Hydride transfer in oxidation of nucleic acid sugars: Electronic effects of 2 '-substituents on activation of the 1 '-C-H bond by oxoruthenium(IV)

The effect of polar 2'-substituents on the oxidation of nucleic acids at th e 1'-C-H bond was investigated. Oligonucleotides with the sequence 5'-ATI C CC2'-X TTI CIT AT-3' (I = inosine, -X = -H, -NH2, - OCH3, -F) were synthesi zed and subjected to oxidation by Ru(tpy)(bpy)O2+ (tpy = 2,2':6',2 "-terpyr idine; bpy = 2,2'-bipyridine). High-resolution electrophoresis revealed a s imilar cleavage pattern for all of the sites in the oligonucleotides except for the 2'-substituted site, which varied in the extent of cleavage relati ve to the other sites according to H > NH2 > OCH3 > F. Because the cleavage was monitored following piperidine treatment, this analysis could not be a pplied to the 2'-hydroxy oligonucleotide. The extent of cleavage was a line ar function of oxidant concentration, and the slope of this plot was used a s a relative rate after normalizing to the adjacent, unsubstituted 5'-cytos ine. When the relative rates were determined using other nucleotides in the sequence for normalization, the results did not change outside the quoted error limits. The log of the relative rates was a linear function of the po lar Hammett parameter, F, and gave a slope of rho = -1.4 +/- 0.1. Rate cons tants on 2'-H and 2'-OH monophosphates from previous studies by stopped-flo w spectrophotometry fall on the line defined by the electrophoresis data, s upporting the assumption that the C-H bond activation is rate-limiting. The observed Hammett correlation supports an accumulation of positive charge a t the 1'-carbon, as would be expected for hydride transfer. These results p rovide a basis for the oxidation resistance of 2'-substituted oligonucleoti des.