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

• Published in: Biochemistry (Easton) 1991-12, Vol.30 (50), p.11719-11724
• Main Authors: Hartley, J A, Berardini, M, Ponti, M, Gibson, N W, Thompson, A S, Thurston, D E, Hoey, B M, Butler, J
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents; Autoradiography; Aziridines - chemistry; Aziridines - pharmacology; Base Sequence; Benzoquinones - chemistry; Benzoquinones - pharmacology; Cross-Linking Reagents; DNA - drug effects; Electrophoresis, Agar Gel; Electrophoresis, Polyacrylamide Gel; Molecular Sequence Data; Oxidation-Reduction; Uracil Mustard - chemistry
• ISSN: 0006-2960
• DOI: 10.1021/bi00114a016

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.