PMID: 9171086Jun 15, 1997Paper

The sequence specificity of alkylation for a series of benzoic acid mustard and imidazole-containing distamycin analogues: the importance of local sequence conformation

Nucleic Acids Research
M D WyattJ A Hartley

Abstract

The covalent sequence specificity of a series of nitrogen mustard and imidazole-containing analogues of distamycin was determined using modified sequencing techniques. The analogues tether benzoic acid mustard (BAM) and possess either one, two or three imidazole units. Examination of the alkylation specificity revealed that BAM produced guanine-N7 lesions in a pattern similar to conventional nitrogen mustards. The monoimidazole-BAM conjugate also produced guanine-N7 alkylation in a similar pattern to BAM, but at a 100-fold lower dose. The diimidazole and triimidazole conjugates did not produce detectable guanine-N7 alkylation but only alkylated at selected sites in the minor groove. Unexpectedly, the alkylation specificity at equivalent doses was nearly identical to that found for the previously reported pyrrole-BAM conjugates. The consensus sequence, 5'-TTTTGPuwas strongly alkylated by the triimidazole conjugate in preference to other similar sites including three occurrences of 5'-TTTTAA. Footprinting studies were carried out to examine the non-covalent DNA binding interactions. These studies revealed that the tripyrrole- BAM conjugate bound non-covalently to the same AT-rich sites as distamycin. In contrast, whereas the Im3l...Continue Reading

References

Apr 1, 1989·Journal of Medicinal Chemistry·F M ArcamoneN Mongelli
Apr 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·J G Nadeau, D M Crothers
Mar 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·M L KopkaR E Dickerson
Jan 1, 1995·Annual Review of Biophysics and Biomolecular Structure·B H Geierstanger, D E Wemmer
Apr 2, 1993·Journal of Medicinal Chemistry·M LeeJ A Hartley

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