DNA cross-linking and sequence selectivity of aziridinylbenzoquinones: a unique reaction at 5'-GC-3' sequences with 2,5-diaziridinyl-1,4-benzoquinone upon reduction.

2.50
Hdl Handle:
http://hdl.handle.net/10541/109894
Title:
DNA cross-linking and sequence selectivity of aziridinylbenzoquinones: a unique reaction at 5'-GC-3' sequences with 2,5-diaziridinyl-1,4-benzoquinone upon reduction.
Authors:
Hartley, John A; Berardini, M; Ponti, M; Gibson, N W; Thompson, A S; Thurston, D E; Hoey, Brigid M; Butler, John
Abstract:
Several bifunctional alkylating agents of the aziridinylbenzoquinone class have been evaluated as potential antitumor agents. 3,6-Bis[(2-hydroxyethyl)amino]-2,5- diaziridinyl-1,4-benzoquinone (BZQ), 2,5-diaziridinyl-1,4-benzoquinone (DZQ), 3,6-bis(carboxyamino)-2,5-diaziridinyl- 1,4-benzoquinone (AZQ), and six analogues of AZQ have been studied for their ability to induce DNA interstrand cross-linking, as measured by an agarose gel technique, and to determine whether they react with DNA in a sequence-selective manner, as determined by a modified DNA sequencing technique. At an equimolar concentration (10 microM), only DZQ and BZQ showed any detectable cross-linking at pH 7 without reduction. Cross-linking was enhanced in both cases at low pH (4). Reduction by ascorbic acid at both pH's increased the cross-linking, which was particularly striking in the case of DZQ. In contrast, AZQ and its analogues only produced a significant level of cross-linking under both low-pH and reducing conditions, the extent of cross-linking decreasing as the size of the alkyl end group increased. The compounds reacted with all guanine-N7 positions in DNA with a sequence selectivity similar to other chemotherapeutic alkylating agents, such as the nitrogen mustards, although some small differences were observed with BZQ. Nonreduced DZQ showed a qualitatively similar pattern of reactivity to the other compounds, but on reduction (at pH 4 or 7) was found to react almost exclusively with 5'-GC-3' sequences, and in particular, at 5'-TGC-3' sites. A model to explain this unique reaction is proposed.
Affiliation:
Department of Oncology, University College and Middlesex School of Medicine, London, U.K.
Citation:
DNA cross-linking and sequence selectivity of aziridinylbenzoquinones: a unique reaction at 5'-GC-3' sequences with 2,5-diaziridinyl-1,4-benzoquinone upon reduction. 1991, 30 (50):11719-24 Biochemistry
Journal:
Biochemistry
Issue Date:
17-Dec-1991
URI:
http://hdl.handle.net/10541/109894
DOI:
10.1021/bi00114a016
PubMed ID:
1751490
Type:
Article
Language:
en
ISSN:
0006-2960
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorHartley, John Aen
dc.contributor.authorBerardini, Men
dc.contributor.authorPonti, Men
dc.contributor.authorGibson, N Wen
dc.contributor.authorThompson, A Sen
dc.contributor.authorThurston, D Een
dc.contributor.authorHoey, Brigid Men
dc.contributor.authorButler, Johnen
dc.date.accessioned2010-08-18T15:39:10Z-
dc.date.available2010-08-18T15:39:10Z-
dc.date.issued1991-12-17-
dc.identifier.citationDNA cross-linking and sequence selectivity of aziridinylbenzoquinones: a unique reaction at 5'-GC-3' sequences with 2,5-diaziridinyl-1,4-benzoquinone upon reduction. 1991, 30 (50):11719-24 Biochemistryen
dc.identifier.issn0006-2960-
dc.identifier.pmid1751490-
dc.identifier.doi10.1021/bi00114a016-
dc.identifier.urihttp://hdl.handle.net/10541/109894-
dc.description.abstractSeveral bifunctional alkylating agents of the aziridinylbenzoquinone class have been evaluated as potential antitumor agents. 3,6-Bis[(2-hydroxyethyl)amino]-2,5- diaziridinyl-1,4-benzoquinone (BZQ), 2,5-diaziridinyl-1,4-benzoquinone (DZQ), 3,6-bis(carboxyamino)-2,5-diaziridinyl- 1,4-benzoquinone (AZQ), and six analogues of AZQ have been studied for their ability to induce DNA interstrand cross-linking, as measured by an agarose gel technique, and to determine whether they react with DNA in a sequence-selective manner, as determined by a modified DNA sequencing technique. At an equimolar concentration (10 microM), only DZQ and BZQ showed any detectable cross-linking at pH 7 without reduction. Cross-linking was enhanced in both cases at low pH (4). Reduction by ascorbic acid at both pH's increased the cross-linking, which was particularly striking in the case of DZQ. In contrast, AZQ and its analogues only produced a significant level of cross-linking under both low-pH and reducing conditions, the extent of cross-linking decreasing as the size of the alkyl end group increased. The compounds reacted with all guanine-N7 positions in DNA with a sequence selectivity similar to other chemotherapeutic alkylating agents, such as the nitrogen mustards, although some small differences were observed with BZQ. Nonreduced DZQ showed a qualitatively similar pattern of reactivity to the other compounds, but on reduction (at pH 4 or 7) was found to react almost exclusively with 5'-GC-3' sequences, and in particular, at 5'-TGC-3' sites. A model to explain this unique reaction is proposed.en
dc.language.isoenen
dc.subjectAnticancerous Agentsen
dc.subject.meshAntineoplastic Agents-
dc.subject.meshAutoradiography-
dc.subject.meshAziridines-
dc.subject.meshBase Sequence-
dc.subject.meshBenzoquinones-
dc.subject.meshCross-Linking Reagents-
dc.subject.meshDNA-
dc.subject.meshElectrophoresis, Agar Gel-
dc.subject.meshElectrophoresis, Polyacrylamide Gel-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshOxidation-Reduction-
dc.subject.meshUracil Mustard-
dc.titleDNA cross-linking and sequence selectivity of aziridinylbenzoquinones: a unique reaction at 5'-GC-3' sequences with 2,5-diaziridinyl-1,4-benzoquinone upon reduction.en
dc.typeArticleen
dc.contributor.departmentDepartment of Oncology, University College and Middlesex School of Medicine, London, U.K.en
dc.identifier.journalBiochemistryen

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