Reaction kinetics and cytosine adducts of chloroethylene oxide and chloroacetaldehyde: direct observation of intermediates by FTNMR and GC-MS.

I. O'Neill, A. Barbin, M. Friesen, H. Bartsch

Research output: Contribution to journalArticlepeer-review

Abstract

As it is not yet known which are the important miscoding adducts formed in the reaction of the relatively unstable compound chloroethylene oxide (CEO) with double-stranded DNA, proton FTNMR and GC-mass spectroscopy were used to directly detect and characterize reaction intermediates. Reaction of CEO with cytidine gave the (hydrated) 2-oxoethyl derivative at the N-3 position prior to ring closure to 3,N4-ethenocytidine; 5-methylcytosine gave an analogous reaction. However, reactions of CEO or chloroacetaldehyde (CAA) with 3-methylcytidine - i.e., with the N-3 blocked as in double-stranded DNA (ds DNA) - were shown by GC-MS of the silylated products to give, at a much slower rate, a pattern of at least 17 adducts all of which contained chlorine. Based on MS fragmentation and considerations of positional, optical and cis/trans isomerism, the reaction products of the 3-methylcytosine moiety were assigned as cis/trans N4-(2-chlorovinyl)-3-methylcytosine which may have arisen from the corresponding N4-(1-hydroxy-2-chloroethyl) adduct. It is postulated that formation of these cytosine-N4 adducts would be more rapid in double-stranded DNA than in the model compound, and that the N4-(2-chlorovinyl) group may be a miscoding adduct. The kinetics for CEO rearrangement, hydrolysis and nucleophilic attack have been studied by proton FTNMR and lead to the hypothesis that concerted nucleophilic attack by cytosine-N4 and CEO rearrangement produce the N4 adducts.

Original languageEnglish (US)
Pages (from-to)57-73
Number of pages17
JournalIARC scientific publications
Issue number70
StatePublished - Dec 1 1986

ASJC Scopus subject areas

  • Medicine(all)

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