title: Potential anti-tumour 2,5-bis (1-aziridinyl)-1,4-benzoquinones: relationship between cytotoxicity against DNA-repair deficient E. coli, inactivation of bacteriophage M13mp19, and in vitro and in vivo anti-tumour activity.
abstract: A series of reductively activated 3,6 substituted 2,5-bis(aziridinyl)benzoquinones, designed as potential anti-tumour agents, was shown to interact with DNA. This was assayed by studying the colony forming ability of DNA-repair deficient E. coli K12 and the inactivation of bacteriophage M13mp19. The activities of the compounds as measured in the two assays show a good correlation. Reduction of the quinone compounds is essential for activity in the two assays. Reduction activates opening of the aziridine ring and formation of an alkylating species. The results suggest that steric factors are important in DNA adduct formation. Methylation of the aziridine rings decreases the activity. Bulky 3,6-substitutes also decrease the activity. No correlation is found between above-mentioned assays for DNA modification and in vivo activity towards tumour cells. It is possible that, as well as DNA, other cellular targets are involved. A correlation is observed between the DNA modifying activity and toxicity against L1210 cells in vitro. The relative high activity against L1210 cells of bromine substituted compounds is possibly related to alternative mechanisms in which bromine acts as an efficient leaving group.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, State University of Utrecht, The Netherlands.
authors.forename: K J
authors.initials: KJ
authors.lastname: Lusthof
authors.forename: I L
authors.initials: IL
authors.lastname: Groothuis-Pielage
authors.forename: J
authors.initials: J
authors.lastname: Decuyper
authors.forename: N J
authors.initials: NJ
authors.lastname: de Mol
authors.forename: L H
authors.initials: LH
authors.lastname: Janssen
authors.forename: W
authors.initials: W
authors.lastname: Verboom
authors.forename: D N
authors.initials: DN
authors.lastname: Reinhoudt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D001388:Aziridines; D001389:Azirines; D003090:Coliphages / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D007939:Leukemia L1210 / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D009152:Mutagenicity Tests; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011048:Polarography; D011809:Quinones; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D001389:Azirines; D011809:Quinones; D013482:Superoxide Dismutase