Methionine S-adenosyltransferase (MAT) occurs in neoplastic rat and human tissue predominantly, and often exclusively, as a unique isozyme that is absent from all of a wide variety of normal tissues studied. The tumor MAT isozyme is thus unusually promising as a target in cancer chemotherapy, particularly since the product of the MAT reaction functions as the methyl donor in at least 35 transmethylation reactions. We propose to design compounds that, in cells in culture, are selective potent inhibitors or high-affinity substrates of MAT from rat Novikoff hepatoma cells in relation to the principal MAT isozyme of vitually all normal rat tissues. Our recent work indicates that studies of substrates that are monosubstituted at various atoms can be a fruitful approach to isozyme-selective substrates or inhibitors, and, when combined with studies of substituted dual-site inhibitors, can sometimes rapidly produce inhibitors that are both potent and isozyme-selective. Following this approach, derivatives of the MAT substrates, ATP and methionine, will be analyzed as potential selective substrates or inhibitors of tumor MAT. Concurrently, we shall synthesize two types of ATP-methionine adducts as potential dual-site substrates or inhibitors of tumor MAT. ATP or methionine substituents that produce selective effects will be incorporated into potent dual-site inhibitors or substrates with the object of conferring tumor isozyme selectivity while retaining substrate or inhibitor effectiveness. To enhance selectivity or potency, further substituents may be added and systematically elaborated. Selective inhibitors or substrates thereby obtained will be converted to derivatives that can diffuse through cytoplasmic membranes and subsequently undergo hydrolysis, to regenerate, intracellularly, the original compounds. We shall determine whether these derivatives can inhibit the MAT-catalyzed reaction in rat Novikoff tumor cells more effectively than in normal rat cells. Compounds with this selectivity will be tested for in vivo antineoplastic activity. Tumor MAT is sometimes the sole species detectable in human colon, lung, cervical, and stomach carcinomas growing in athymic mice, indicating that selective inhibitors of tumor MAT might be clinically effective against these high morbidity malignancies.
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