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

Abstract

A 2′-deoxycytidin-N4-yl radical (dC•), a strong oxidant that also abstracts hydrogen atoms from carbon−hydrogen bonds, is produced in a variety of DNA damaging processes. We describe here the independent generation of dC• from oxime esters under UV-irradiation or single electron transfer conditions. Support for this σ-type iminyl radical generation is provided by product studies carried out under aerobic and anaerobic conditions, as well as electron spin resonance (ESR) characterization of dC• in a homogeneous glassy solution at low temperature. Density functional theory (DFT) calculations also support fragmentation of the corresponding radical anions of oxime esters 2d and 2e to dC• and subsequent hydrogen atom abstraction from organic solvents. The corresponding 2′-deoxynucleotide triphosphate (dNTP) of isopropyl oxime ester 2c (5) is incorporated opposite 2′-deoxyadenosine and 2′-deoxyguanosine by a DNA polymerase with approximately equal efficiency. Photolysis experiments of DNA containing 2c support dC• generation and indicate that the radical produces tandem lesions when flanked on the 5′-side by 5′-d(GGT). These experiments suggest that oxime esters are reliable sources of nitrogen radicals in nucleic acids that will be useful mechanistic tools and possibly radiosensitizing agents when incorporated in DNA.

Nitrogen-Centered Radicals Derived from Azidonucleosides

“…Photolysis studies also revealed 88 can recombine with the aryloxyl radical to regenerate 87, undergo C5-C6 addition to produce diradicals, generate deoxycytidine via reduction, or react under aerobic conditions to generate other radicals/products. Iminyl radical 88 was also independently generated (and characterized by EPR) via single-electron transfer to oxime ester 89 [110]. Like with adeninyl radical 72, tandem lesion formation from cytosinyl radical 88 is traceless because it is reduced to dC during the process.…”

“…The tautomerization of syn-aminyl radical also leads to the iminyl σ-radical 88 [111,112]. Interestingly, contrary to these findings, [109][110][111] the one-electron reduction (conditions for DEA) of azide precursors at the C4 positions of pyrimidine bases (62 or 63) led to the formation of anion radicals 66 or 67 (see Figure 11) [94,95]. One-electron oxidation and ESR studies of 1-methylcytosine and 2 ′ -deoxycytidine 91 showed that the cytidine cation radical 92 preferentially deprotonates to form an aminyl radical 94 syn to the carbonyl moiety (Figure 17).…”

“…The tautomerization of syn-aminyl radical also leads to the iminyl σ-radical 88 [111,112]. Interestingly, contrary to these findings, [109][110][111] the one-electron reduction (conditions for DEA) of azide precursors at the C4 positions of pyrimidine bases (62 or 63) led to the formation of anion radicals 66 or 67 (see Figure 11) [94,95].…”

DABCO‐Promoted Selective Photochemical C−N Coupling: Access to Unsymmetrical Azahelicenes

“…While much progress has been made in this area over the past decade, significant limitations still remain, such as the need for pre-functionalization of substrates, the need for toxic and hazardous reagents, a narrow range of substrates, and drastic reaction conditions. [11] Consequently, there is still a high demand to develop efficient and simple methods for generation of iminyl radicals from readily available starting compounds and their application in the syn-thesis of N-heterocyclic compounds. Of particular interest is the photochemical strategy for generating the iminyl radical from biaryl acyl oximes, which makes it possible to carry out the reaction under mostly mild conditions (room temperature) and without metal catalysts.…”