The influence of the aziridinyl substituent of benzimidazoles and benzimidazolequinones on toxicity towards normal and Fanconi anaemia cells

Aziridinyl substituted benzimidazolequinones are more toxic than methoxy analogues towards normal human fibroblast cells (GM00637). The aziridinyl substituent is required for hypersensitive killing of Fanconi anaemia (FA) cells (PD20i) deficient in FANCD2. Despite lacking quinone functionality, 4,7-...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2010-05, Vol.45 (5), p.1873-1879
Main Authors: Fahey, Karen, O'Donovan, Liz, Carr, Miriam, Carty, Michael P., Aldabbagh, Fawaz
Format: Article
Language:English
Subjects:
Antineoplastic agents
Aziridine
Aziridines - chemistry
Benzimidazoles - chemistry
Benzimidazoles - toxicity
Biological and medical sciences
Bioreductive
Cell Survival - drug effects
Cells, Cultured
Cytotoxicity
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Fanconi Anemia - pathology
Fibroblasts - drug effects
General aspects
Humans
Medical sciences
Mitomycin C
Molecular Structure
Pharmacology. Drug treatments
Quinones
Quinones - chemistry
Quinones - toxicity
Stereoisomerism
Structure-Activity Relationship
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Summary:Aziridinyl substituted benzimidazolequinones are more toxic than methoxy analogues towards normal human fibroblast cells (GM00637). The aziridinyl substituent is required for hypersensitive killing of Fanconi anaemia (FA) cells (PD20i) deficient in FANCD2. Despite lacking quinone functionality, 4,7-dimethoxy- N-[(aziridin-2-yl)methyl]benzimidazole also induces hypersensitivity from FA cells, similar to their response towards mitomycin C. Expression of FANCD2 (in PD20:RV) corrects FA cell hypersensitivity supporting cellular response via the FANC pathway. Despite lacking the quinone functionality required for bioreduction, 4,7-dimethoxy- N-[(aziridin-2-yl)methyl]benzimidazole induces hypersensitivity from Fanconi anaemia cells lacking FANCD2. [Display omitted]
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2010.01.026