Cross-Linking and Sequence-Specific Alkylation of DNA by Aziridinylquinones. 3. Effects of Alkyl Substituents

• Published in: Journal of medicinal chemistry Vol. 42; no. 12; pp. 2245 - 2250
• Main Authors: Hargreaves, Robert H. J, O'Hare, C. Caroline, Hartley, John A, Ross, David, Butler, John
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.06.1999; Amer Chemical Soc
• Subjects: Antineoplastic agents; Antineoplastic Agents, Alkylating - chemical synthesis; Antineoplastic Agents, Alkylating - chemistry; Antineoplastic Agents, Alkylating - pharmacology; Aziridines - chemical synthesis; Aziridines - chemistry; Aziridines - pharmacology; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Cross-Linking Reagents - chemical synthesis; Cross-Linking Reagents - chemistry; Cross-Linking Reagents - pharmacology; diaziridinylquinone; DNA - chemistry; DNA - metabolism; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; NAD(P)H Dehydrogenase (Quinone) - deficiency; NAD(P)H Dehydrogenase (Quinone) - metabolism; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Quinones - chemical synthesis; Quinones - chemistry; Quinones - pharmacology; Science & Technology; CELLS; OXIDOREDUCTASE DT-DIAPHORASE; IN-VITRO; AZIRIDINYLBENZOQUINONES; METABOLISM; REDUCTION; DIAZIRIDINYLBENZOQUINONES; AGENTS; CYTOTOXICITY; SELECTIVITY; Antineoplastic agent; Human; Sequence specificity; Nitrogen heterocycle; Quinone; Three membered ring; Cytotoxicity; Crosslinking; Aziridine derivatives; In vitro; Alkylating agent; Cell line; Structure activity relation; DNA; Benzenic compound; Colon; Mechanism of action; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm991007y

The cytotoxicities and DNA cross-linking abilities of several alkyl-substituted diaziridinylquinones have been investigated. The cytotoxicities were determined in DT-diaphorase-rich (H460 and HT29) and -deficient (H596 and BE) cell lines. It was shown that the cytotoxicities in these cell lines correlated with the relative rates of reduction by the purified human enzyme and with the cross-linking efficiencies. The rates of reduction by DT-diaphorase were more dependent on the structures of the compounds than the reduction potentials, as determined by cyclic voltammetry. A computer model was also used to explain high efficiency of cross-linking and the GNC sequence selectivity of the reduced methyl-substituted diaziridinylquinones.