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dc.contributor.authorHartley, John A
dc.contributor.authorBerardini, M
dc.contributor.authorPonti, M
dc.contributor.authorGibson, N W
dc.contributor.authorThompson, A S
dc.contributor.authorThurston, D E
dc.contributor.authorHoey, Brigid M
dc.contributor.authorButler, John
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.
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
html.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.


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