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Alkylation specificity for a series of distamycin analogues that tether chlorambucil

Wyatt, MD; Lee, M; Hartley, JA; (1997) Alkylation specificity for a series of distamycin analogues that tether chlorambucil. ANTI-CANCER DRUG DES , 12 (1) 49 - 60.

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Abstract

The sequence specificity of alkylation for a series of pyrrole- and imidazole-containing analogues of distamycin that tether the nitrogen mustard chlorambucil (CHL) was determined using modified sequencing techniques. Examination of the sequence specificity of alkylation for the imidazole-CHL conjugates using a Tag polymerase stop assay revealed that although the doses required to produce similar amounts of damage were at least 10-fold lower, the sequence specificity of alkylation was essentially identical to that seen for CHL. The guanine-N7 alkylation pattern, which consisted of guanines within runs of guanines, was confirmed using a piperidine cleavage assay. The pyrrole-CHL conjugates also produced a similar pattern of alkylation to that seen for CHL, but one exception was a unique site strongly alkylated only by the di- and tripyrrole-CHL conjugates. The unique lesions, at AG for the dipyrrole-CHL conjugate and G for the tripyrrole-CHL conjugate in the sequence 5'-GAAGAT, were confirmed as minor groove adenine- and guanine-N3 lesions using a thermal cleavage assay.

Type: Article
Title: Alkylation specificity for a series of distamycin analogues that tether chlorambucil
Keywords: alkylating agents, DNA, minor groove binders, DNA-SEQUENCE SELECTIVITY, AFFINITY CROSS-LINKING, MINOR-GROOVE, MOLECULAR RECOGNITION, BIOLOGICAL EVALUATION, NITROGEN MUSTARDS, ANILINE MUSTARDS, STRAND BREAKAGE, ADENINE ADDUCTS, BINDING
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/109081
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