Interactions of platinum(ll)-derivatized triplexforming oligonucleotides with DNA1

Meghan A. Campbell, Tracey McGregor Mason, Paul S. Miller

Research output: Contribution to journalArticle

Abstract

Polypyrimidine oligonucleotides can bind to tracts of contiguous purines in double-stranded DNA to form triple-stranded complexes. The stability of the triplex is reduced significantly if the target purine tract is interrupted by a single pyrimidine. Previous studies have shown that incorporation of an N 4-aminoalkylcytosine into the triplexforming oligonucleotide (TFO), opposite a single CG interruption, facilitates triplex formation. Examination of molecular models suggested that further modification of the amino group of the aminoalkyl arm might enable adduct formation with the N7 of the guanine of the CG interruption. To test this, we prepared 2'-deoxyribo-and 2'-O-methylriboTFOs that contained cytosine (C), N4-(2-aminoethyl)cytosine (ae-C), or diethylenetriamineplatinum(II) (DPt-C) or cisaquodiammineplatinum(II) (cPt-C) derivatives of N4-(2-aminoethyl)cytosine, positioned opposite a CG interruption of a polypurine tract found in the pol gene of HIV-1 proviral DNA. Although the C- and ae-C-derivatized deoxyribo-TFOs formed triplexes of modest stability and the DPt-C-modified TFO failed to form a triplex, the C- and ae-C-derivatized 2/-O-methylribo-TFOs formed remarkably stable triplexes (T m = 57 °C). The DPt-C- and cPt-C-modified 2-Omethylribo-TFOs also formed triplexes, although their stabilities were reduced (Tm = 33 °C), suggesting that the tethered platinum group may interfere sterically with TFO binding. Consistent with this hypothesis was the observation that triplex stability was restored (Tm = 57 °C) when the diethylenetriamineplatinum(II) group was tethered to the 5'end of the Z-O-methylribo-TFO via a 2-aminoethylcarbamate linkage. Taken together, these results suggest that 2′-Omethylribo-TFOs may be particularly useful in targeting purine tracts in DNA that have CG interruptions, and that further modification with platinum derivatives could lead to the design of TFOs that are capable of covalent binding to their target, thus increasing the effectiveness of the TFO.

Original languageEnglish (US)
Pages (from-to)241-248
Number of pages8
JournalCanadian Journal of Chemistry
Volume85
Issue number4
DOIs
StatePublished - Apr 2007

Fingerprint

Oligonucleotides
Platinum
Cytosine
DNA
Derivatives
Purines
Guanine
Genes

Keywords

  • Cisplatin
  • Interrupted polypurine tract
  • TFO
  • Triplex-forming oligonucleotide

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Interactions of platinum(ll)-derivatized triplexforming oligonucleotides with DNA1. / Campbell, Meghan A.; Mason, Tracey McGregor; Miller, Paul S.

In: Canadian Journal of Chemistry, Vol. 85, No. 4, 04.2007, p. 241-248.

Research output: Contribution to journalArticle

Campbell, Meghan A. ; Mason, Tracey McGregor ; Miller, Paul S. / Interactions of platinum(ll)-derivatized triplexforming oligonucleotides with DNA1. In: Canadian Journal of Chemistry. 2007 ; Vol. 85, No. 4. pp. 241-248.
@article{5430e9149af240ac88ba93e5cad9f855,
title = "Interactions of platinum(ll)-derivatized triplexforming oligonucleotides with DNA1",
abstract = "Polypyrimidine oligonucleotides can bind to tracts of contiguous purines in double-stranded DNA to form triple-stranded complexes. The stability of the triplex is reduced significantly if the target purine tract is interrupted by a single pyrimidine. Previous studies have shown that incorporation of an N 4-aminoalkylcytosine into the triplexforming oligonucleotide (TFO), opposite a single CG interruption, facilitates triplex formation. Examination of molecular models suggested that further modification of the amino group of the aminoalkyl arm might enable adduct formation with the N7 of the guanine of the CG interruption. To test this, we prepared 2'-deoxyribo-and 2'-O-methylriboTFOs that contained cytosine (C), N4-(2-aminoethyl)cytosine (ae-C), or diethylenetriamineplatinum(II) (DPt-C) or cisaquodiammineplatinum(II) (cPt-C) derivatives of N4-(2-aminoethyl)cytosine, positioned opposite a CG interruption of a polypurine tract found in the pol gene of HIV-1 proviral DNA. Although the C- and ae-C-derivatized deoxyribo-TFOs formed triplexes of modest stability and the DPt-C-modified TFO failed to form a triplex, the C- and ae-C-derivatized 2/-O-methylribo-TFOs formed remarkably stable triplexes (T m = 57 °C). The DPt-C- and cPt-C-modified 2-Omethylribo-TFOs also formed triplexes, although their stabilities were reduced (Tm = 33 °C), suggesting that the tethered platinum group may interfere sterically with TFO binding. Consistent with this hypothesis was the observation that triplex stability was restored (Tm = 57 °C) when the diethylenetriamineplatinum(II) group was tethered to the 5'end of the Z-O-methylribo-TFO via a 2-aminoethylcarbamate linkage. Taken together, these results suggest that 2′-Omethylribo-TFOs may be particularly useful in targeting purine tracts in DNA that have CG interruptions, and that further modification with platinum derivatives could lead to the design of TFOs that are capable of covalent binding to their target, thus increasing the effectiveness of the TFO.",
keywords = "Cisplatin, Interrupted polypurine tract, TFO, Triplex-forming oligonucleotide",
author = "Campbell, {Meghan A.} and Mason, {Tracey McGregor} and Miller, {Paul S.}",
year = "2007",
month = "4",
doi = "10.1139/V07-016",
language = "English (US)",
volume = "85",
pages = "241--248",
journal = "Canadian Journal of Chemistry",
issn = "0008-4042",
publisher = "National Research Council of Canada",
number = "4",

}

TY - JOUR

T1 - Interactions of platinum(ll)-derivatized triplexforming oligonucleotides with DNA1

AU - Campbell, Meghan A.

AU - Mason, Tracey McGregor

AU - Miller, Paul S.

PY - 2007/4

Y1 - 2007/4

N2 - Polypyrimidine oligonucleotides can bind to tracts of contiguous purines in double-stranded DNA to form triple-stranded complexes. The stability of the triplex is reduced significantly if the target purine tract is interrupted by a single pyrimidine. Previous studies have shown that incorporation of an N 4-aminoalkylcytosine into the triplexforming oligonucleotide (TFO), opposite a single CG interruption, facilitates triplex formation. Examination of molecular models suggested that further modification of the amino group of the aminoalkyl arm might enable adduct formation with the N7 of the guanine of the CG interruption. To test this, we prepared 2'-deoxyribo-and 2'-O-methylriboTFOs that contained cytosine (C), N4-(2-aminoethyl)cytosine (ae-C), or diethylenetriamineplatinum(II) (DPt-C) or cisaquodiammineplatinum(II) (cPt-C) derivatives of N4-(2-aminoethyl)cytosine, positioned opposite a CG interruption of a polypurine tract found in the pol gene of HIV-1 proviral DNA. Although the C- and ae-C-derivatized deoxyribo-TFOs formed triplexes of modest stability and the DPt-C-modified TFO failed to form a triplex, the C- and ae-C-derivatized 2/-O-methylribo-TFOs formed remarkably stable triplexes (T m = 57 °C). The DPt-C- and cPt-C-modified 2-Omethylribo-TFOs also formed triplexes, although their stabilities were reduced (Tm = 33 °C), suggesting that the tethered platinum group may interfere sterically with TFO binding. Consistent with this hypothesis was the observation that triplex stability was restored (Tm = 57 °C) when the diethylenetriamineplatinum(II) group was tethered to the 5'end of the Z-O-methylribo-TFO via a 2-aminoethylcarbamate linkage. Taken together, these results suggest that 2′-Omethylribo-TFOs may be particularly useful in targeting purine tracts in DNA that have CG interruptions, and that further modification with platinum derivatives could lead to the design of TFOs that are capable of covalent binding to their target, thus increasing the effectiveness of the TFO.

AB - Polypyrimidine oligonucleotides can bind to tracts of contiguous purines in double-stranded DNA to form triple-stranded complexes. The stability of the triplex is reduced significantly if the target purine tract is interrupted by a single pyrimidine. Previous studies have shown that incorporation of an N 4-aminoalkylcytosine into the triplexforming oligonucleotide (TFO), opposite a single CG interruption, facilitates triplex formation. Examination of molecular models suggested that further modification of the amino group of the aminoalkyl arm might enable adduct formation with the N7 of the guanine of the CG interruption. To test this, we prepared 2'-deoxyribo-and 2'-O-methylriboTFOs that contained cytosine (C), N4-(2-aminoethyl)cytosine (ae-C), or diethylenetriamineplatinum(II) (DPt-C) or cisaquodiammineplatinum(II) (cPt-C) derivatives of N4-(2-aminoethyl)cytosine, positioned opposite a CG interruption of a polypurine tract found in the pol gene of HIV-1 proviral DNA. Although the C- and ae-C-derivatized deoxyribo-TFOs formed triplexes of modest stability and the DPt-C-modified TFO failed to form a triplex, the C- and ae-C-derivatized 2/-O-methylribo-TFOs formed remarkably stable triplexes (T m = 57 °C). The DPt-C- and cPt-C-modified 2-Omethylribo-TFOs also formed triplexes, although their stabilities were reduced (Tm = 33 °C), suggesting that the tethered platinum group may interfere sterically with TFO binding. Consistent with this hypothesis was the observation that triplex stability was restored (Tm = 57 °C) when the diethylenetriamineplatinum(II) group was tethered to the 5'end of the Z-O-methylribo-TFO via a 2-aminoethylcarbamate linkage. Taken together, these results suggest that 2′-Omethylribo-TFOs may be particularly useful in targeting purine tracts in DNA that have CG interruptions, and that further modification with platinum derivatives could lead to the design of TFOs that are capable of covalent binding to their target, thus increasing the effectiveness of the TFO.

KW - Cisplatin

KW - Interrupted polypurine tract

KW - TFO

KW - Triplex-forming oligonucleotide

UR - http://www.scopus.com/inward/record.url?scp=34250323101&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34250323101&partnerID=8YFLogxK

U2 - 10.1139/V07-016

DO - 10.1139/V07-016

M3 - Article

VL - 85

SP - 241

EP - 248

JO - Canadian Journal of Chemistry

JF - Canadian Journal of Chemistry

SN - 0008-4042

IS - 4

ER -