EXPLORATORY STUDIES ON AZOLE CARBOXAMIDES AS NUCLEOBASE ANALOGS - THERMAL-DENATURATION STUDIES ON OLIGODEOXYRIBONUCLEOTIDE DUPLEXES CONTAINING PYRROLE-3-CARBOXAMIDE

In order to study base pairing properties of the amide group in DNA du plexes, a nucleoside analog, -deoxy-beta-D-ribofuranosyl)pyrrole-3-car boxamide, was synthesized by a new route from the ester, methyl ta-D-e rythro-pentofuranosyl)pyrrole-3-carboxylate, obtained from the couplin g reaction between ro-2-deoxy-3,5-di-O-toluoyl-D-erythropentofuranose and methyl pyrrole-3-carboxylate by treatment with dimethylaluminum am ide. '-Deoxy-beta-D-ribofuranosyl)pyrrole-3-carboxamide was incorporat ed into a series of oligodeoxyribonucleotides by solid-phase phosphora midite technology. The corresponding oligodeoxyribonucleotides with 3- nitropyrrole in the same position in the sequence were synthesized for UV comparison of helix-coil transitions. The thermal melting studies indicate that pyrrole-3-carboxamide, which could conceptually adopt ei ther a dA-like or a dl-like hydrogen bond conformation, pairs with sig nificantly higher affinity to T than to dC. Pyrrole-3-carboxamide furt her resembles dA in the relative order of its base pairing preferences (T > dG > dA > dC), Theoretical calculations on the model compound N- methylpyrrole-3-carboxamide using density functional theory show littl e difference in the preference for a syn(tau) versus anti(tau) conform ation about the bond from pyrrole C3 to the amide carbonyl, The amide groups in both the minimized anti(tau) and syn(tau) conformations are twisted out of the plane of the pyrrole ring by 6-14 degrees. This twi st may be one source of destabilization when the amide group is placed in the helix. Another contribution to the difference in stability bet ween the base pairs of pyrrole-3-carboxamide with T and pyrrole-3-carb oxamide with C may be the presence of a hydrogen bond in the former in volving an acidic proton (N3-H of T).