The Organic and Macromolecular Chemistry Program supports Professor Steven E. Rokita at the University of Maryland- College Park who proposes to explore research at the interface of chemistry and biochemistry in order to develop a predictive understanding of how low molecular weight reagents react with their biological targets. The research will identify the time-dependent evolution of quinone methide adducts in duplex DNA and assess, in a fundamental manner, the impact of reversibility on macromolecular reaction. A new assay relying on oxidative trapping has been developed so that transient products formed in duplex DNA may finally receive the same scrutiny previously afforded to only individual nucleotides. The role of nucleotide sequence in quinone methide regeneration will also be determined since formation and reaction of this intermediate have previously shown sensitivity to solvent conditions. As a complement to studies on electron transfer in DNA, further investigations will measure the ability of DNA to act as a conduit for electrophile (quinone methide) migration that may otherwise be quenched by competing nucleophiles in a biochemical system. The results of this proposal should provide a conceptual foundation for how the reversibility of covalent reaction can profoundly affect the lifetime and target selectivity of transient intermediates forming DNA adducts.
The Organic and Macromolecular Chemistry Program supports Professor Steven E. Rokita who will explore the fundamental physical organic chemistry underlying the reaction of quinone methides with nucleic acids. Professor Rokita has discovered that quinone methides can react with DNA to form reversible covalent bonds. The concept of reversible covalent interactions with DNA has been recognized for years but only recently has it been appreciated for its potential significance in understanding cellular responses to DNA damage. This work has significant implications for our basic understanding of the interactions of drugs and toxins with DNA, for understanding the chemical basis for cellular responses to DNA damage, and ultimately for designing DNA-reactive therapeutics for many human diseases. The planned investigations span the disciplines of chemistry and biochemistry and have attracted a number of students at all levels, many of which are underrepresented in science. Efforts will continue to ensure that such students participate in this research and share the experience with their colleagues by participating in departmental and college programs serving minorities, high school teachers and their students.
