Concluding the trilogy: The interaction of 2,2′‐dihydroxy‐benzophenones and their carbonyl N‐analogues with human glutathione transferase M1‐1 face to face with the P1‐1 and A1‐1 isoenzymes involved in MDR

A series of 2,2′‐dihydroxybenzophenones and their carbonyl N‐analogues were studied as potential inhibitors against human glutathione transferase M1‐1 ( hGSTM 1‐1) purified from recombinant E. coli . Their screening revealed an inhibition against hGSTM 1‐1 within a range of 0‐42% (25 μM). The IC 50 values for the two stronger ones, 16 and 13 , were 53.5 ± 5.6 μΜ and 28.5 ± 2.5 μΜ, respectively. The results were compared with earlier ones for isoenzymes hGSTP 1‐1 and hGSTA 1‐1 involved in MDR . All but one bind more strongly to A1‐1, than M1‐1 and P1‐1, the latter being a poor binder. An order of potency A1‐1 > > M1‐1 >  P1‐1 meritted 13 , 14 and 16 as the most potent inhibitors with hGSTM 1‐1. Enzyme kinetics with hGSTM 1‐1 ( K m( CDNB ) 213 ± 10 μΜ and K m( GSH ) 303 ± 11 μΜ) revealed a competitive modality for 16 ( K i( 16)  =  22.3 ± 1.1 μΜ) and a mixed one for 13 versus CDNB ( K i (13)  = 33.3 ± 1.6 μM for the free enzyme and K i (13) ′ = 17.7 ± 1.7 μM for the enzyme‐ CDNB complex). 5‐ or 5′‐Bromo‐ or phenyl‐substituted (but not in combination) inhibitors, having a H‐bonded oxime weakly acidic group of a small volume, are optimal candidates for binding hGSTM 1‐1. The outcome of the isoenzyme trilogy identified good binder leads for the investigated GST s involved in MDR.