Stereoisomeric C5-C5'-Linked Dihydrothymine Dimers Produced by Radiolytic One-Electron Reduction of Thymine Derivatives in Anoxic Aqueous Solution: Structural Characteristics in Reference to Cyclobutane Photodimers.

Abstract

Radiolytic one-electron reduction of 1-methylthymine (1a) and 1,3-dimethylthymine (1b) in anoxic aqueous solution afforded stereoisomeric C5-C5'-linked dihydrothymine dimers, fractionated into the meso forms of (5R,5'S)- and (5S,5'R)-bi-5,6-dihydrothymine (3a,b[meso]) and a racemic mixture of (5R,5'R)- and (5S,5'S)-bi-5,6-dihydrothymines (3a,b[rac]), along with 5,6-dihydrothymines (2a,b). The meso and racemic dimers were produced in almost equivalent yields, possessing structural similarity with cis-syn-cyclobutane pyrimidine photodimers that are identified as highly mutagenic and carcinogenic photolesions induced by UV light. Similar radiolytic one-electron reduction of thymidine (1c) resulted in the pseudo-meso form of (5R,5'S)- and (5S,5'R)-bi-5,6-dihydrothymidine (3c[RS]) and two diastereormers of (5R,5'R)- and (5S,5'S)-bi-5,6-dihydrothymidine (3c[RR] and 3c[SS]). X-ray crystal structures indicated that two pyrimidine rings of the stereoisomeric dimers except 3a[rac] overlap with each other to a considerable extent, as in the cis-syn-cyclobutane photodimers. The pyrimidine rings of the dimers were twisted around 5-Me-C5-C5'-5'-Me by 51.1(2)° for 3a[meso], -85.4(4)° for 3a[rac], -65(1)° for 3b[meso], 43(2)° for 3b[rac], and 64.9(4)° for 3c[RS], respectively. It was predicted that the C5-C5'-linked dihydrothymine dimers may cause some distortion within a DNA duplex if they were incorporated. The pH dependence of the reactivities was in accord with a mechanism of the C5-C5'-linked dimerization by which electron adducts of 1a-c are irreversibly protonated at C6 and the resulting 5,6-dihydrothymin-5-yl radicals undergo bimolecular coupling.