Chemistry of 4'-Hydroperoxy Nucleosides as a Model for the Intermediate in Bleomycin-Induced Degradation of DNA

Article abstract of DOI:10.1021/jo00382a007

The reaction of 1-(3-O-benzoyl-2,5-dideoxy-β-D-glycero-pent-4-enofuranosyl)thymine (5) with anhydrous hydrogen peroxide in the presence of trifluoroacetic acid gave two isomeric 4'-hydroperoxides (6 and 7).The structure of the major product was assigned as 3'-O-benzoyl-5'-deoxy-4'-hydroperoxythymine (6) on the basis of spectral data.It has been demonstrated that the 4'-hydroperoxide 6 is capable of undergoing a Criegee-type rearrangement in an aqueous buffered solution to give trans-3-(thymin-1'-yl)propenal (10) stereospecifically, whereas the more stable isomer 7 does not produce 10 under the same conditions.These model experiments suggest that once a 4'-hydroperoxy intermediate of β-D-deoxyribo configuration is formed by action of the activated bleomycin on DNA, it spontaneously decomposes to afford DNA strand scission and trans base propenal.Reduction of these 4'-hydroperoxy nucleosides with dimethyl sulfide in methanol gave thymine and γ-keto aldehyde 14 quantitatively.The result indicates that the 4'-hydroxy nucleoside might be the precursor of alkali-labile lesion in DNA.