Chemical Basis for the Biological Activity of Imexon and Related Cyanoaziridines

Chemical aspects of mode of action of imexon and related cyanoaziridines were studied. These compounds do not alkylate DNA nor react with the ε-amino groups of l-lysine, despite the presence of an aziridine ring. They do react readily with biologically important sulfhydryl compounds to give products...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-01, Vol.47 (1), p.218-223
Main Authors: Iyengar, Bhashyam S, Dorr, Robert T, Remers, William A
Format: Article
Language:English
Subjects:
Acetylcysteine - chemistry
Animals
Antineoplastic agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Aziridines - chemistry
Aziridines - pharmacology
Biological and medical sciences
Cell Line, Tumor
Drug Resistance, Neoplasm
General aspects
Hexanones - chemistry
Hexanones - pharmacology
Humans
Medical sciences
Mice
Nitriles - chemistry
Nitriles - pharmacology
Pharmacology. Drug treatments
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Summary:Chemical aspects of mode of action of imexon and related cyanoaziridines were studied. These compounds do not alkylate DNA nor react with the ε-amino groups of l-lysine, despite the presence of an aziridine ring. They do react readily with biologically important sulfhydryl compounds to give products derived from either aziridine ring opening, interaction with the cyano group of cyanoaziridines, or opening of the iminopyrrolidone ring of imexon. The products from reactions of imexon and related cyanoaziridines with thiols are not as potent as their parent compounds against tumor cells. These results are consistent with biological studies that show that the mechanism of cytotoxicity involves thiol depletion followed by oxidative stress leading to apoptosis.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm030225v