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.
dc.contributor.author | Hartley, John A | |
dc.contributor.author | Berardini, M | |
dc.contributor.author | Ponti, M | |
dc.contributor.author | Gibson, N W | |
dc.contributor.author | Thompson, A S | |
dc.contributor.author | Thurston, D E | |
dc.contributor.author | Hoey, Brigid M | |
dc.contributor.author | Butler, John | |
dc.date.accessioned | 2010-08-18T15:39:10Z | |
dc.date.available | 2010-08-18T15:39:10Z | |
dc.date.issued | 1991-12-17 | |
dc.identifier.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 | en |
dc.identifier.issn | 0006-2960 | |
dc.identifier.pmid | 1751490 | |
dc.identifier.doi | 10.1021/bi00114a016 | |
dc.identifier.uri | http://hdl.handle.net/10541/109894 | |
dc.description.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. | |
dc.language.iso | en | en |
dc.subject | Anticancerous Agents | en |
dc.subject.mesh | Antineoplastic Agents | |
dc.subject.mesh | Autoradiography | |
dc.subject.mesh | Aziridines | |
dc.subject.mesh | Base Sequence | |
dc.subject.mesh | Benzoquinones | |
dc.subject.mesh | Cross-Linking Reagents | |
dc.subject.mesh | DNA | |
dc.subject.mesh | Electrophoresis, Agar Gel | |
dc.subject.mesh | Electrophoresis, Polyacrylamide Gel | |
dc.subject.mesh | Molecular Sequence Data | |
dc.subject.mesh | Oxidation-Reduction | |
dc.subject.mesh | Uracil Mustard | |
dc.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. | en |
dc.type | Article | en |
dc.contributor.department | Department of Oncology, University College and Middlesex School of Medicine, London, U.K. | en |
dc.identifier.journal | Biochemistry | en |
html.description.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. |