Exploratory studies on azole carboxamides as nucleobase analogs: Thermal denaturation studies on oligodeoxyribonucleotide duplexes containing pyrrole-3-carboxamide

Peiming Zhang, W. Travis Johnson, Douglas Klewer, Natasha Paul, Geoffrey Hoops, V. J. Davisson, Donald E. Bergstrom

Research output: Contribution to journalArticle

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Abstract

In order to study base pairing properties of the amide group in DNA duplexes, a nucleoside analog, 1-(2'-deoxy-β-D-ribofuranosyl)pyrrole-3-carboxamide, was synthesized by a new route from the ester, methyl 1-(2'-deoxy-3',5'-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)pyrrole 3-carboxylate, obtained from the coupling reaction between 1-chloro-2-deoxy-3,5-di-O-toluoyl-D-erythropentofuranose and methyl pyrrole-3-carboxylate by treatment with dimethylaluminum amide. 1-(2'-Deoxy-β-D-ribofuranosyl)pyrrole-3-carboxamide, was incorporated into a series of oligodeoxyribonucleotides by solid-phase phosphoramidite 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 either a dA-like or a dI-like hydrogen bond conformation, pairs with significantly higher affinity to T than to dC. Pyrrole-3-carboxamide further 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 little difference in the preference for a syn(τ) versus anti(τ) conformation about the bond from pyrrole C3 to the amide carbonyl. The amide groups in both the minimized anti(τ) and syn(τ) conformations are twisted out of the plane of the pyrrole ring by 6-14°. This twist may be one source of destabilization when the amide group is placed in the helix. Another contribution to the difference in stability between the base pairs of pyrrole-3-carboxamide with T and pyrrole-3-carboxamide with C may be the presence of a hydrogen bond in the former involving an acidic proton (N3-H of T).

Original languageEnglish (US)
Pages (from-to)2208-2215
Number of pages8
JournalNucleic Acids Research
Volume26
Issue number9
DOIs
StatePublished - May 1 1998
Externally publishedYes

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Azoles
Pyrroles
Oligodeoxyribonucleotides
Hot Temperature
Amides
Base Pairing
Hydrogen
Pair Bond
Nucleosides
Freezing
Protons
Esters
Technology

ASJC Scopus subject areas

  • Genetics

Cite this

Exploratory studies on azole carboxamides as nucleobase analogs : Thermal denaturation studies on oligodeoxyribonucleotide duplexes containing pyrrole-3-carboxamide. / Zhang, Peiming; Johnson, W. Travis; Klewer, Douglas; Paul, Natasha; Hoops, Geoffrey; Davisson, V. J.; Bergstrom, Donald E.

In: Nucleic Acids Research, Vol. 26, No. 9, 01.05.1998, p. 2208-2215.

Research output: Contribution to journalArticle

Zhang, Peiming ; Johnson, W. Travis ; Klewer, Douglas ; Paul, Natasha ; Hoops, Geoffrey ; Davisson, V. J. ; Bergstrom, Donald E. / Exploratory studies on azole carboxamides as nucleobase analogs : Thermal denaturation studies on oligodeoxyribonucleotide duplexes containing pyrrole-3-carboxamide. In: Nucleic Acids Research. 1998 ; Vol. 26, No. 9. pp. 2208-2215.
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abstract = "In order to study base pairing properties of the amide group in DNA duplexes, a nucleoside analog, 1-(2'-deoxy-β-D-ribofuranosyl)pyrrole-3-carboxamide, was synthesized by a new route from the ester, methyl 1-(2'-deoxy-3',5'-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)pyrrole 3-carboxylate, obtained from the coupling reaction between 1-chloro-2-deoxy-3,5-di-O-toluoyl-D-erythropentofuranose and methyl pyrrole-3-carboxylate by treatment with dimethylaluminum amide. 1-(2'-Deoxy-β-D-ribofuranosyl)pyrrole-3-carboxamide, was incorporated into a series of oligodeoxyribonucleotides by solid-phase phosphoramidite 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 either a dA-like or a dI-like hydrogen bond conformation, pairs with significantly higher affinity to T than to dC. Pyrrole-3-carboxamide further 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 little difference in the preference for a syn(τ) versus anti(τ) conformation about the bond from pyrrole C3 to the amide carbonyl. The amide groups in both the minimized anti(τ) and syn(τ) conformations are twisted out of the plane of the pyrrole ring by 6-14°. This twist may be one source of destabilization when the amide group is placed in the helix. Another contribution to the difference in stability between the base pairs of pyrrole-3-carboxamide with T and pyrrole-3-carboxamide with C may be the presence of a hydrogen bond in the former involving an acidic proton (N3-H of T).",
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AU - Klewer, Douglas

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AU - Davisson, V. J.

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