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- Title
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.
- Authors
Georgakis, Nikolaos D.; Karagiannopoulos, Dionisis A.; Thireou, Trias N.; Eliopoulos, Elias E.; Labrou, Nikolaos E.; Tsoungas, Petros G.; Koutsilieris, Michael N.; Clonis, Yannis D.
- Abstract
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 ( 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 hGSTM1-1. The outcome of the isoenzyme trilogy identified good binder leads for the investigated GSTs involved in MDR.
- Subjects
BENZOPHENONES; CARBONYL compounds; GLUTATHIONE transferase; ENZYME inhibitors; MOLECULAR models
- Publication
Chemical Biology & Drug Design, 2017, Vol 90, Issue 5, p900
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.13011