Photochemical and Single Electron Transfer Generation of 2′-Deoxycytidin-N4-yl Radical from Oxime Esters

A 2 '-deoxycytidin-N4-yl radical (dC center dot),a strong oxidant that also abstracts hydrogen atoms from carbon-hydrogenbonds, is produced in a variety of DNA damaging processes. We describehere the independent generation of dC center dot from oxime esters underUV-irradiation or single electron transfer conditions. Support forthis sigma-type iminyl radical generation is provided by productstudies carried out under aerobic and anaerobic conditions, as wellas electron spin resonance (ESR) characterization of dC center dot in ahomogeneous glassy solution at low temperature. Density functionaltheory (DFT) calculations also support fragmentation of the correspondingradical anions of oxime esters 2d and 2e to dC center dot and subsequent hydrogen atom abstraction from organicsolvents. The corresponding 2 '-deoxynucleotide triphosphate(dNTP) of isopropyl oxime ester 2c (5) isincorporated opposite 2 '-deoxyadenosine and 2 '-deoxyguanosineby a DNA polymerase with approximately equal efficiency. Photolysisexperiments of DNA containing 2c support dC center dot generation and indicate that the radicalproduces tandem lesions when flanked on the 5 '-side by 5 '-d-(GGT).These experiments suggest that oxime esters are reliable sources ofnitrogen radicals in nucleic acids that will be useful mechanistictools and possibly radiosensitizing agents when incorporated in DNA.

Automated summary

We independently generated dC center dot from oxime esters under UV-irradiation or single electron transfer conditions, which is a strong oxidant that can abstract hydrogen atoms from carbon-hydrogen bonds and is produced in various DNA damaging processes. Product studies, electron spin resonance (ESR) characterization, and density functional theory (DFT) calculations supported the generation of this sigma-type iminyl radical. These experiments suggest that oxime esters are reliable sources of nitrogen radicals in nucleic acids and can be useful mechanistic tools and possibly radiosensitizing agents when incorporated in DNA.