EVALUATION OF THE ELECTROPHILICITY OF DNA-BINDING PYRROLO[2, 1-c][1, 4]BENZODIAZEPINES BY HPLC

An HPLC assay is described that can be used to study the covalent bonding interaction of carbinolamine-containing pyrrolo[2, 1-c][1, 4]benzodiazepines with the model nucleophile thiophenol, in order to evaluate electrophilicity at the C-11-position. Preliminary experiments with anthramycin, tomaymyc...

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Bibliographic Details
Published in:Journal of antibiotics 1990/10/25, Vol.43(10), pp.1286-1292
Main Authors: MORRIS, STEPHEN J., THURSTON, DAVID E., NEVELL, THOMAS G.
Format: Article
Language:English
Subjects:
Anthramycin - chemistry
Anthramycin - metabolism
Antibiotics, Antineoplastic - chemistry
Antibiotics, Antineoplastic - metabolism
Antineoplastic agents
Benzodiazepinones - chemistry
Benzodiazepinones - metabolism
Biological and medical sciences
Chromatography, High Pressure Liquid
DNA - metabolism
Electron Transport
General aspects
Kinetics
Magnetic Resonance Spectroscopy
Medical sciences
Pharmacology. Drug treatments
Phenols - metabolism
Structure-Activity Relationship
Sulfhydryl Compounds
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Description
Summary:An HPLC assay is described that can be used to study the covalent bonding interaction of carbinolamine-containing pyrrolo[2, 1-c][1, 4]benzodiazepines with the model nucleophile thiophenol, in order to evaluate electrophilicity at the C-11-position. Preliminary experiments with anthramycin, tomaymycin and neothramycin show that their reaction with thiophenol follows second-order kinetics, but the ranking order of reactivity (neothramycin > tomaymycin > anthramycin), does not correlate with either in vitro cytotoxicity or in vivo antitumour activity. This suggests that other factors such as non-covalent DNA-interaction or drug transport play a more crucial role in biological activity than simple alkylating ability. This assay should, however, prove a useful tool in the study of structure-activity relationships for this series of compounds and provide "C-11-electrophilicity" parameters for use in Hansch analysis and related studies.
ISSN:0021-8820
1881-1469
DOI:10.7164/antibiotics.43.1286