The Design, Synthesis, and Screening of GSH-porphyrin-GSH Bifunctional Inhibitor
The goals of this project are to generate a small library of glutathione-porphyrin-glutathione compounds and to screen these compounds for inhibition of P1-1 glutathione transferase (GST). The glutathione-porphyrin-glutathione compound has been designed to be a bifunctional inhibitor of GST and to have varying distances between the conjugated glutathione (GSH) thiols in order to select for specific isoforms. In order to test the hypothesis that the bidentate nature of the inhibitor is an essential property, and what effect the porphyrin linker has on K(sub)I, corresponding monoGSH porphyrin and GSH butyrylamidebenzene will be screened for inhibition of P1-1 GST. Finally, the library will be screened against human A1-1, which has a different distance between the two thiols of GSH as seen in x-ray structure, in order to determine if the compounds in the library are isozyme selective. The relevance of this project to cancer research lies in the need for GST inhibitors to perturb GSH metabolism which might give antitumoral agents new potency. The use of a porphyrin linker to create this bifunctional inhibitor would possibly give the opportunity of a "multimodality therapy" wherein chemotherapy is enhanced due to the inhibition of GST-dependent drug resistance in combination with photodynamic therapy utilizing the porphyrin inhibitor as a photosensitizer.