Historically, natural products have proven a rich source of anticancer drugs. A recent review estimated that 74% of the clinically used drugs in this field of medicine are natural products or are derived from natural product lead compounds. This statistic suggests that it is important for the cancer community to continue studies of novel anticancer agents isolated from natural sources. The work described in this proposal is designed to characterize the chemical and biological mechanisms of the antineoplastic, DNA- damaging natural product leinamycin. Leinamycin displays very potent activity against human cancer cell lines (e.g. IC50 of 0.014 ng/mL - this translates to an IC50 of 27 nM - against HeLa cells) and is currently in development as a potential anticancer agent at Kyowa Hakko Kogyo Pharmaceuticals. Exposure of duplex DNA to leinamycin leads to production of a rapid """"""""burst"""""""" of apurinic sites (AP sites). In addition, reaction with leinamycin converts the attacking thiol residue into a persulfide (RSSH) species that has the potential to cause oxidative stress in cells. Leinamycin does not generate DNA-crosslinks or double-strand breaks, but displays biological activity comparable to clinically used agents that do. Thus, the unusual DNA-damaging properties of leinamycin may represent a new biochemical route to potent anticancer activity. Experiments described in this proposal are designed to relate leinamycin's unique biochemical properties to its potent activity against cancer cell lines. We will test the hypothesis that leinamycin's ability to simultaneously generate a burst of AP sites along with oxidative stress account for its very potent biological activity. ? ? The work is divided into the following five Specific Aims: 1. Test the Hypothesis That the Rapid Generation of AP Sites Is Central to Leinamycin's Cancer Cell Killing Properties. 2. Explore the Chemical Basis for the Exceedingly Rapid Depurination of the Leinamycin-Guanine Adduct in Duplex DNA. 3. Test the Hypothesis That Leinamycin Causes Oxidative Stress In Human Cancer Cell Lines. 4. Explore the Chemical Mechanisms by Which Leinamycin Generates Reactive Oxygen Species Under Physiologically Relevant Conditions. 5. Characterize Cellular Responses to Leinamycin. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA119131-02
Application #
7286021
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2006-09-12
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$258,701
Indirect Cost
Name
University of Missouri-Columbia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Parsons, Zachary D; Gates, Kent S (2013) Thiol-dependent recovery of catalytic activity from oxidized protein tyrosine phosphatases. Biochemistry 52:6412-23
Keerthi, Kripa; Rajapakse, Anuruddha; Sun, Daekyu et al. (2013) Synthesis and characterization of a small analogue of the anticancer natural product leinamycin. Bioorg Med Chem 21:235-41
Rajapakse, Anuruddha; Gates, Kent S (2012) Hypoxia-selective, enzymatic conversion of 6-nitroquinoline into a fluorescent helicene: pyrido[3,2-f]quinolino[6,5-c]cinnoline 3-oxide. J Org Chem 77:3531-7
Hoffman, Marjorie; Rajapakse, Anuruddha; Shen, Xiulong et al. (2012) 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 H(2)S. Chem Res Toxicol 25:1609-15
Viswesh, Velliyur; Hays, Allison M; Gates, Kent et al. (2012) DNA cleavage induced by antitumor antibiotic leinamycin and its biological consequences. Bioorg Med Chem 20:4413-21
Sivaramakrishnan, Santhosh; Breydo, Leonid; Sun, Daekyu et al. (2012) The macrocycle of leinamycin imparts hydrolytic stability to the thiol-sensing 1,2-dithiolan-3-one 1-oxide unit of the natural product. Bioorg Med Chem Lett 22:3791-4
Fekry, Mostafa I; Price, Nathan E; Zang, Hong et al. (2011) Thiol-activated DNA damage by ýý-bromo-2-cyclopentenone. Chem Res Toxicol 24:217-28
Fekry, Mostafa I; Szekely, Jozsef; Dutta, Sanjay et al. (2011) Noncovalent 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. J Am Chem Soc 133:17641-51
Zhou, Haiying; Singh, Harkewal; Parsons, Zachary D et al. (2011) The biological buffer bicarbonate/CO2 potentiates H2O2-mediated inactivation of protein tyrosine phosphatases. J Am Chem Soc 133:15803-5
Sivaramakrishnan, Santhosh; Cummings, Andrea H; Gates, Kent S (2010) Protection of a single-cysteine redox switch from oxidative destruction: On the functional role of sulfenyl amide formation in the redox-regulated enzyme PTP1B. Bioorg Med Chem Lett 20:444-7

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