Synthesis and structure–activity relationship of ethacrynic acid analogues on glutathione-s-transferase P1-1 activity inhibition

Ethacrynic acid (EA) is a glutathione-s-transferase π (GSTP1-1) inhibitor. Fifteen of EA analogues were designed and synthesized and their inhibition on GSTP1-1 activity was tested in lysate of human leukemia HL-60 cells. These compounds were synthesized using substituted phenol as precursors through reacting with 2-chlorocarboxylic acid and acylation. Structure–activity analysis indicates that replacements of chlorides of EA by methyl, bromide, and fluoride at 3′ position remain the GSTP1-1 inhibitory effect. The compounds without any substitute at 3′ position lose the activity on GSTP1-1 inhibition. These data suggest that the substitution of 3′ position of EA is necessary for inhibiting GSTP1-1 activity.

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