Isoenzyme-specific glutathione-S-transferase inhibitors: design and synthesis

Abstract

Glutathione-S-transferase (GST) isozyme-selective inhibitors were designed by an empirically guided strategy. In the first phase, literature data were used to select C-terminal modifications which generated maximum variation in the catalytic efficiency (Vmax/Km) for glutathione (GSH) analogs used as substrates with different rat GSTs. Also, on the basis of literature data, the sulfhydryl group was functionalized with a selection of alkyl and aryl groups to maximize potential isozyme specificity. Affinity chromatography sorbents were prepared from these which showed isozyme selectivity for both rat tissue and recombinant human GST isozymes. Some of these compounds also showed selective inhibition 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 sorbents, varied substantially, with hydrophobic substituents favoring the human GST M1a isozyme and electronegative moieties favoring GST P1. In the third phase, information obtained from testing both series of compounds was combined and used to prepare GSH analogs with chemical features responsible for isozyme specificity at both the C-terminus and the 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 functional groups for maximum potency and selectivity is included.

The metabolic bioactivation of caffeic acid phenethyl ester (CAPE) mediated by tyrosinase selectively inhibits glutathione S-transferase

“…Literature search on previous works has also shown that glutathione conjugates are involved in inhibition of GST [53,54]. One recent study revealed that GSH conjugate of doxorubicin inhibited GST activity [53].…”

“…Doxorubicin showed an increased cytotoxicity not only towards MDR cells but also doxorubicin sensitive cells suggesting that glutathione conjugates of drugs such as doxorubicin may play a vital role in the GST expression and hence drug induced cytotoxicity. Lyttle group also reported that a number of compounds which are coupled to the thiol group of glutathione showed significant inhibition of GST activity [54]. Tyrosinase catalyzes the metabolism of quercetin to quinone and glutathione adducts [55].…”

Programmed Delivery of Novel Functional Groups to the Alpha Class Glutathione Transferases

“…The reason the alpha class and not the others react with GSB is still not clear. The differences could potentially be due to binding preferences, but similar compounds have been shown to bind to the alpha, mu, and pi class with K D values that are comparable (37). Also, within the alpha class, the enzymes display different substrate preferences (29,38,39), and the crystal structures (6,40) also reveal differences; for example, the H-site of hGST A4-4 appears to be more narrow and elongated than that of hGST A1-1.…”

8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1

“…Almost two decades ago, clinical studies indicated ethacrynic acid as a candidate for modulation of drug resistance (Lacreta et al, 1994). At the same time, the selective GST-π inhibitor TER-117 was synthesized (Lyttle et al, 1994 include on references), but there are no recent studies with this. Other GST-π specific inhibitors were able to revert multiple drug resistance in cholangiocarcinoma (Nakajima et al, 2003).…”