NIH, 1998 Member, American Chemical Society Member, American Association for the Advancement of Science Member, American Association for Cancer Research

研究领域

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

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. research image 1 research image 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. 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.

近期论文

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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. 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. 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, doi: 10.1093/nar/gkv174. 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. 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. 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. Kevin M. Johnson, Nathan E. Price, Jin Wang, Mostafa I. Fekry, Sanjay Dutta, Derrick R. Seiner, Yinsheng Wang, and Kent S. Gates J. Am. Chem. Soc. 2013, 135, 1015-1025. Thiol-dependent recovery of activity from oxidized protein tyrosine phosphatases (PTPs). Zachary D. Parsons and Kent S. Gates Biochemistry 2013, 52, doi:10.1021/bi400451m. Redox regulation of protein tyrosine phosphatases: Methods for kinetic analysis of covalent enzyme inactivation. Zachary D. Parsons, and Kent S. Gates Methods Enzymol. 2013, 528, 129-154. Fapy lesions and DNA mutations. Kent S. Gates Nat. Chem. Biol. 2013, 9, 412-413. Enzymatic Conversion of 6-Nitroquinoline to the Fluorophore 6-Aminoquinoline Selectively under Hypoxic Conditions. Anuruddha Rajapakse, Collette Linder, Ryan D. Morrison, Ujjal Sarkar, Nathan D. Leigh, Charles L. Barnes, J. Scott Daniels, and Kent S. Gates Chem. Res. Toxicol. 2013, 26, 555-563. Synthesis and characterization of a small analogue of the anticancer natural product leinamycin. Keerthi, K.; Rajapakse, A.; Sun, D.; Gates, K. S.Bioorg. Med. Chem. 2013, 21, 235-241. 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. DNA cleavage induced by the antitumor antibiotic leinamycin and its biological consquences. Viswesh, V.; Hayes, A.; Gates, K. S.; Sun, D. Bioorg. Med. Chem. 2012, 20, 4413-4421.