Developing model systems for the NMR study of substituent effects on the N-H•••N hydrogen bond in duplex DNA

The substitution effects on various parameters, which may influence the hydrogen bond strengths of Watson-Crick-type base pairs, were investigated for DNA dodecamers containing 5-substituted-2'-deoxyuridine derivatives. In doing so, a series of [3-N-15]-2'-deoxyuridine derivatives, including thymidine, 2'-deoxyuridine, 5-bromo-2'-deoxyuridine, 5-fluoro-2'-deoxyuridine and 5-cyano-2'-deoxyuridine, and [ul-N-15]-2'-deoxyadenosine, were synthesized and incorporated into the DNA dodecamer, d(CGCGA* ATX* CGCG)(2), where X* and A* were a [3-N-15]-2'-deoxyuridine derivative and [ul-N-15]-2'-deoxyadenosine, respectively. The imino proton chemical shift and the spin coupling constant between the imino proton and nitrogen [(1)J(N,H)] were measured for the Watson-Crick-type A*-X* base pair of all five duplexes. The substitution with an electron-withdrawing group results in downfield shift of the imino proton and a concomitant decrease in magnitude of the (1)J(N,H) value, and a good, linear correlation was found between the two effects. These substitution effects on the NMR parameters were linearly correlated with the pK(a) values of the 2'-deoxyuridine derivatives and also with the theoretically calculated hydrogen bond energy. The linear correlations found here indicate that the DNA oligomers with 5-substituted-2'-deoxyuridine provide a good model to study the nature of the hydrogen bond in Watson-Crick-type base pairs. Copyright (C) 2001 John Wiley & Sons, Ltd.