π-Radical to σ-Radical Tautomerization in One-Electron-Oxidized 1-Methylcytosine and Its Analogs

J Phys Chem B. 2015 Sep 3;119(35):11496-505. doi: 10.1021/acs.jpcb.5b05162. Epub 2015 Aug 13.

Abstract

In this work, iminyl σ-radical formation in several one-electron-oxidized cytosine analogs, including 1-MeC, cidofovir, 2'-deoxycytidine (dCyd), and 2'-deoxycytidine 5'-monophosphate (5'-dCMP), were investigated in homogeneous, aqueous (D2O or H2O) glassy solutions at low temperatures by employing electron spin resonance (ESR) spectroscopy. Upon employing density functional theory (DFT) (DFT/B3LYP/6-31G* method), the calculated hyperfine coupling constant (HFCC) values of iminyl σ-radical agree quite well with the experimentally observed ones, thus confirming its assignment. ESR and DFT studies show that the cytosine iminyl σ-radical is a tautomer of the deprotonated cytosine π-cation radical [cytosine π-aminyl radical, C(N4-H)(•)]. Employing 1-MeC samples at various pHs ranging from ca. 8 to 11, ESR studies show that the tautomeric equilibrium between C(N4-H)(•) and the iminyl σ-radical at low temperature is too slow to be established without added base. ESR and DFT studies agree that, in the iminyl σ-radical, the unpaired spin is localized on the exocyclic nitrogen (N4) in an in-plane pure p-orbital. This gives rise to an anisotropic nitrogen hyperfine coupling (Azz = 40 G) from N4 and a near isotropic β-nitrogen coupling of 9.7 G from the cytosine ring nitrogen at N3. Iminyl σ-radical should exist in its N3-protonated form, as the N3-protonated iminyl σ-radical is stabilized in solution by over 30 kcal/mol (ΔG = -32 kcal/mol) over its conjugate base, the N3-deprotonated form. This is the first observation of an isotropic β-hyperfine ring nitrogen coupling in an N-centered DNA radical. Our theoretical calculations predict that the cytosine iminyl σ-radical can be formed in double-stranded DNA by a radiation-induced ionization-deprotonation process that is only 10 kcal/mol above the lowest energy path.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cations / chemistry
  • Cold Temperature
  • Cytosine / analogs & derivatives*
  • Cytosine / chemistry
  • Electron Spin Resonance Spectroscopy
  • Hydrogen-Ion Concentration
  • Models, Chemical
  • Molecular Structure
  • Nitrogen / chemistry
  • Solutions / chemistry
  • Water / chemistry

Substances

  • Cations
  • Solutions
  • Water
  • 1-methylcytosine
  • Cytosine
  • Nitrogen