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1.
Braz J Biol ; 83: e251219, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34669914

RESUMO

The most common form of psycho-social dysfunction is anxiety with depression being related closely without any age bar. They are present with combined state of sadness, confusion, stress, fear etc. Glyoxalase system contains enzyme named glyoxalase 1 (GLO1).It is a metabolic pathway which detoxifies alpha-oxo-aldehydes, particularly methylglyoxal (MG). Methylglyoxal is mainly made by the breakdown of the glycolytic intermediates, glyceraldehyde-3-phosphates and dihydroxyacetone phosphate. Glyoxylase-1 expression is also related with anxiety behavior. A casual role or GLO-1 in anxiety behavior by using viral vectors for over expression in the anterior cingulate cortex was found and it was found that local GLO-1 over expression increased anxiety behavior. The present study deals with the molecular mechanism of protective activity of eugenol against anxiolytic disorder. A pre-clinical animal study was performed on 42 BALB/c mice. Animals were given stress through conventional restrain model. The mRNA expression of GLO-1 was analyzed by real time RT-PCR. Moreover, the GLO-1 protein expression was also examined by immunohistochemistry in whole brain and mean density was calculated. The mRNA and protein expressions were found to be increased in animals given anxiety as compared to the normal control. Whereas, the expressions were decreased in the animals treated with eugenol and its liposome-based nanocarriers in a dose dependent manner. However, the results were better in animals treated with nanocarriers as compared to the compound alone. It is concluded that the eugenol and its liposome-based nanocarriers exert anxiolytic activity by down-regulating GLO-1 protein expression in mice.


Assuntos
Eugenol , Lactoilglutationa Liase/antagonistas & inibidores , Animais , Ansiedade/tratamento farmacológico , Eugenol/farmacologia , Eugenol/uso terapêutico , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C
2.
Chem Biol Interact ; 345: 109511, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-33989593

RESUMO

Methylglyoxal is a dicarbonyl compound recruited as a potential cytotoxic marker, initially presents in cells and considered as a metabolite of the glycolytic pathway. Our aim is to demonstrate the inhibitory effect of 3, 3'-[3-(5-chloro-2-hydroxyphenyl)-3-oxopropane-1, 1-diyl] Bis (4-hydroxycoumarin) on the glyoxalase system, and indirectly its anticancer activity. The docking of OT-55 was conducted by using Flexible docking protocol, ChiFlex and libdock tools inside the active site of Glo-I indicated that both hydrogen bonding and hydrophobic interactions contributed significantly in establishing potent binding with the active site which is selected as a strong inhibitor with high scoring values and maximum Gibbs free energy. Coumarin-liposome formulation was characterized and evaluated in vivo against chemically induced hepatocarcinoma in Wistar rats. After Diethylnitrosamine (DEN) induction, microscopic assessment was realized; precancerous lesions were developed showing an increase of both tumor-associated lymphocyte and multiple tumor acini supported by the blood investigation. Our finding also suggested a preferential uptake of liposomes respectively in liver, kidney, lung, brain and spleen in the DEN-treated animals. OT-55 has also been shown to inhibit the activity of Glo-I in vitro as well as in DEN-treated rats. An abnormal high level of MGO of up to 50% was recorded followed by a reduction in glucose consumption and lactate dehydrogenase production validated in the positive control. MGO generates apoptosis as depicted by focal hepatic lesions. Also, no deleterious effects in the control group were observed after testing our coumarin but rather a vascular reorganization leading to nodular regenerative hyperplasia. Involved in the detoxification process, liver GSH is restored in intoxicated rats, while no changes are seen between controls. At the endothelial cell, OT-55 appears to modulate the release of NO only in the DEN-treated group. OT-55 would behave both as an anticancer agent but also as an angiogenic factor regarding results obtained.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Espaço Intracelular/efeitos dos fármacos , Lactoilglutationa Liase/antagonistas & inibidores , Neoplasias Hepáticas/patologia , Modelos Moleculares , Aldeído Pirúvico/metabolismo , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transporte Biológico , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Espaço Intracelular/metabolismo , Lactoilglutationa Liase/química , Lactoilglutationa Liase/metabolismo , Lipossomos/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Terapia de Alvo Molecular , Conformação Proteica , Ratos , Ratos Wistar , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Bioorg Med Chem Lett ; 40: 127918, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33711442

RESUMO

Glyoxalase I (GLO I) is a known therapeutic target in cancer. Even though TLSC702, a GLO I inhibitor that we discovered, induces apoptosis in tumor cells, exceptionally higher doses are required compared with those needed to inhibit GLO I activity in vitro. In this work, structure-activity optimization studies were conducted on four sections of the TLSC702 molecule to determine the partial structural features necessary for the inhibition of GLO I. Herein, we found that the carboxy group in TLSC702 was critical for binding with the divalent zinc at the active site of GLO I. In contrast, the side chain substituents in the meta- and para- positions of the benzene ring had little influence on the in vitro inhibition of GLO I. The CLogP values of the TLSC702 derivatives showed a positive correlation with the antiproliferative effects on NCI-H522 cells. Thus, two derivatives of TLSC702, which displayed either high or low lipophilicity due to the types of substituents at the phenyl position, were selected. Even though both derivatives showed comparable inhibitory effects as that of their parent compound, the derivative with the high CLogP value was distinctly more antiproliferative than TLSC702. In contrast, the derivative with the low CLogP value did not decrease cell viability in NCI-H522 and HL-60 cells. These findings suggested that structural improvements, such as the addition of hydrophobic moieties to the phenyl group, enhanced the ability of TLSC702 to induce apoptosis by increasing cell membrane permeability.


Assuntos
Butiratos/química , Inibidores Enzimáticos/química , Lactoilglutationa Liase/antagonistas & inibidores , Tiazóis/química , Apoptose/efeitos dos fármacos , Benzeno/química , Butiratos/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/metabolismo , Glutationa/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Ligação Proteica , Aldeído Pirúvico/química , Relação Estrutura-Atividade , Tiazóis/metabolismo
4.
Int J Mol Sci ; 22(4)2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33562355

RESUMO

Synphilin-1 has previously been identified as an interaction partner of α-Synuclein (αSyn), a primary constituent of neurodegenerative disease-linked Lewy bodies. In this study, the repercussions of a disrupted glyoxalase system and aldose reductase function on Synphilin-1 inclusion formation characteristics and cell growth were investigated. To this end, either fluorescent dsRed-tagged or non-tagged human SNCAIP, which encodes the Synphilin-1 protein, was expressed in Saccharomyces cerevisiae and Schizosaccharomyces pombe yeast strains devoid of enzymes Glo1, Glo2, and Gre3. Presented data shows that lack of Glo2 and Gre3 activity in S. cerevisiae increases the formation of large Synphilin-1 inclusions. This correlates with enhanced oxidative stress levels and an inhibitory effect on exponential growth, which is most likely caused by deregulation of autophagic degradation capacity, due to excessive Synphilin-1 aggresome build-up. These findings illustrate the detrimental impact of increased oxidation and glycation on Synphilin-1 inclusion formation. Similarly, polar-localised inclusions were observed in wild-type S. pombe cells and strains deleted for either glo1+ or glo2+. Contrary to S. cerevisiae, however, no growth defects were observed upon expression of SNCAIP. Altogether, our findings show the relevance of yeasts, especially S. cerevisiae, as complementary models to unravel mechanisms contributing to Synphilin-1 pathology in the context of neurodegenerative diseases.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Lactoilglutationa Liase/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Glicosilação , Humanos , Corpos de Inclusão , Lactoilglutationa Liase/genética , Lactoilglutationa Liase/metabolismo , Oxirredução , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética
5.
Acta Pharm ; 71(1): 115-130, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32697740

RESUMO

The glyoxalase system, particularly glyoxalase-I (GLO-I), has been approved as a potential target for cancer treatment. In this study, a set of structurally diverse polyphenolic natural compounds were investigated as potential GLO-I inhibitors. Ellagic acid was found, computationally and experimentally, to be the most potent GLO-I inhibitor among the tested compounds which showed an IC50 of 0.71 mmol L-1. Its binding to the GLO-I active site seemed to be mainly driven by ionic interaction via its ionized hydroxyl groups with the central Zn ion and Lys156, along with other numerous hydrogen bonding and hydrophobic interactions. Due to its unique and rigid skeleton, it can be utilized to search for other novel and potent GLO-I inhibitors via computational approaches such as pharmacophore modeling and similarity search methods. Moreover, an inspection of the docked poses of the tested compounds showed that chlorogenic acid and dihydrocaffeic acid could be considered as lead compounds worthy of further optimization.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ácido Elágico/química , Ácido Elágico/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lactoilglutationa Liase/antagonistas & inibidores , Domínio Catalítico , Simulação por Computador , Ensaios de Triagem em Larga Escala , Ligação de Hidrogênio , Lactoilglutationa Liase/química , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Zinco/química
6.
Biomed Pharmacother ; 131: 110663, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32858501

RESUMO

The glyoxalase system is a ubiquitous enzymatic network which plays important roles in biological life. It consists of glyoxalase 1 (GLO1), glyoxalase 2 (GLO2), and reduced glutathione (GSH), which perform an essential metabolic function in cells by detoxifying methylglyoxal (MG) and other endogenous harmful metabolites into non-toxic d-lactate. MG and MG-derived advanced glycation endproducts (AGEs) are associated with various diseases, such as diabetes, cardiovascular disease, neurodegenerative disorders and cancer, and GLO1 is a key rate-limiting enzyme in the anti-glycation defense. The abnormal activity and expression of GLO1 in various diseases make this enzyme a promising target for drug design and development. This review focuses on the regulatory mechanism of GLO1 in diverse pathogenic conditions with a thorough discussion of GLO1 regulators since their discovery, including GLO1 activators and inhibitors. The different classes, chemical structure and structure-activity relationship are embraced. Moreover, assays for the discovery of small molecule regulators of the glyoxalase system are also introduced in this article. Compared with spectrophotometer-based assay, microplate-based assay is a more simple, rapid and quantitative high-throughput method. This review will be useful to design novel and potent GLO1 regulators and hopefully provide a convenient reference for researchers.


Assuntos
Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Lactoilglutationa Liase/metabolismo , Aldeído Pirúvico/metabolismo , Animais , Produtos Biológicos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glicosilação/efeitos dos fármacos , Humanos , Lactoilglutationa Liase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Aldeído Pirúvico/antagonistas & inibidores
7.
Bioorg Med Chem ; 28(16): 115608, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32690268

RESUMO

The enzyme glyoxalase-I (Glo-I) is an essential therapeutic target in cancer treatment. Significant efforts have been made to discover competitive inhibitors of Glo-I as potential anticancer agents. Herein, we report the synthesis of a series of diazenylbenzenesulfonamide derivatives, their in vitro evaluation against Glo-I and the resulting structure-activity relationships. Among the compounds tested, compounds 9h and 9j exhibited the highest activity with IC50 1.28 µM and 1.13 µM, respectively. Docking studies to explore the binding mode of the compounds identified key moieties that may contribute to the observed activities. The active compounds will serve as suitable leads for further chemical optimization.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Lactoilglutationa Liase/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/química , Inibidores Enzimáticos/química , Humanos , Lactoilglutationa Liase/metabolismo , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
8.
Anticancer Res ; 40(6): 3271-3276, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487622

RESUMO

BACKGROUND/AIM: This study aimed to determine the anxiolytic effect of a putative glyoxalase 1 inhibitor, piceatannol, as well as its antitumor activities on the stress-induced tumor growth of Lewis lung carcinoma. MATERIALS AND METHODS: The anxiolytic activities of piceatannol (1-30 mg/kg) were assessed using the elevated plus maze (EPM) test. We also evaluated the pharmacological modulation of stress-induced tumor growth; the mice were treated with piceatannol (3 and 30 mg/kg) from the 10th day till the 19th day after administration of the LLC cells. RESULTS: At the low dose (3 mg/kg), piceatannol significantly increased the time spent in the open arms of the EPM test when compared with the vehicle. At higher doses (30 mg/kg), it significantly suppressed the stress-induced enhancement of tumor growth. CONCLUSION: A low dose of piceatannol exerts an anxiolytic effect, and high doses have an antitumor effect.


Assuntos
Ansiolíticos/uso terapêutico , Antineoplásicos/uso terapêutico , Lactoilglutationa Liase/antagonistas & inibidores , Proteínas Tirosina Quinases/uso terapêutico , Estilbenos/uso terapêutico , Animais , Ansiolíticos/farmacologia , Antineoplásicos/farmacologia , Lactoilglutationa Liase/uso terapêutico , Masculino , Camundongos , Proteínas Tirosina Quinases/farmacologia , Estilbenos/farmacologia
9.
Cell Chem Biol ; 27(6): 708-718.e10, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32402240

RESUMO

Pharmacophore-focused chemical libraries are continuously being created in drug discovery programs, yet screening assays to maximize the usage of such libraries are not fully explored. Here, we report a chemical proteomics approach to reutilizing a focused chemical library of 1,800 indole-containing molecules for discovering uncharacterized ligand-protein pairs. Gel-based protein profiling of the library using a photo-affinity indole probe 1 enabled us to find new ligands for glyoxalase 1 (Glo1), an enzyme involved in the detoxification of methylglyoxal. Structure optimization of the ligands yielded an inhibitor for Glo1 (9). Molecule 9 increased the cellular methylglyoxal levels in human cells and suppressed the osteoclast formation of mouse bone marrow-derived macrophages. X-ray structure analyses revealed that the molecule lies at a site abutting the substrate binding site, which is consistent with the enzyme kinetic profile of 9. Overall, this study exemplifies how chemical proteomics can be used to exploit existing focused chemical libraries.


Assuntos
Lactoilglutationa Liase/antagonistas & inibidores , Proteômica , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Células Cultivadas , Cristalografia por Raios X , Humanos , Cinética , Lactoilglutationa Liase/metabolismo , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
10.
Sci Rep ; 10(1): 785, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964958

RESUMO

Present work aims to utilize systems biology and molecular modelling approach to understand the inhibition kinetics of Leishmania major GLO I and identifying potential hit followed by their validation through in vitro and animal studies. Simulation of GLO I inhibition has shown to affect reaction fluxes of almost all reactions in the model that led to increased production of various AGEs and free radicals. Further, in vitro testing of C1 and C2, selected through molecular modelling revealed remarkable morphological alterations like size reduction, membrane blebbing and loss in motility of the parasite, however, only C1 showed better antileishmanial activity. Additionally, C1 showed apoptosis mediated leishmanicidal activity (apoptosis-like cell death) along with cell-cycle arrest at sub-G0/G1 phase and exhibited potent anti-leishmanial effect against intracellular amastigotes. Furthermore, decrease in parasite load was also observed in C1 treated BALB/c female mice. Our results indicate that C1 has healing effect in infected mice and effectively reduced the parasitic burden. Hence, we suggest C1 as a lead molecule which on further modification, may be used to develop novel therapeutics against Leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Lactoilglutationa Liase/química , Lactoilglutationa Liase/metabolismo , Leishmania major/crescimento & desenvolvimento , Animais , Antiprotozoários/química , Ciclo Celular/efeitos dos fármacos , Modelos Animais de Doenças , Lactoilglutationa Liase/antagonistas & inibidores , Leishmania major/efeitos dos fármacos , Leishmania major/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Carga Parasitária , Células RAW 264.7 , Biologia de Sistemas
11.
Bioorg Med Chem ; 28(4): 115243, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31879183

RESUMO

Glyoxalase I (GLO1) is a homodimeric Zn2+-metalloenzyme that catalyses the transformation of methylglyoxal (MG) to d-lacate through the intermediate S-d-lactoylglutathione. Growing evidence indicates that GLO1 has been identified as a potential target for the treatment cancer and other diseases. Various inhibitors of GLO1 have been discovered or developed over the past several decades including natural or natural product-based inhibitors, GSH-based inhibitors, non-GSH-based inhibitors, etc. The aim of this review is to summarize recent achievements of concerning discovery, design strategies, as well as pharmacological aspects of GLO1 inhibitors with the target of promoting their development toward clinical application.


Assuntos
Produtos Biológicos/farmacologia , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/farmacologia , Lactoilglutationa Liase/antagonistas & inibidores , Produtos Biológicos/síntese química , Produtos Biológicos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Lactoilglutationa Liase/metabolismo , Estrutura Molecular
12.
Anal Chem ; 91(24): 15577-15584, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31794195

RESUMO

The accurate detection of tumorous methylglyoxal (MGO) and its detoxifier glyoxalase 1 (GLO1) in living systems is critical for understanding their roles in tumor initiation and progression. To date, the in situ fluorescence detection of endogenous MGO and GLO1 in tumor has not been reported. Herein we developed a near-infrared (NIR) fluorescent probe MEBTD to specifically detect tumorous MGO. Compared with previously reported MGO fluorescent probes, MEBTD exhibits several distinct advantages, including NIR emission, high selectivity with an MGO detection limit of 18 nM, and a 131-fold off-on ratio. The probe could sense GLO1 activity and monitor the therapeutic effect of GLO1 inhibitors by imaging tumorous MGO in a both a real-time and in situ manner, demonstrating that the biological effect of GLO1 inhibitors is dependent on the GLO1 activity. Furthermore, MEBTD enables the visualization of tumorous MGO induced by GLO1 inhibitors in vivo. To the best of our knowledge, MEBTD is the first NIR fluorescent probe for specifically imaging tumorous MGO in living animals, indicating the promising potential for tumor diagnosis and therapeutic evaluation.


Assuntos
Neoplasias da Mama/patologia , Corantes Fluorescentes/química , Raios Infravermelhos , Lactoilglutationa Liase/metabolismo , Aldeído Pirúvico/metabolismo , Animais , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Lactoilglutationa Liase/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Sci Rep ; 9(1): 14867, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619723

RESUMO

We previously showed that curcumin, a phytopolyphenol found in turmeric (Curcuma longa), targets a series of enzymes in the ROS metabolic pathway, induces irreversible growth arrest, and causes apoptosis. In this study, we tested Pentagamavunon-1 (PGV-1), a molecule related to curcumin, for its inhibitory activity on tumor cells in vitro and in vivo. PGV-1 exhibited 60 times lower GI50 compared to that of curcumin in K562 cells, and inhibited the proliferation of cell lines derived from leukemia, breast adenocarcinoma, cervical cancer, uterine cancer, and pancreatic cancer. The inhibition of growth by PGV-1 remained after its removal from the medium, which suggests that PGV-1 irreversibly prevents proliferation. PGV-1 specifically induced prometaphase arrest in the M phase of the cell cycle, and efficiently induced cell senescence and cell death by increasing intracellular ROS levels through inhibition of ROS-metabolic enzymes. In a xenograft mouse model, PGV-1 had marked anti-tumor activity with little side effects by oral administration, whereas curcumin rarely inhibited tumor formation by this administration. Therefore, PGV-1 is a potential therapeutic to induce tumor cell apoptosis with few side effects and low risk of relapse.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Curcumina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Prometáfase/efeitos dos fármacos , Administração Oral , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Morte Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Curcumina/análogos & derivados , Glutationa S-Transferase pi/antagonistas & inibidores , Glutationa S-Transferase pi/genética , Glutationa S-Transferase pi/metabolismo , Glutationa Transferase/antagonistas & inibidores , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Células HEK293 , Células HeLa , Humanos , Células K562 , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/genética , Lactoilglutationa Liase/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células MCF-7 , Camundongos Nus , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Peroxirredoxinas/antagonistas & inibidores , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Prometáfase/genética , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Comput Aided Mol Des ; 33(9): 799-815, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31630312

RESUMO

The glyoxalase-I (GLO-I) enzyme, which is the initial enzyme of the glyoxalase system that is responsible for the detoxification of cytotoxic α-ketoaldehydes, such as methylglyoxal, has been approved as a valid target in cancer therapy. Overexpression of GLO-I has been observed in several types of carcinomas, including breast, colorectal, prostate, and bladder cancer. In this work we aimed to identify potential GLO-I inhibitors via employing different structure-based drug design techniques including structure-based poly-pharmacophore modelling, virtual screening, and molecular docking. Poly-pharmacophore modelling was applied in this study in order to thoroughly explore the binding site of the target enzyme, thereby, revealing hits that could bind in a nonconventional way which can pave the way for designing more potent and selective ligands with novel chemotypes. The modelling phase has resulted in the selection of 31 compounds that were biologically evaluated against human GLO-I enzyme. Among the tested set, seven compounds showed excellent inhibitory activities with IC50 values ranging from 0.34 to 30.57 µM. The most active compound (ST018515) showed an IC50 of 0.34 ± 0.03 µM, which, compared to reported GLO-I inhibitors, can be considered a potent inhibitor, making it a good candidate for further optimization towards designing more potent GLO-I inhibitors.


Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Lactoilglutationa Liase/química , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Lactoilglutationa Liase/antagonistas & inibidores , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos
15.
Molecules ; 24(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487813

RESUMO

Glyoxalase-I (Glo-I) enzyme was established to be a valid target for anticancer drug design. It performs the essential detoxification step of harmful byproducts, especially methylglyoxal. A robust computer-aided drug design approach was used to design and validate a series of compounds with selenium or sulfur based heterorings. A series of in-house multi-armed 1,2,3-selenadiazole and 1,2,3-thiadiazole benzene derivatives were tested for their Glo-I inhibitory activity. Results showed that these compounds bind Glo-I active sites competitively with strong potential to inhibit this enzyme with IC50 values in micro-molar concentration. Docking poses revealed that these compounds interact with the zinc atom at the bottom of the active site, which plays an essential role in its viability.


Assuntos
Acetanilidas/farmacologia , Inibidores Enzimáticos/farmacologia , Lactoilglutationa Liase/antagonistas & inibidores , Acetanilidas/química , Sítios de Ligação , Inibidores Enzimáticos/química , Humanos , Ligação de Hidrogênio , Lactoilglutationa Liase/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
16.
Mar Drugs ; 17(9)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438528

RESUMO

Glucose degradation is aberrantly increased in hyperglycemia, which causes various harmful effects on the liver. Glyoxalase-1 (Glo-1) is a ubiquitous cellular enzyme that participates in the detoxification of methylglyoxal (MGO), a cytotoxic byproduct of glycolysis that induces protein modification (advanced glycation end-products, AGEs) and inflammation. Here, we investigated the anti-inflammatory effect of indole-4-carboxaldehyde (ST-I4C), which was isolated from the edible seaweed Sargassum thunbergii, on MGO-induced inflammation in HepG2 cells, a human hepatocyte cell line. ST-I4C attenuated the MGO-induced expression of inflammatory-related genes, such as tumor necrosis factor (TNF)-α and IFN-γ by activating nuclear factor-kappa B (NF-κB) without toxicity in HepG2 cells. In addition, ST-I4C reduced the MGO-induced AGE formation and the expression of the receptor for AGE (RAGE). Interestingly, both the mRNA and protein expression levels of Glo-1 increased following ST-I4C treatment, and the decrease in Glo-1 mRNA expression caused by MGO exposure was rescued by ST-I4C pretreatment. These results suggest that ST-I4C shows anti-inflammatory activity against MGO-induced inflammation in human hepatocytes by preventing an increase in the pro-inflammatory gene expression and AGE formation. Therefore, it represents a potential therapeutic agent for the prevention of hepatic steatosis.


Assuntos
Anti-Inflamatórios/farmacologia , Indóis/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Aldeído Pirúvico/toxicidade , Sargassum/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Produtos Finais de Glicação Avançada/metabolismo , Glicólise/efeitos dos fármacos , Células Hep G2 , Humanos , Indóis/isolamento & purificação , Indóis/uso terapêutico , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/metabolismo , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Alga Marinha/química , Transdução de Sinais/efeitos dos fármacos
17.
Eur J Pharmacol ; 857: 172419, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31136758

RESUMO

Advanced glycation end products (AGEs) play an important role in the onset of diabetic retinopathy. Therefore, in the current study, we investigate whether and how Tanshinone IIa (Tan IIa) from Salvia miltiorrhiza protects bovine retinal endothelial cells (BRECs) against methylglyoxal (MGO) mediated cell dysfunction. The results showed that MGO reduced cell viability in dose dependent manner. The treatment of Tan IIa (50 µM) significantly improved cell viability induced by MGO in BRECs. MGO increased cellular reactive oxygen species formation and cellular nitric oxide (NO) level; enhanced nox1 and iNOS mRNA levels; inhibited prdx1 mRNA level. The treatment of Tan IIa effectually ameliorated cellular oxidative stress. Exposure of MGO resulted in mitochondrial fission and decrease of opa1 and mfn1. No significant difference in mRNA levels of mfn2 and drp1 was detected between MGO and medium. Tan IIa reduced mitochondrial fragmentation, enhanced the mRNA levels of mfn1 and opa1 in MGO cultured BRECs. The short time exposure of cellular antioxidatants, dimethylthiourea (10 mM) and tiron (10 mM) had no effect on mitochondrial fission although they ameliorated cellular reactive oxygen species level. Moreover, overexpression of glyoxalase 1 (GLO1) increased key proteins of mitochondrial fusion, including opa1 and mfn1 in BRECs cultured with MGO. However, inhibition of GLO1 by siRNA abolished the effect of Tan IIa on induction of mitochondrial fusion in MGO cultured BRECs. In conclusion, MGO caused the injury of retinal endothelial cells through induction of mitochondrial dysfunction and mitochondrial fission, the treatment of Tan IIa ameliorated mitochondrial dysfunction and fission induced by AGEs through enhancing GLO1.


Assuntos
Abietanos/farmacologia , Citoproteção/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Lactoilglutationa Liase/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Retina/citologia , Animais , Apoptose/efeitos dos fármacos , Bovinos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Lactoilglutationa Liase/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Aldeído Pirúvico/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Comput Biol Chem ; 80: 102-110, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30947068

RESUMO

Glyoxalase system is an ubiquitous system in human cells which has been examined thoroughly for its role in different diseases. It comprises two enzymes; Glyoxalase I (Glo-I) and Glyoxalase II (Glo-II) which perform detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic bystanders. In silico computer Aided Drug Design approaches were used and ninety two diverse pharmacophore models were generated from eighteen Glyoxalase I crystallographic complexes. Subsequent QSAR modeling followed by ROC evaluation identified a single pharmacophore model which was able to predict the expected Glyoxalase I inhibition. Screening of the National Cancer Institute (NCI) database using the optimal pharmacophore Hypo(3VW9) identified several promising hits. Thirty eight hits were successfully predicted then ordered and evaluated in vitro. Seven hits out of the thirty eight tested compounds showed more than 50% inhibition with low micromolar IC50.


Assuntos
Antineoplásicos/metabolismo , Inibidores Enzimáticos/metabolismo , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/metabolismo , Antineoplásicos/química , Domínio Catalítico , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Humanos , Lactoilglutationa Liase/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Curva ROC , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
19.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1389-1401, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771486

RESUMO

Methylglyoxal (MG), a highly reactive dicarbonyl derived from metabolic processes, is the most powerful precursor of advanced glycation end products (AGEs). Glycative stress has been recently associated with ovarian dysfunctions in aging and PCOS syndrome. We have investigated the role of the NAD+-dependent Class III deacetylase SIRT1 in the adaptive response to MG in mouse oocytes and ovary. In mouse oocytes, MG induced up-expression of glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2) genes, components of the main MG detoxification system, whereas inhibition of SIRT1 by Ex527 or sirtinol reduced this response. In addition, the inhibition of SIRT1 worsened the effects of MG on oocyte maturation rates, while SIRT1 activation by resveratrol counteracted MG insult. Ovaries from female mice receiving 100 mg/kg MG by gastric administration for 28 days (MG mice) exhibited increased levels of SIRT1 along with over-expression of catalase, superoxide dismutase 2, SIRT3, PGC1α and mtTFA. Similar levels of MG-derived AGEs were observed in the ovaries from MG and control groups, along with enhanced protein expression of glyoxalase 1 in MG mice. Oocytes ovulated by MG mice exhibited atypical meiotic spindles, a condition predisposing to embryo aneuploidy. Our results from mouse oocytes revealed for the first time that SIRT1 could modulate MG scavenging by promoting expression of glyoxalases. The finding that up-regulation of glyoxalase 1 is associated with that of components of a SIRT1 functional network in the ovaries of MG mice provides strong evidence that SIRT1 participates in the response to methylglyoxal-dependent glycative stress in the female gonad.


Assuntos
Produtos Finais de Glicação Avançada/genética , Oócitos/efeitos dos fármacos , Ovário/efeitos dos fármacos , Aldeído Pirúvico/farmacologia , Sirtuína 1/genética , Animais , Benzamidas/farmacologia , Carbazóis/farmacologia , Catalase/genética , Catalase/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Regulação da Expressão Gênica , Produtos Finais de Glicação Avançada/metabolismo , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/genética , Lactoilglutationa Liase/metabolismo , Camundongos , Camundongos Endogâmicos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Naftóis/farmacologia , Oócitos/citologia , Oócitos/metabolismo , Ovário/citologia , Ovário/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Cultura Primária de Células , Aldeído Pirúvico/antagonistas & inibidores , Resveratrol/farmacologia , Transdução de Sinais , Sirtuína 1/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Tioléster Hidrolases/antagonistas & inibidores , Tioléster Hidrolases/genética , Tioléster Hidrolases/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
20.
J Med Chem ; 62(3): 1609-1625, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30628789

RESUMO

Anxiety and depression are common, highly comorbid psychiatric diseases that account for a large proportion of worldwide medical disability. Glyoxalase 1 (GLO1) has been identified as a possible target for the treatment of anxiety and depression. GLO1 is a Zn2+-dependent enzyme that isomerizes a hemithioacetal, formed from glutathione and methylglyoxal, to a lactic acid thioester. To develop active inhibitors of GLO1, fragment-based drug discovery was used to identify fragments that could serve as core scaffolds for lead development. After screening a focused library of metal-binding pharmacophores, 8-(methylsulfonylamino)quinoline (8-MSQ) was identified as a hit. Through computational modeling and synthetic elaboration, a potent GLO1 inhibitor was developed with a novel sulfonamide core pharmacophore. A lead compound was demonstrated to penetrate the blood-brain barrier, elevate levels of methylglyoxal in the brain, and reduce depression-like behavior in mice. These findings provide the basis for GLO1 inhibitors to treat depression and related psychiatric illnesses.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Lactoilglutationa Liase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/uso terapêutico , Aminoquinolinas/química , Aminoquinolinas/uso terapêutico , Animais , Antidepressivos/química , Encéfalo/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/química , Feminino , Humanos , Masculino , Camundongos , Estrutura Molecular , Aldeído Pirúvico/metabolismo , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/uso terapêutico
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