Nitrosative Cytosine Deamination. An Exploration of the Chemistry Emanating from Deamination with Pyrimidine Ring-Opening

Abstract

A discussion of nitrosative deamination of cytosine 1 is presented that argues for the formation of 6 by diazotization of 1 to cytosinediazonium ion 2 and its electrostatic complex 3, dediazoniation to 4 <--> 5, and amide-bond cleavage to 6. The reaction channels available to 6 include hydrolytic deglycation to 3-isocyanatoacrylonitrile 7, water addition to carbamic acid 9 with the possibility for re-closure to uracil 13, water addition to carbamic acid 9, and decarboxylation to 3-aminoacrylonitrile 10. With a view to the instability of the carbamic acid 9, the carbamate models ethyl (Z)-2-cyanovinylcarbamate 14 and (Z)-2-cyano-1-tert-butylvinylcarbamate 20 were studied. Acid-catalyzed hydrolysis of 14 leads to 2-amino-carbonylphenylcarbamate 15, and its cyclization yields the benzo-fused uracil quinazoline-2,4-dione 16. In contrast to the aromatic system 14, acid-catalyzed cyclization cannot compete with oligomerization in the case of 20, and 5-tert-butyluracil 22 is accessible only with base-catalysis. It is shown that 23, the parent of 10, also easily polymerizes. The experimental results provide a rationale as to why 9, 10, and 12 would have escaped detection in in vitro studies: they would have oligomerized. In contrast to the in vitro experiments, the oligomerizations of 9, 10, or 12 clearly are not relevant in vivo because of low monomer concentrations. With the exclusion of recyclization and of oligomerization in vivo, attention thus needs to focus on (Z)-3-aminoacrylonitrile 10 as the most likely deamination product of cytosine aside from uracil.

Mechanistic Study of the Deamination Reaction of Guanine: A Computational Study

“…However, their reported activation energy [213 kJ mol -1 at B3LYP/6-31G(d)] was not very close to the experimentally accepted value (117 ( 4 kJ mol -1 ). 22, 23 Rayat et al studied the nitrosative deamination reactions of both guanine 24 and cytosine 25 and found several possible pathways, from which they proposed that the reactions proceed via a pyrimidine ringopened intermediate. For both guanine and cytosine, the intermediates were formed by dediazoniation and deprotonation of the guaninediazonium ion.…”

Urinary Volatile Organic Compounds as Potential Biomarkers in Idiopathic Membranous Nephropathy

“…It has been reported that carbamic acid monoammonium salt is an important organic raw material of rubber auxiliary material, binder, UV absorbent, dyes, pharmaceuticals, explosives, etc. [30] . However, previous studies showed no data on the 2 urinary VOCs.…”

Chemical carcinogens in non-enzymatic cytosine deamination: 3-isocyanatoacrylonitrile

“…The proton affinity of 10 suggests that 10 and its isomers and conformers are formed in nitrosative cytosine deamination in aqueous solution. The possibility for recyclization of 10 to uracils has been explored experimentally and it is not likely [ 35 ]. Thus, toxicological studies of nitrosative cytosine deamination need to direct attention at 3-aminoacrylonitrile 9 and 3-isocyanatoacrylonitrile 10 .…”