ISOZYME-SPECIFIC GLUTATHIONE-S-TRANSFERASE INHIBITORS - DESIGN AND SYNTHESIS

Glutathione-S-transferase (GST) isozyme-selective inhibitors were desi gned by an empirically guided strategy. In the first phase, literature data were used to select 6-terminal modifications which generated max imum variation in the catalytic efficiency (V-max/K-m) for glutathione (GSH) analogs cased as substrates with different rat GSTs. Also, on t he basis of literature data, the sulfhydryl group was functionalized w ith a selection of alkyl and aryl groups to maximize potential isozyme specificity. affinity. chromatography sorbents were prepared from the se which showed isozyme selectivity for both rat tissue and recombinan t human GST isozymes. Some of these compounds also showed selective in hibition of GST activity in catalysis of the reaction of 1-chloro-2,4- dinitrobenzene with GSH. In the second phase, electronic effects were explored through synthesis of an isostructural series of S-benzyl GSH ligands with different substituents on the aromatic ring. GST isozyme specificity for these ligands, measured by binding to derivatized sorb ents, varied substantially, with hydrophobic substituents favoring the human GST M1a isozyme and electronegative moieties favoring GST P1. I n the third phase, information obtained from testing both series of co mpounds was combined and used to prepare GSH analogs with chemical fea tures responsible for isozyme specificity at both the C-terminus and t he sulfur. This approach gave two new compounds which showed improved potency while still maintaining selectivity in the inhibition of GSTs. A detailed discussion of the logic used in the selection of functiona l groups for maximum potency and selectivity is included.