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1.
Chem Biol Drug Des ; 90(5): 900-908, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28440951

RESUMO

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.


Assuntos
Benzofenonas/química , Benzofenonas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glutationa S-Transferase pi/antagonistas & inibidores , Glutationa Transferase/antagonistas & inibidores , Resistência a Múltiplos Medicamentos , Glutationa S-Transferase pi/metabolismo , Glutationa Transferase/metabolismo , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
2.
Chem Biol Drug Des ; 86(5): 1055-63, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25891019

RESUMO

The selectivity of certain benzophenones and their carbonyl N-analogues was investigated towards the human GSTP1-1 allozymes A, B and C involved in MDR. The allozymes were purified from extracts derived from E. coli harbouring the plasmids pEXP5-CT/TOPO-TA-hGSTP1*A, pOXO4-hGSTP1*B or pOXO4-hGSTP1*C. Compound screening with each allozyme activity indicated three compounds with appreciable inhibitory potencies, 12 and 13 with P1-1A 62% and 67%, 11 and 12 with P1-1C 51% and 70%, whereas that of 15 fell behind with P1-1B (41%). These findings were confirmed by IC50 values (74-125 µm). Enzyme inhibition kinetics, aided by molecular modelling and docking, revealed that there is competition with the substrate CDNB for the same binding site on the allozyme (Ki(13/A)  = 63.6 ± 3.0 µm, Ki(15/B)  = 198.6 ± 14.3 µm, and Ki(11/C)  = 16.5 ± 2.7 µm). These data were brought into context by an in silico structural comparative analysis of the targeted proteins. Although the screened compounds showed moderate inhibitory potency against hGSTP1-1, remarkably, some of them demonstrated absolute isoenzyme and/or allozyme selectivity.


Assuntos
Benzofenonas/química , Benzofenonas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glutationa S-Transferase pi/antagonistas & inibidores , Glutationa Transferase/antagonistas & inibidores , Isoenzimas/antagonistas & inibidores , Glutationa S-Transferase pi/química , Glutationa S-Transferase pi/metabolismo , Glutationa Transferase/química , Glutationa Transferase/metabolismo , Humanos , Isoenzimas/química , Isoenzimas/metabolismo , Cinética , Simulação de Acoplamento Molecular
3.
Bioorg Med Chem ; 22(15): 3957-70, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25002233

RESUMO

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.


Assuntos
Benzofenonas/química , Inibidores Enzimáticos/química , Glutationa Transferase/antagonistas & inibidores , Isoenzimas/antagonistas & inibidores , Benzofenonas/metabolismo , Benzofenonas/toxicidade , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/toxicidade , Glutationa Transferase/metabolismo , Humanos , Isoenzimas/metabolismo , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-Atividade , Termodinâmica
4.
J Biomol Screen ; 18(9): 1092-102, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23749766

RESUMO

Glutathione transferases (GSTs) are cell detoxifiers involved in multiple drug resistance (MDR), hampering the effectiveness of certain anticancer drugs. To our knowledge, this is the first report on well-defined synthetic xanthones as GST inhibitors. Screening 18 xanthones revealed three derivatives bearing a bromomethyl and a methyl group (7) or two bromomethyl groups (8) or an aldehyde group (17), with high inhibition potency (>85%), manifested by low IC(50) values (7: 1.59 ± 0.25 µM, 8: 5.30 ± 0.30 µM, and 17: 8.56 ± 0.14 µM) and a competitive modality of inhibition versus CDNB (Ki(7) = 0.76 ± 0.18 and Ki(17) = 1.69 ± 0.08 µM). Of them, derivative 17 readily inhibited hGSTA1-1 in colon cancer cell lysate (IC(50) = 10.54 ± 2.41 µM). Furthermore, all three derivatives were cytotoxic to Caco-2 intact cells, with 17 being the least cytotoxic (LC(50) = 151.3 ± 16.3 µM). The xanthone scaffold may be regarded as a pharmacophore for hGSTA1-1 and the three derivatives, especially 17, as potent precursors for the synthesis of new inhibitors and conjugate prodrugs for human GSTs.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/antagonistas & inibidores , Xantonas/farmacologia , Antineoplásicos/síntese química , Ligação Competitiva , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Compostos de Diazônio/farmacologia , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Glutationa Transferase/metabolismo , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Xantonas/síntese química
5.
J Med Chem ; 55(15): 6802-13, 2012 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-22849615

RESUMO

Overexpression of human GSTA1-1 in tumor cells is part of MDR mechanisms. We report on the synthesis of 11 pyrrole derivatives as hGSTA1-1 inhibitors starting from 1-methyl-2-[(2-nitrobenzylsulfanyl]-1H-pyrrole. Molecular modeling revealed two locations in the enzyme H binding site: the catalytic primary one accommodating shorter and longer derivatives and the secondary one, where shorter derivatives can occupy. Derivative 9, displaying the highest inhibition and bearing a p-nitroarylimino moiety, and derivative 4, lacking this moiety, were studied kinetically. Derivative 9 binds (K(i(9)) = 71 ± 4 µM) at the primary site competitively vs CDNB. Derivative 4 binds (K(i(4)) = 135 ± 27 µM) at the primary and secondary sites, allowing the binding of a second molecule (4 or CDNB) leading to formation of unreactive and reactive complexes, respectively. The arylmethylsulfonylpyrrole core structure is a new pharmacophore for hGSTA1-1, whereas its derivative 9 may serve as a lead structure.


Assuntos
Compostos de Anilina/síntese química , Glutationa Transferase/antagonistas & inibidores , Iminas/síntese química , Isoenzimas/antagonistas & inibidores , Pirróis/síntese química , Sulfonas/síntese química , Compostos de Anilina/química , Ensaios Enzimáticos , Glutationa Transferase/química , Humanos , Iminas/química , Isoenzimas/química , Cinética , Modelos Moleculares , Ligação Proteica , Pirróis/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/química
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