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.
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.
authors.affiliation: Department of Oncology, University College and Middlesex School of Medicine, London, U.K.
authors.forename: J A
authors.initials: JA
authors.lastname: Hartley
authors.forename: M
authors.initials: M
authors.lastname: Berardini
authors.forename: M
authors.initials: M
authors.lastname: Ponti
authors.forename: N W
authors.initials: NW
authors.lastname: Gibson
authors.forename: A S
authors.initials: AS
authors.lastname: Thompson
authors.forename: D E
authors.initials: DE
authors.lastname: Thurston
authors.forename: B M
authors.initials: BM
authors.lastname: Hoey
authors.forename: J
authors.initials: J
authors.lastname: Butler
mesh_terms: D000970:Antineoplastic Agents; D001345:Autoradiography; D001388:Aziridines / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D003432:Cross-Linking Reagents; D004247:DNA / Q000187:drug effects*; D004587:Electrophoresis, Agar Gel; D004591:Electrophoresis, Polyacrylamide Gel; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D014499:Uracil Mustard / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D016227:Benzoquinones; D003432:Cross-Linking Reagents; C045315:NSC 224070; D004247:DNA; C029108:diaziquone; D014499:Uracil Mustard