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

Article abstract of DOI:10.1021/jo990059s

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 la-c are irreversibly protonated at C6 and the resulting 5,6-dihydrothymin-5-yl radicals undergo bimolecular coupling.