Interactions of cytosine derivatives with T·A interruptions in pyrimidine·purine·pyrimidine DNA triplexes

Sandeep Verma, Paul S. Miller

Research output: Contribution to journalArticle

Abstract

The ability of triplex-forming oligopyrimidines to interact with duplex targets which contain a single pyr·pur interruption in their homopurine triplex binding site was studied. These oligonucleotides contain either N4- (3-carboxypropyl) deoxycytidine (3) or N4-(5-carboxytriazolyl)deoxycytidine (4) to target the pyr·pur interruption. The 3-carboxypropyl and the 5- carboxytriazolyl groups of these cytosine derivatives are designed to span the major groove of the duplex target. Molecular models suggest that the carboxyl group of 3 or 4 can serve as a hydrogen bond acceptor for the N6- amino hydrogen of A in a T·A base pair. Additional contacts are possible between the N4-amino hydrogen of 3 or 4 and the O4-carbonyl oxygen of T. UV melting experiments showed that a 15-mer, I(3), containing nucleoside 3 formed a stable triplex with duplex targets containing a single T·A interruption. The melting temperature of this triplex was 7 °C higher than that of a similar triplex containing a single G·T·A triad when a Tris buffer was employed. Oligomer I(3) also formed a triplex of lower stability with a target containing a G·C base pair but not with targets containing C·G, U·A, or A·T base pairs. A similar 15-mer, II, containing nucleoside 4 was found to be less selective than I(3) in its interaction with duplex targets. Thus, gel mobility shift experiments showed that in addition to interacting with T·A, oligomer II also formed triplexes with duplex targets containing U·A and C·G interruptions. These studies suggest that nucleoside derivatives which can potentially contact both bases of a pyr·pur interruption might provide a means to extend the range of sequences which can be recognized by triplex-forming oligonucleotides.

Original languageEnglish (US)
Pages (from-to)600-605
Number of pages6
JournalBioconjugate Chemistry
Volume7
Issue number5
DOIs
StatePublished - Sep 1996

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Cytosine
Nucleosides
Base Pairing
Hydrogen
DNA
Oligonucleotides
Derivatives
Oligomers
Freezing
Deoxycytidine
Tromethamine
Molecular Models
Binding sites
Melting point
Hydrogen bonds
Melting
Gels
Experiments
Binding Sites
Oxygen

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Interactions of cytosine derivatives with T·A interruptions in pyrimidine·purine·pyrimidine DNA triplexes. / Verma, Sandeep; Miller, Paul S.

In: Bioconjugate Chemistry, Vol. 7, No. 5, 09.1996, p. 600-605.

Research output: Contribution to journalArticle

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abstract = "The ability of triplex-forming oligopyrimidines to interact with duplex targets which contain a single pyr·pur interruption in their homopurine triplex binding site was studied. These oligonucleotides contain either N4- (3-carboxypropyl) deoxycytidine (3) or N4-(5-carboxytriazolyl)deoxycytidine (4) to target the pyr·pur interruption. The 3-carboxypropyl and the 5- carboxytriazolyl groups of these cytosine derivatives are designed to span the major groove of the duplex target. Molecular models suggest that the carboxyl group of 3 or 4 can serve as a hydrogen bond acceptor for the N6- amino hydrogen of A in a T·A base pair. Additional contacts are possible between the N4-amino hydrogen of 3 or 4 and the O4-carbonyl oxygen of T. UV melting experiments showed that a 15-mer, I(3), containing nucleoside 3 formed a stable triplex with duplex targets containing a single T·A interruption. The melting temperature of this triplex was 7 °C higher than that of a similar triplex containing a single G·T·A triad when a Tris buffer was employed. Oligomer I(3) also formed a triplex of lower stability with a target containing a G·C base pair but not with targets containing C·G, U·A, or A·T base pairs. A similar 15-mer, II, containing nucleoside 4 was found to be less selective than I(3) in its interaction with duplex targets. Thus, gel mobility shift experiments showed that in addition to interacting with T·A, oligomer II also formed triplexes with duplex targets containing U·A and C·G interruptions. These studies suggest that nucleoside derivatives which can potentially contact both bases of a pyr·pur interruption might provide a means to extend the range of sequences which can be recognized by triplex-forming oligonucleotides.",
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