Glutathione s-transferase has been found to be a major factor in the drug resistant behavior of many cancers. Finding a viable inhibitor to glutathione s-transferase could potentially combat these drug resistant properties. This group focuses on synthesizing novel derivatives of ethacrynic acid, a loop diuretic shown to inhibit glutathione s-transferase. The ethacrynic acid moiety, a phenolic ketone, was synthesized by first acylating various phenolic starting materials. Afterwards, eliminations were performed to generate the alpha-beta unsaturated ketone, culminating in the acetic acid moiety via an ether synthesis/hydrolysis approach. Furthermore, our group aims to enhance the inhibitory effects of the ethacrynic acid by modifying the alpha carbon in an effort to make it a better Michael acceptor for the sulfur present in glutathione s-transferase. To model these inhibitory effects, various thiols will undergo a Michael addition reaction with our synthesized ethacrynic acid derivatives. Our preliminary results on the synthesis of these ethacrynic acid derivatives as well as the possible inhibitory effects modeled by these Michael addition reactions will be presented.

Combating drug resistant cancer: Inhibiting glutathione s-transferase via ethacrynic acid derivatives

255th National Meeting (2018)

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