title: 2,2'-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1.
abstract: The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2'-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2'-dihydroxy-benzophenones (5-9) and subsequent formation of their N-derivatives (oximes 11-13 and N-acyl hydrazones 14-16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC₅₀ values in the range 0.18 ± 0.02 to 1.77 ± 0.10 μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC₅₀ values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4 ± 0.4 μM and 87 ± 1.9 μM, respectively), in addition to the strong enzyme inhibition profile (IC₅₀(6)=1,77 ± 0.10 μM; IC₅₀(14)=0.33 ± 0.05 μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs.
authors.affiliation: Laboratory of Enzyme Technology, Department of Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-118 55 Athens, Greece.
authors.forename: Fereniki D
authors.initials: FD
authors.lastname: Perperopoulou
authors.affiliation: Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Petros G
authors.initials: PG
authors.lastname: Tsoungas
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.
authors.forename: Trias N
authors.initials: TN
authors.lastname: Thireou
authors.affiliation: Division of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece.
authors.forename: Vagelis E
authors.initials: VE
authors.lastname: Rinotas
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece; Division of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece.
authors.forename: Eleni K
authors.initials: EK
authors.lastname: Douni
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.
authors.forename: Elias E
authors.initials: EE
authors.lastname: Eliopoulos
authors.affiliation: Laboratory of Enzyme Technology, Department of Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-118 55 Athens, Greece.
authors.forename: Nikolaos E
authors.initials: NE
authors.lastname: Labrou
authors.affiliation: Laboratory of Enzyme Technology, Department of Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-118 55 Athens, Greece. Electronic address: clonis@aua.gr.
authors.forename: Yannis D
authors.initials: YD
authors.lastname: Clonis
mesh_terms: D001577:Benzophenones / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D001577:Benzophenones; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C047723:benzophenone; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha
keywords: Benzophenone; Enzyme inhibition; Glutathione transferase; Ketoxime; Multiple drug resistance; N-Acyl hydrazone