The action of many DNA cleaving drugs is based on the formation of a reactive polyatomic mono- or biradical that then abstracts a hydrogen atom from a sugar moiety in DNA, inducing a strand cleavage. Understanding the factors that control the efficiency of his hydrogen atom abstraction reaction is crucial for strategic antitumor and antiviral drug design. However, little is currently known about these factors or about the properties of the reactive radical intermediates formed from drugs. This study addresses these issues by using mass spectrometry experiments to examine the intrinsic reactivity of differently substituted phenyl radicals and biradicals pertinent to the action of antitumor and antiviral (AIDS) drugs. The structural features are explored that determine a radicals ability to abstract a hydrogen atom from deoxyribose, its selectivity toward different hydrogen atoms, and its reactivity toward different substances. Solvent effects are addressed by examining reactions as a function of stepwise solvation. The experimental data is complemented by thermochemical information obtained from molecular orbital calculations. In addition to examination of the factors that control the reactivity of known types of nonhydrolytic DNA cleavers, various novel mono-, bi- and triradicals are screened for their ability to abstract a hydrogen atom from DNA. The goal is to discover efficient DNA cleavers that may provide the basis for the development of new types of pharmaceuticals. Further, the use of photolysis to generate DNA-cleaving radicals is explored as an effort to advance the design of artificial DNA photo cleaving agents for site-specific medical treatments. Finally, different methods to trap radicals are evaluated for possible application in prevention of free radical damage caused by such conditions as Alzheimer s disease and strokes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG3-SSS-6 (18))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Purdue University
Schools of Arts and Sciences
West Lafayette
United States
Zip Code
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

Showing the most recent 10 out of 18 publications