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

• Published in: Chemical biology & drug design Vol. 90; no. 5; pp. 900 - 908
• Main 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.
• Format: Journal Article
• Language: English
• Published: England 01-11-2017
• Subjects: Benzophenones - chemistry; Benzophenones - pharmacology; dihydroxybenzophenones; Drug Resistance, Multiple; enzyme inhibition; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glutathione S-Transferase pi - antagonists & inhibitors; Glutathione S-Transferase pi - metabolism; Glutathione Transferase - antagonists & inhibitors; Glutathione Transferase - metabolism; human glutathione transferase; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; ketoximes; Molecular Docking Simulation; molecular modelling; N‐acyl hydrazones; Structure-Activity Relationship; human glutathione transferase; dihydroxybenzophenones; enzyme inhibition; molecular modelling; N-acyl hydrazones; ketoximes
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13011

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.