Acyl Migration in the Production of Thymine Propenal from 3'-O-Benzoyl-5'-deoxy-4'-hydroperoxythymidine: A Reinterpretation of a Putative Model for Bleomycin-Mediated DNA Degradation

Article abstract of DOI:10.1021/jo00001a011

Studies of Saito et al. (Saito, I.; Morii, T.; Matsuura, T.J.Org.Chem. 1987, 52, 1008) analyzing the decomposition of 3'-O-benzoyl-5'-deoxy-4'-hydroperoxythymidine (7) claimed to model the decomposition of the putative 4'-hydroxyperoxynucleotide intermediate in the bleomycin (BLM) mediated production of base propenal, 3'-phosphoglycolate, and 5'-phosphate termini from double-stranded DNA.A number of puzzling observations reported in this paper prompted a reinvestigation of this model system in detail. <4'-H¹⁸O2>-7 and its 4'-epimer 8 were prepared and their fate in aqueous solution as a function of pH was examined.Compound 7 decompos ed in aqueous solution to produce thymine propenal accompanied by stoichiometric formation of benzoate containing 1 atom of ¹⁸O.In addition, thymine accompanied by stoichiometric amounts of malondialdehyde and <¹⁸O>benzoate was also observed.Acetate containing 1 atom of ¹⁸O accompanied production of both thymine and thymine propenal.The ratio of thymine propenal to thymine varied as a function of pH and temperature.Production of <¹⁸O>benzoate and a detailed kinetic analysis of the decomposition of 7 unequivocally demonstrated that conversion of 7 to thymine propenal required the intermediacy of a 4'-perbenzoate ester.This perester produced by migration of the 3'-benzoyl blocking group of 7 to the terminal oxygen of its 4'-hydroperoxy moiety would then greatly facilitate heterolytic cleavage of the oxygen-oxygen bond.For stereochemical reasons a similar intramolecular benzoyl migration cannot occur with 8, explaining its lack of reactivity.These results call into question the relevance of the Model proposed by Saito et al. to understanding the base propenal pathway in the BLM-catalyzed degradation of DNA.In addition, preparation of a second model of a putative intermediate in the base propenal pathway, <1-<<2-(acetyloxy)acetyl>oxy>-3-oxopropyl>thymine (12) is reported.The detailed kinetics of its decomposition as well as identification of the products accompanying ist decomposition are reported.The relevance of these two model systems to the mechanism of degradation of DNA by BLM is discussed.