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631528 
Book/Book Chapter 
Michael addition-elimination reactions: Roles in toxicity and potential new therapeutic applications 
Elfarra, AA; Krause, RJ 
2008 
Springer 
New York, NY 
Advances in Bioactivation Research 
57-68 
Activated olefins of the type XCH = CHY, where Y is an electron- withdrawing group and X is a good leaving group, can undergo nucleophilic vinylic substitution reactions by a single-step or a multistep addition-limination mechanism, depending on the chemical structure of the olefin and the reaction conditions. While nucleophilic vinylic substitution reactions have been extensively characterized and described in the chemical literature (Koch and Kielbania 1970; Kahn and Hehre 1986; Hackett et al. 1990; Rappoport 1992; Galli, Gentili and Rappoport 1994), only recently have these reactions been recognized to occur at physiological conditions and have been implicated in biological activity. The purpose of this chapter is to review recent experimental evidence that documents occurrence of Michael addition-limination reactions in intact mammalian cells, both in vitro and in vivo. Evidence implicating these reactions in the mechanisms of nephrotoxicity and renal carcinogenicity of the halogenated hydrocarbons, trichloroethylene, and tetrachloroethylene will also be discussed. Finally, adaptation of Michael addition-limination reactions to design new anticancer prodrugs that can undergo bioactivation by biological thiols, such as glutathione (GSH) and glutathione S-transferases (GST), to release the cytoxic drug 6-mercaptopurine (6-MP) or 6-thioguanine (6-TG) will also be described. Furthermore, data demonstrating the effectiveness of this prodrug approach in increasing the efficacy of 6-MP and 6-TG against tumor cells while decreasing the known side-effects of these drugs on the bone marrow and small intestine will be reviewed. 
6-mercaptopurine-- antineoplastic-drug,enzyme inhibitor-drug; 6-thioguanine--antineoplastic-drug; Acids; activated olefins--biological activity; Animals; Biochemistry and Molecular Biophysics; Biosis 07/14/08 to 03/03/09; cancer chemotherapy--laboratory techniques; Chordates; elimination reaction; glutathione S-transferase {GST}; glutathione {GSH}; Literature Review; Mammalia--Vertebrata,Chordata,Animalia; mammalian cell line (Mammalia); Mammals; methods; Michael addition; Nonhuman Mammals; Nonhuman Vertebrates; nucleophilic vinylic substitution; pathology; Peptides; pharmacology; physiological condition; renal carcinogenicity; Tetrachloroethylene; tetrachloroethylene--toxin,nephrotoxin; therapeutic application; therapy; toxicity; Toxicology; Trichloroethylene; trichloroethylene--toxin,nephrotoxin; Vertebrates 
AA Elfarra