First Synthesis Of N-[(aziridin-2-yl)methyl]benzimidazolequinone And Analysis Of Toxicity Towards Normal And Fanconi Anemia Cells

摘要

A diazole is N-substituted with 1-trityl-2-methyIaziridine and de-methylated and oxidised with NBS under acidic conditions to give a benzimidazolequinone; this novel anti-tumour agent is marginally more cytotoxic than mitomycin C (MMC) towards the normal human fibroblast cell line GM00637, while the MMC-hypersensi-tive human Fanconi anaemia (FA) cell Une, PD20i, lacking the FANCD2 protein, is also hypersensitive to the benzimidazolequinone, with expression of FANCD2 protein decreasing sensitivity to both MMC and the benzimidazolequinone.rnMany bioreductive antitumour agents utilise a quinone for reductive activation and a strained aziridine ring as a DNA-alkylating center. This includes mitomycin C (MMC, Fig. 1) the naturally occurring prototype bioreductive antitumour agent. Cytotoxicity is known to be initiated by enzymatic reduction giving rise to electrophilic sites at Cl and C10 due to respective aziridine ring-opening and carbamate elimination. The Cl DNA-alkylation always precedes reaction at C10, resulting in inter- and intrastrand crosslinks that prevent DNA replication.