Cross-linkable Nitrosamines with a Chloroalkyl Group as Candidates for Anticancer Lead Compounds
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概要
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DNA alkylation and cross-linking are classical mechan-isms underlying the activity of cancer chemotherapeutic agents such as procarbazine and mitomycin C, which are currently used in the clinic. Chloroethyl A/-nitrosoureas is one group of anticancer cross-linking agents, and exert their biological activities by formation of DNA cross-links. Because anticancer chloroethyl A/-nitrosoureas shows toxic side-effects due to protein carbamoylation, many efforts have been exercised to reduce unwanted side-effects by design of new drugs with low carbamoylating activity. AMMitrosamines, another category of A/-nitroso compounds, alkylate cellular nucleophiles in vivo, and might induce gene mutation and lead to carcinogenesis by DNA alkylation. Its active form is released after elimination of aldehyde; i.e. A/-nitrosamines do not carbamoylate proteins. We have an interest in structure modification of alkylating nitrosamines as useful candidates for anticancer lead compounds. Three A/-nitroso-A/-{acetoxymethyl)-w-chloroalkylamines, chloroethyl, chloropropyl and chlorobutylamines have been synthesized and their chemical and biological properties were evaluated. The chloropropyl nitrosamine showed mutagenicity in Salmonella typhimurium TA92 that is positively responsive to DNA cross-linker, and also showed interstrand cross-linking activity towards plasmid DNA assayed by agarose gel electrophoresis. Then three-ring aromatic moieties were introduced into the structure of chloropropyl nitrosamine to potentiate its binding affinity to DNA molecules. Although three aromatic analogs intercalated to double-stranded DNA, only acridine analog had DNA cross-linking activity. In TA92 strain, the acridine analog showed the highest mutagenicity among all nine A/-nitroso compounds used in this study. These results suggest that the aromatic ring moiety confers DNA-intercalating ability to the cross-linkable chloropropyl nitrosamine; the acridine analog that forms DNA cross-links efficiently might be a potential new anticancer lead compound. To assess the application of cross-linkable nitrosamines as new anticancer agents, further investigations such as that on DNA adducts or on their activity towards cancer cells are required.
- 日本環境変異原学会の論文
- 2007-02-20
著者
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ISHIKAWA Satoko
Kyoritsu University of Pharmacy
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MOCHIZUKI Masataka
Kyoritsu University of Pharmacy
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Ishikawa Satoko
Kyoritsu College Of Pharmacy
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Mochizuki Masataka
Kyoritsu College Of Pharmacy
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