The action of many non-hydrolytic DNA cleaving agents is believed to be based on reactive phenyl radicals that abstract hydrogen atoms from deoxyribose in DNA. Various issues relating to this process, including the drug's binding site on DNA, the mechanism of radical formation, its accessibility to various DNA sites, and the fate of the resulting DNA radicals, are being addressed by scientists to advance the rational design of better antitumor and antiviral drugs. However, the key part of the process, the reaction of the radical intermediate with DNA, remains unexplored. Although information on the factors that control this reaction is critically needed for drug design, nearly nothing is known about the radical intermediates formed from drugs because of severe experimental difficulties in studying such highly reactive species. Our goal is to learn how to control the reactivity and intrinsic selectivity of a radical warhead by structural changes. We have developed a novel experimental approach based on mass spectrometry to study biologically relevant radical reactions. The method involves attaching a charged group to a radical of interest for manipulation in an FT-ICR mass spectrometer wherein small neutral biomolecules are introduced by laser-induced acoustic desorption. This proposal presents a continuation of a four-year project that involved 1) purchase and set-up of the necessary instrumentation, 2) demonstration of the feasibility of the approach, 3) examination of known systems to show that the method yields data relevant to neutral radicals and solution conditions, and 4) collection of kinetic reactivity data to provide several novel structure/reactivity relationships for advancement of the design of better non-hydrolytic DNA cleavers. The most important areas of the currently proposed work include (1) development of structure/reactivity relationships for more complex systems, (2) exploration of the selectivity of different radicals toward different sites in oligonucleotides, (3) examination of the propensity of the radicals to attack peptides to model protein damage, and (4) based on the insights gained in the above studies, development of a reactivity paradigm that provides general predictive power. (5) This paradigm will be used to design target-specific radical warheads and prodrugs. Professors Rick Borch (Medicinal Chemistry and Molecular Pharmacology, Purdue), a specialist in cancer drug design and mechanisms,and Mark Lipton (Organic Chemistry, Purdue), an expert in synthesis of biradical producing prodrugs, will guide the research and help in finding the best way to incorporate knowledge into the design and testing of novel drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM052418-08
Application #
7178547
Study Section
Special Emphasis Panel (ZRG1-BECM (01))
Program Officer
Edmonds, Charles G
Project Start
1997-06-01
Project End
2008-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
8
Fiscal Year
2007
Total Cost
$136,701
Indirect Cost
Name
Purdue University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Wittrig, Ashley M; Archibold, Enada F; Sheng, Huaming et al. (2015) Polar Effects Control the Gas-phase Reactivity of Charged para-Benzyne Analogs. Int J Mass Spectrom 377:39-43
Williams, Peggy E; Jankiewicz, Bart?omiej J; Yang, Linan et al. (2013) Properties and reactivity of gaseous distonic radical ions with aryl radical sites. Chem Rev 113:6949-85
Widjaja, Fanny; Jin, Zhicheng; Nash, John J et al. (2013) Comparison of the reactivity of the three distonic isomers of the pyridine radical cation toward tetrahydrofuran in solution and in the gas phase. J Am Soc Mass Spectrom 24:469-80
Yang, Linan; Bekele, Tefsit; Lipton, Mark A et al. (2013) Generation and characterization of a distonic biradical anion formed from an enediynone prodrug in the gas phase. J Am Soc Mass Spectrom 24:563-72
Widjaja, Fanny; Jin, Zhicheng; Nash, John J et al. (2012) Direct comparison of solution and gas-phase reactions of the three distonic isomers of the pyridine radical cation with methanol. J Am Chem Soc 134:2085-93
Jin, Zhicheng; Daiya, Shivani; Kenttamaa, Hilkka I (2011) Characterization of Nonpolar Lipids and Selected Steroids by Using Laser-Induced Acoustic Desorption/Chemical Ionization, Atmospheric Pressure Chemical Ionization, and Electrospray Ionization Mass Spectrometry. Int J Mass Spectrom 301:234-239
Pates, George O; Guler, Leonard; Nash, John J et al. (2011) Reactivity and selectivity of charged phenyl radicals toward amino acids in a Fourier transform ion cyclotron resonance mass spectrometer. J Am Chem Soc 133:9331-42
Gao, Jinshan; Borton 2nd, David J; Owen, Benjamin C et al. (2011) Laser-induced acoustic desorption/atmospheric pressure chemical ionization mass spectrometry. J Am Soc Mass Spectrom 22:531-8
Habicht, Steven C; Amundson, Lucas M; Duan, Penggao et al. (2010) Laser-induced acoustic desorption coupled with a linear quadrupole ion trap mass spectrometer. Anal Chem 82:608-14
Fu, Mingkun; Li, Sen; Archibold, Enada et al. (2010) Reactions of an aromatic ýý,ýý-biradical with amino acids and dipeptides in the gas phase. J Am Soc Mass Spectrom 21:1737-52

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