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, tomaymycin and neothramycin show that their reaction with thiophenol follows second-order kinetics, but the ranking order of reactivity (neothramycin greater than tomaymycin greater than 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.
Morris
S J
SJ
Division of Medicinal Chemistry, School of Pharmacy and Biomedical Sciences, Portsmouth Polytechnic, Hants., UK.
Thurston
D E
DE
Nevell
T G
TG
D000876:Anthramycin / Q000737:chemistry* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism; D001570:Benzodiazepinones / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D004579:Electron Transport; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010636:Phenols / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds
D000903:Antibiotics, Antineoplastic; D001570:Benzodiazepinones; D010636:Phenols; D013438:Sulfhydryl Compounds; D000876:Anthramycin; C003619:tomaymycin; C030006:neothramycin B; C030005:neothramycin A; C042983:thiophenol; D004247:DNA