DNA alkylating agents

A large number of DNA-alkylating agents are known and we will not attempt a comprehensive survey here. A number of excellent reviews provide an overview of this area. " Here we will review DNA alkylation by three types of reactive intermediates that are important in medicinal chemistry and toxicology— episulfonium ions, aziridinium ions, and carbocations. 

Ouyang, A. Skibo, E. B. The iminium ion chemistry of mitosene DNA alkylating agents, enriched 13C-NMR studies. Biochemistry 2000, 39, 5817-5830. 

Another class of DNA alkylating agents, the Mitomycins, proved to be most promising in clinical trials. Among these, mitomycin C, shown in Fig. 6.1, exhibits significant anti-tumor activity. Its mechanism of activation consists of a complex bioreductive process. The first step is the reduction to hydroquinone, followed by a loss of methanol. This reaction fa-... 

Dihydropyrrolizines 272, their salts and solvates, were prepared and evaluated as potential antitumor drugs or as site-specific DNA alkylating agents in the gene-relating technologies <1998WO9827095>. 

DNA injury can initiate apoptosis by a powerful, early activated mechanism mediated by the nuclear phosphoprotein p53. This protein is activated by both transcriptional and posttranslational means and is critical in the cellular response to double-strand DNA breaks, which can be induced by high-energy radiation such as UV light. Although the detailed mechanisms are not well understood, p53 apparently plays a regulatory role whereby the cell is directed either toward the completion of repair or to apoptosis (W20). In fact, p53 was proven to be essential for the induction of apoptosis of some cells treated with DNA alkylating agent (W19). 

Yen and Hsieh328 have shown that the mutagenicity of IQ on S. typhimurium TA98 and TA100 was strongly inhibited in the presence of Maillard products from xylose-lysine (1 2 mol, 100 °C, pH 9, 1 h). They demonstrated that the effect was due to the formation of inactive adducts with IQ metabolites and not to the direct inhibition of the hepatic microsomal activation required to transform inactive IQ into a DNA-alkylating agent. 

Because sulfur mustard is known to be a strong and direct DNA alkylating agent, the likelihood is very high that it functions as a non-threshold carcinogen. Conseqnently, the risks associated with exposures to low concentrations require evaluation, and the McNamara et al. (1975) stndy provides the only data set that allows for a quantification of carcinogenic potency following exposnre to snlfnr mnstard vapors. 

Schatzschneider U, Barton JK. Bifunctional rhodium intercalator conjugates as mismatch-directing DNA alkylating agents. J. Am. Chem. Soc. 2004 126 8630-8631. 

Streptozotocin (48) is an N-nitroso urea isolated from Strep-tomyces achromogenes. It acts as a DNA-alkylating agent (87), and it is recommended for use in combination with doxorubicin (35) as the drug of choice for the chemotherapy for patients with malignant neuroendocrine pancreatic tumors (88). 

Chemical/Pharmaceutical/Other Class Alkylating agent DNA alkylating agent Chemotherapeutic agent... 

Methyinitrosourea is a DNA alkylating agent. Methyinitrosourea causes dermal sensitization. It is also an inhibitor of protein and nucleic acid synthesis in tissues. 

As methyinitrosourea is a DNA alkylating agent, the major toxic effects result from severe damage to... 

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