3 years ago

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

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
Yannis D. Clonis, Elias E. Eliopoulos, Trias N. Thireou, Michael N. Koutsilieris, Petros G. Tsoungas, Nikolaos D. Georgakis, Nikolaos E. Labrou, Dionisis A. Karagiannopoulos
A series of 2,2′-dihydroxybenzophenones and their carbonyl N-analogues were studied as potential inhibitors against human glutathione transferase M1-1 (hGSTM1-1) purified from recombinant E. coli. Their screening revealed an inhibition against hGSTM1-1 within a range of 0-42% (25 μM). The IC50 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 hGSTP1-1 and hGSTA1-1 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 hGSTM1-1. Enzyme kinetics with hGSTM1-1 (Km(CDNB) 213 ± 10 μΜ and Km(GSH) 303 ± 11 μΜ) revealed a competitive modality for 16 (Ki(16) = 22.3 ± 1.1 μΜ) and a mixed one for 13 versus CDNB (Ki(13) = 33.3 ± 1.6 μM for the free enzyme and Ki(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 hGSTM1-1. The outcome of the isoenzyme trilogy identified good binder leads for the investigated GSTs involved in MDR. When the substrates CDNB and GSH (both in green) are bound to hGSTM1-1, 2,2’-dihydroxy-5-phenyl-benzophenone oxime (13) (in yellow) can still be accommodated in the binding pocket, effecting good inhibition. 13 is also a good inhibitor with hGSTA1-1 and a weaker one with hGSTP1-1, thus, qualifying as lead structure for designing hGST inhibitors.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13011

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