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1.
Acta Crystallogr C Struct Chem ; 78(Pt 8): 437-448, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35924362

RESUMO

Creatinine, a biologically important compound, is used to analyze kidney function and kidney diseases in the human body. The salt form of creatinine is used in the formation of drug materials like anti-HIV, antifungal, antiprotozoal, antiviral and antitumour compounds. Here we report the solid-state structures of three new crystalline salts, namely, creatininium (2-amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-3-ium) bromide, C4H8N3O+·Br-, (I), creatininium 3-aminobenzoate, C4H8N3O+·C7H6NO2-, (II), and creatininium 3,5-dinitrobenzoate, C4H8N3O+·C7H3N2O6-, (III). These salts have been synthesized and characterized by single-crystal X-ray diffraction and Hirshfeld surface analysis. The structural chemistry of salts (I)-(III) and their crystal packing are discussed in detail. The primary interaction between the creatinine cation and the acid anion in the three salts is N-H...Br/O hydrogen bonds. In salt (I), the creatinine cation and bromide anion are connected through a pair of N-H...Br hydrogen bonds forming R42(8) and R42(12) ring motifs. In salts (II) and (III), the creatinine cation interacts with the corresponding anion via a pair of N-H...O hydrogen bonds. The crystal structure is further stabilized by C-H...O and O-H...O hydrogen bonds with the ring motifs R22(8), R21(7) and R21(6). Furthermore, the crystal structures are stabilized by π-π, C-H...π, C-O...π and N-O...π stacking interactions. The contributions made by each hydrogen bond in maintaining the crystal structure stability has been quantified by Hirshfeld surface analysis.


Assuntos
Ácido Bromídrico , Sais , Brometos , Creatinina , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Estrutura Molecular , Nitrobenzoatos , Sais/química , meta-Aminobenzoatos
2.
Phys Chem Chem Phys ; 23(40): 23242-23255, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34632473

RESUMO

The negative effects of ultraviolet radiation (UVR) on human skin have led to the widespread use of sunscreens, i.e. skincare products containing UV filters to absorb, reflect or otherwise block UVR. The mechanisms by which UV filters dissipate energy following photoexcitation, i.e. their photodynamics, can crucially determine a molecule's performance as a sunscreen UV filter. In this work, we evaluate the effects of substituent position on the in-solution relaxation pathways of two derivates of methyl anthranilate (an ortho compound that is a precursor to the UV filter meradimate), meta- and para-methyl anthranilate, m-MA and p-MA, respectively. The photodynamics of m-MA were found to be sensitive to solvent polarity: its emission spectra show larger Stokes shifts with increasing polarity, and both the fluorescence quantum yield and lifetimes for m-MA increase in polar solvents. While the Stokes shifts for p-MA are much milder and more independent of solvent environment than those of m-MA, we find its fluorescence quantum yields to be sensitive not only to solvent polarity but to the hydrogen bonding character of the solvent. In both cases (m- and p-MA) we have found common computational methods to be insufficient to appropriately model the observed spectroscopic data, likely due to an inability to account for explicit solvent interactions, a known challenge in computational chemistry. Therefore, apart from providing insight into the photodynamics of anthranilate derivatives, the work presented here also provides a case study that may be of use to theoretical chemists looking to improve and develop explicit solvent computational methods.


Assuntos
Ácido 4-Aminobenzoico/química , meta-Aminobenzoatos/química , Teoria Quântica , Solventes/química , Espectrometria de Fluorescência , Protetores Solares/química , Raios Ultravioleta
3.
Chem Asian J ; 16(22): 3729-3742, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34549886

RESUMO

Half-sandwich RuII complexes, [(YZ)RuII (η6 -arene)(X)]+, (YZ=chelating bidentate ligand, X=halide), with N,N and N,O coordination (1-9) show significant antiproliferative activity against the metastatic triple-negative breast carcinoma (MDA-MB-231). 3-aminobenzoic acid or its methyl ester is used in all the ligands while varying the aldehyde for N,N and N,O coordination. In the N,N coordinated complex the coordinated halide(X) is varied for enhancing stability in solution (X=Cl, I). Rapid aquation and halide exchange of the pyridine analogues, 2 and 3, in solution are a major bane towards their antiproliferative activity. Presence of free -COOH group (1 and 4) make complexes hydrophilic and reduces toxicity. The imidazolyl 3-aminobenzoate based N,N coordinated 5 and 6 display better solution stability and efficient antiproliferative activity (IC50 ca. 2.3-2.5 µM) compared to the pyridine based 2 and 3 (IC50 >100 µM) or the N,O coordinated complexes (7-9) (IC50 ca. 7-10 µM). The iodido coordinated, 6, is resistant towards aquation and halide exchange. The N,O coordinated 7-9 underwent instantaneous aquation at pH 7.4 generating monoaquated complexes stable for at least 6 h. Complexes 5 and 6, bind to 9-ethylguanine (9-EtG) showing propensity to interact with DNA bases. The complexes may kill via apoptosis as displayed from the study of 8. The change in coordination mode and the aldehyde affected the solution stability, antiproliferative activity and mechanistic pathways. The N,N coordinated (5 and 6) exhibit arrest in the G2/M phase while the N,O coordinated 8 showed arrest in the G0/G1 phase.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Rutênio/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , meta-Aminobenzoatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Rutênio/química , Bases de Schiff/química , Bases de Schiff/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , meta-Aminobenzoatos/química
4.
PLoS One ; 15(10): e0240517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33052980

RESUMO

Mitochondrial diseases are a clinically heterogenous group of disorders caused by respiratory chain dysfunction and associated with progressive, multi-systemic phenotype. There is no effective treatment or cure, and no FDA-approved drug for treating mitochondrial disease. To identify and characterize potential therapeutic compounds, we developed an in vitro screening assay and identified a group of direct AMP-activated protein kinase (AMPK) activators originally developed for the treatment of diabetes and metabolic syndrome. Unlike previously investigated AMPK agonists such as AICAR, these compounds allosterically activate AMPK in an AMP-independent manner, thereby increasing specificity and decreasing pleiotropic effects. The direct AMPK activator PT1 significantly improved mitochondrial function in assays of cellular respiration, energy status, and cellular redox. PT1 also protected against retinal degeneration in a mouse model of photoreceptor degeneration associated with mitochondrial dysfunction and oxidative stress, further supporting the therapeutic potential of AMP-independent AMPK agonists in the treatment of mitochondrial disease.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Doenças Mitocondriais/tratamento farmacológico , Tiazóis/administração & dosagem , meta-Aminobenzoatos/administração & dosagem , Regulação Alostérica/efeitos dos fármacos , Animais , Compostos de Bifenilo , Respiração Celular/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Camundongos , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Pironas/administração & dosagem , Pironas/farmacologia , Tiazóis/farmacologia , Tiofenos/administração & dosagem , Tiofenos/farmacologia , meta-Aminobenzoatos/farmacologia
5.
Australas Psychiatry ; 28(1): 106-111, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31512482

RESUMO

OBJECTIVES: This paper is a follow-up of a previous introduction to systematic reviews and presents a step-by-step approach updated in the light of developments in the field. CONCLUSIONS: We describe resources such as bibliographic software, electronic translation and programs to assist in article selection, as well as the need for prospective registration of a protocol with an appropriate register. Lastly, we suggest freeware for meta-analysis and basic techniques.


Assuntos
Pesquisa Biomédica/métodos , Guias como Assunto , Revisões Sistemáticas como Assunto , meta-Aminobenzoatos , Humanos
6.
Chembiochem ; 20(19): 2458-2462, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059166

RESUMO

Pactamycin is an antibiotic produced by Streptomyces pactum with antitumor and antimalarial properties. Pactamycin has a unique aminocyclitol core that is decorated with 3-aminoacetophenone, 6-methylsaliciate, and an N,N-dimethylcarbamoyl group. Herein, we show that the adenylation enzyme PctU activates 3-aminobenzoic acid (3ABA) with adenosine triphosphate and ligates it to the holo form of the discrete acyl carrier protein PctK to yield 3ABA-PctK. Then, 3ABA-PctK is N-glycosylated with uridine diphosphate-N-acetyl-d-glucosamine (UDP-GlcNAc) by the glycosyltransferase PctL to yield GlcNAc-3ABA-PctK. Because 3ABA is known to be a precursor of the 3-aminoacetophenone moiety, PctU appears to be a gatekeeper that selects the appropriate 3-aminobenzoate starter unit. Overall, we propose that acyl carrier protein-bound glycosylated 3ABA derivatives are biosynthetic intermediates of pactamycin biosynthesis.


Assuntos
Adenina/metabolismo , Adenilato Quinase/metabolismo , Enzimas/metabolismo , Glicosiltransferases/metabolismo , Pactamicina/biossíntese , Uridina Difosfato N-Acetilglicosamina/metabolismo , meta-Aminobenzoatos/metabolismo , Proteínas de Bactérias/metabolismo
7.
Future Med Chem ; 11(5): 407-422, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30887814

RESUMO

AIM: To investigate a novel series of quinazoline monopeptide esters for the in vitro antibacterial activity. METHODOLOGY/RESULTS: The compounds were synthesized via one-pot Dimroth rearrangement of suitable formamidine intermediates with 3-aminobenzoic acid, followed by coupling the resulting acids with amino acid esters and screening for their antibacterial activity by broth dilution method. The compounds 5a, 5b, 5c, 5g, 5i and 5j showed promising activity against the Gram-positive bacteria, 5c and 5g being the most potent against Enterococcus faecalis and Staphylococcus aureus, respectively, with a minimal inhibitory concentration of 0.51 µM. The percentage hemolysis of the compounds ranged from 2.79 to 12.92 at a concentration of 100 µg/ml. The molecular docking studies revealed their GlmU inhibitory action. CONCLUSION: The compounds 5a and 5g emerged as antibacterial hits.


Assuntos
Antibacterianos/química , Ésteres/química , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Oligopeptídeos/química , Quinazolinas/química , Amidinas/química , Antibacterianos/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Enterococcus faecalis/efeitos dos fármacos , Ésteres/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , meta-Aminobenzoatos/química
8.
Bioelectrochemistry ; 127: 125-135, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30818262

RESUMO

A facile one-step electrochemical synthesis of a platinum/reduced graphene oxide/poly(3-aminobenzoic acid) (Pt/rGO/P3ABA) nanocomposite film on a screen-printed carbon electrode (SPCE) and its application in the development of sensitive amperometric biosensors was successfully demonstrated herein. The electropolymerization of P3ABA together with co-electrodeposition of rGO and Pt was conducted by cyclic voltammetry, as was the GO reduction to rGO. A Pt/rGO/P3ABA-modified SPCE exhibited excellent electrocatalytic oxidation towards hydrogen peroxide (H2O2) and can be employed as an electrochemical platform for the immobilization of glucose oxidase (GOx) and cholesterol oxidase (ChOx) to fabricate glucose and cholesterol biosensors, respectively. Under the optimized conditions at a working potential of +0.50 V, the proposed biosensors revealed excellent linear responses to glucose and cholesterol in the concentration ranges of 0.25-6.00 mM and 0.25-4.00 mM, respectively, with high sensitivities of 22.01 and 15.94 µA mM-1 cm-2 and low detection limits (LODs) of 44.3 and 40.5 µM. Additionally, the Michaelis-Menten constant (Km) of GOx was 3.54 mM, while the Km of ChOx was 3.82 mM. Both biosensors displayed a good anti-interference ability and clearly exhibited acceptable recoveries for the detection of glucose and cholesterol in a human serum sample (98.2-104.1%).


Assuntos
Técnicas Biossensoriais/métodos , Glicemia/análise , Colesterol/sangue , Grafite/química , Nanocompostos/química , Platina/química , meta-Aminobenzoatos/química , Aspergillus niger/enzimologia , Colesterol Oxidase/química , Técnicas Eletroquímicas/métodos , Enzimas Imobilizadas/química , Glucose Oxidase/química , Humanos , Limite de Detecção , Masculino , Nanocompostos/ultraestrutura , Oxirredução , Polímeros/química , Streptomyces/enzimologia
9.
Trials ; 19(1): 375, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30005644

RESUMO

BACKGROUND: The potential of neuroprotective agents should be revisited in the era of endovascular thrombectomy (EVT) for acute large-artery occlusion because their preclinical effects have been optimized for ischemia and reperfusion injury. Neu2000, a derivative of sulfasalazine, is a multi-target neuroprotectant. It selectively blocks N-methyl-D-aspartate receptors and scavenges for free radicals. This trial aimed to determine whether neuroprotectant administration before EVT is safe and leads to a more favorable outcome. METHODS: This trial is a phase-II, multicenter, three-arm, randomized, double-blinded, placebo-controlled, blinded-endpoint drug trial that enrolled participants aged ≥ 19 years undergoing an EVT attempt less than 8 h from symptom onset, with baseline National Institutes of Health Stroke Scale (NIHSS) score ≥ 8, Alberta Stroke Program Early CT score ≥ 6, evidence of large-artery occlusion, and at least moderate collaterals on computed tomography angiography. EVT-attempted patients are randomized into control, low-dose (2.75 g), and high-dose (5.25 g) Neu2000KWL over 5 days. Seventy participants per group are enrolled for 90% power, assuming that the treatment group has a 28.4% higher proportion of participants with functional independence than the placebo group. The primary outcome, based on intention-to-treat criteria is the improvement of modified Rankin Scale (mRS) scores at 3 months using a dichotomized model. Safety outcomes include symptomatic intracranial hemorrhage within 5 days. Secondary outcomes are distributional change of mRS, mean differences in NIHSS score, proportion of NIHSS score 0-2, and Barthel Index > 90 at 1 and 4 weeks, and 3 months. DISCUSSION: The trial results may provide information on new therapeutic options as multi-target neuroprotection might mitigate reperfusion injury in patients with acute ischemic stroke before EVT. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02831088 . Registered on 13 July 2016.


Assuntos
Isquemia Encefálica/terapia , Procedimentos Endovasculares , Fluorbenzenos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Salicilatos/uso terapêutico , Acidente Vascular Cerebral/terapia , Trombectomia/métodos , meta-Aminobenzoatos/uso terapêutico , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Ensaios Clínicos Fase II como Assunto , Avaliação da Deficiência , Método Duplo-Cego , Procedimentos Endovasculares/efeitos adversos , Fluorbenzenos/efeitos adversos , Humanos , Estudos Multicêntricos como Assunto , Fármacos Neuroprotetores/efeitos adversos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , República da Coreia , Salicilatos/efeitos adversos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Trombectomia/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , meta-Aminobenzoatos/efeitos adversos
10.
Appl Microbiol Biotechnol ; 102(11): 4843-4852, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29696333

RESUMO

The biodegradation pathway of 3-aminobenzoate has been documented, but little is known about the sequence and biochemical properties of the proteins involved. In the present study, a 10,083-bp DNA fragment involved in 3-aminobenzoate degradation was identified in 3-aminobenzoate-degrading Comamonas sp. strain QT12. The mabA gene, whose encoded protein shares 39% amino acid sequence identity with 3-hydroxybenzoate 6-hydroxylase of Polaromonas naphthalenivorans CJ2, was identified on this DNA fragment, and the mabA-disrupted mutant was unable to grow on and convert 3-aminobenzoate. MabA was heterologously expressed in Escherichia coli and purified to homogeneity as an approximately ~ 48-kDa His-tagged protein. It was characterized as 3-aminobenzoate 6-hydroxylase capable of catalyzing the conversion of 3-aminobenzoate to 5-aminosalicylate, incorporating one oxygen atom from dioxygen into the product. It contains a non-covalent but tightly bound FAD as the prosthetic group and NADH as an external electron donor. 5-Aminosalicylate was produced with equimolar consumption of NADH. The apparent Km and kcat values of the purified enzyme for 3-aminobenzoate were 158.51 ± 4.74 µM and 6.49 ± 0.17 s-1, respectively, and those for NADH were 189.85 ± 55.70 µM and 7.41 ± 1.39 s-1, respectively. The results suggest that mabA is essential for 3-aminobenzoate degradation in strain QT12, and that 3-aminobenzoate is the primary and physiological substrate of MabA.


Assuntos
Comamonas/enzimologia , Comamonas/genética , Oxigenases de Função Mista/genética , meta-Aminobenzoatos/metabolismo , Sequência de Aminoácidos
11.
Virology ; 515: 223-234, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29306785

RESUMO

The crystal structure of chikungunya (CHIKV) virus capsid protease domain has been determined at 2.2Å. Structure reveals a chymotrypsin-like protease fold with a conserved hydrophobic pocket in CHIKV capsid protein (CP) for interaction with the cytoplasmic tail of E2 (cdE2) similar to the capsid protein of other alphaviruses. Molecular contacts between CP-cdE2 were determined by fitting structures of CHIKV CP and cdE2 into the cryo-EM map of Venezuelan equine encephalitis virus (VEEV). Binding of (S)-(+)-Mandelic acid (MDA) and Ethyl 3-aminobenzoate (EAB) to the hydrophobic pocket of CP was evaluated by molecular docking. Surface plasmon resonance (SPR) and fluorescence spectroscopy experiments confirmed MDA and EAB binding to the CP. The binding constants (KD) obtained from SPR for MDA and EAB were 1.2 × 10-3 M and 0.2 × 10-9 M, respectively. This study adds to the understanding of chikungunya virus structural proteins and may serve as the basis for antiviral development against chikungunya disease.


Assuntos
Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Febre de Chikungunya/virologia , Vírus Chikungunya/metabolismo , Antivirais/química , Antivirais/farmacologia , Capsídeo/química , Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Proteínas do Capsídeo/genética , Vírus Chikungunya/química , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/genética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Ácidos Mandélicos/química , Ácidos Mandélicos/farmacologia , Simulação de Acoplamento Molecular , Domínios Proteicos , meta-Aminobenzoatos/química , meta-Aminobenzoatos/farmacologia
12.
J Bacteriol ; 200(1)2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29038259

RESUMO

The 1,125-bp mabB gene encoding 5-aminosalicylate (5ASA) 1,2-dioxygenase, a nonheme iron dioxygenase in the bicupin family that catalyzes the cleavage of the 5ASA aromatic ring to form cis-4-amino-6-carboxy-2-oxohexa-3,5-dienoate in the biodegradation of 3-aminobenzoate, was cloned from Comamonas sp. strain QT12 and characterized. The deduced amino acid sequence of the enzyme has low sequence identity with that of other reported ring-cleaving dioxygenases. MabB was heterologously expressed in Escherichia coli cells and purified as a His-tagged enzyme. The optimum pH and temperature for MabB are 8.0 and 10°C, respectively. FeII is required for the catalytic activity of the purified enzyme. The apparent Km and Vmax values of MabB for 5ASA are 52.0 ± 5.6 µM and 850 ± 33.2 U/mg, respectively. The two oxygen atoms incorporated into the product of the MabB-catalyzed reaction are both from the dioxygen molecule. Both 5ASA and gentisate could be converted by MabB; however, the catalytic efficiency of MabB for 5ASA was much higher (∼70-fold) than that for gentisate. The mabB-disrupted mutant lost the ability to grow on 3-aminobenzoate, and mabB expression was higher when strain QT12 was cultivated in the presence of 3-aminobenzoate. Thus, 5ASA is the physiological substrate of MabB.IMPORTANCE For several decades, 5-aminosalicylate (5ASA) has been advocated as the drug mesalazine to treat human inflammatory bowel disease and considered the key intermediate in the xenobiotic degradation of many aromatic organic pollutants. 5ASA biotransformation research will help us elucidate the microbial degradation of these pollutants. Most studies have reported that gentisate 1,2-dioxygenases (GDOs) can convert 5ASA with significantly high activity; however, the catalytic efficiency of these enzymes for gentisate is much higher than that for 5ASA. This study showed that MabB can convert 5ASA to cis-4-amino-6-carboxy-2-oxohexa-3,5-dienoate, incorporating two oxygen atoms from the dioxygen molecule into the product. Unlike GDOs, MabB uses 5ASA instead of gentisate as the primary substrate. mabB is the first reported 5-aminosalicylate 1,2-dioxygenase gene.


Assuntos
Comamonas/enzimologia , Dioxigenases/genética , Dioxigenases/metabolismo , Biocatálise , Biodegradação Ambiental , Clonagem Molecular , Comamonas/efeitos dos fármacos , Comamonas/genética , Comamonas/crescimento & desenvolvimento , Dioxigenases/química , Dioxigenases/isolamento & purificação , Escherichia coli/genética , Gentisatos/metabolismo , Cinética , Mesalamina/metabolismo , Mutação , Oxigênio/metabolismo , Especificidade por Substrato , meta-Aminobenzoatos/metabolismo , meta-Aminobenzoatos/farmacologia
13.
J Med Chem ; 60(20): 8631-8646, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-28991459

RESUMO

Previously, we reported a hypoxia-inducible factor (HIF)-1 inhibitor LW6 containing an (aryloxyacetylamino)benzoic acid moiety inhibits malate dehydrogenase 2 (MDH2) using a chemical biology approach. Structure-activity relationship studies on a series of (aryloxyacetylamino)benzoic acids identified selective MDH1, MDH2, and dual inhibitors, which were used to study the relationship between MDH enzyme activity and HIF-1 inhibition. We hypothesized that dual inhibition of MDH1 and MDH2 might be a powerful approach to target cancer metabolism and selected methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)-benzoate (16c) as the most potent dual inhibitor. Kinetic studies revealed that compound 16c competitively inhibited MDH1 and MDH2. Compound 16c inhibited mitochondrial respiration and hypoxia-induced HIF-1α accumulation. In xenograft assays using HCT116 cells, compound 16c demonstrated significant in vivo antitumor efficacy. This finding provides concrete evidence that inhibition of both MDH1 and MDH2 may provide a valuable platform for developing novel therapeutics that target cancer metabolism and tumor growth.


Assuntos
Anilidas/farmacologia , Inibidores Enzimáticos/farmacologia , Isoenzimas/antagonistas & inibidores , Malato Desidrogenase/antagonistas & inibidores , Neoplasias/metabolismo , meta-Aminobenzoatos/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Med Chem ; 60(16): 6942-6990, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28699740

RESUMO

A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of ß-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates ß-adrenergic receptor (ßAR)-mediated cAMP accumulation and prevents internalization of ßARs in ß2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.


Assuntos
Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Triazóis/farmacologia , meta-Aminobenzoatos/farmacologia , Cristalografia por Raios X , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Desenho de Fármacos , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Proteína Quinase C-alfa/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Receptores Adrenérgicos beta/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , meta-Aminobenzoatos/síntese química , meta-Aminobenzoatos/química , Quinases Associadas a rho/antagonistas & inibidores
15.
PLoS One ; 12(1): e0169882, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28118359

RESUMO

Voltage-gated sodium channels (VGSC) regulate neuronal excitability by governing action potential (AP) generation and propagation. Recent studies have revealed that AMP-activated protein kinase (AMPK) activators decrease sensory neuron excitability, potentially by preventing sodium (Na+) channel phosphorylation by kinases such as ERK or via modulation of translation regulation pathways. The direct positive allosteric modulator A769662 displays substantially greater efficacy than other AMPK activators in decreasing sensory neuron excitability suggesting additional mechanisms of action. Here, we show that A769662 acutely inhibits AP firing stimulated by ramp current injection in rat trigeminal ganglion (TG) neurons. PT1, a structurally dissimilar AMPK activator that reduces nerve growth factor (NGF) -induced hyperexcitability, has no influence on AP firing in TG neurons upon acute application. In voltage-clamp recordings, application of A769662 reduces VGSC current amplitudes. These findings, based on acute A769662 application, suggest a direct channel blocking effect. Indeed, A769662 dose-dependently blocks VGSC in rat TG neurons and in Nav1.7-transfected cells with an IC50 of ~ 10 µM. A769662 neither displayed use-dependent inhibition nor interacted with the local anesthetic (LA) binding site. Popliteal fossa administration of A769662 decreased noxious thermal responses with a peak effect at 5 mins demonstrating an analgesic effect. These data indicate that in addition to AMPK activation, A769662 acts as a direct blocker/modulator of VGSCs, a potential mechanism enhancing the analgesic property of this compound.


Assuntos
Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Analgésicos/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos , Pironas/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Tiofenos/farmacologia , Anestésicos Locais/metabolismo , Animais , Sítios de Ligação/genética , Compostos de Bifenilo , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Temperatura Alta/efeitos adversos , Humanos , Masculino , Metformina/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Condução Nervosa/efeitos dos fármacos , Dor/tratamento farmacológico , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Proteínas Recombinantes de Fusão/efeitos dos fármacos , Proteínas Recombinantes de Fusão/metabolismo , Resveratrol , Células Receptoras Sensoriais/enzimologia , Estilbenos/farmacologia , Tiazóis/farmacologia , Gânglio Trigeminal/efeitos dos fármacos , meta-Aminobenzoatos/farmacologia
16.
Eur J Med Chem ; 123: 673-683, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27517812

RESUMO

Through structure-based virtual screening and subsequent activity assays of selected natural products, Lavendustin B was previously identified as an inhibitor of HIV-1 integrase (IN) interaction with its cognate cellular cofactor, lens epithelium-derived growth factor (LEDGF/p75). In order to improve the inhibitory potency we have employed in silico-based approaches. Particularly, a series of new analogues was designed and docked into the LEDGF/p75 binding pocket of HIV-1 IN. To identify promising leads we used the Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation (MM-GBSA) method, molecular dynamics simulations and analysis of hydrogen bond occupancies. On the basis of these studies, six analogues of Lavendustine B, containing the benzylamino-hydroxybenzoic scaffold, were selected for synthesis and structure activity-relationship (SAR) studies. Our results demonstrated a good correlation between computational and experimental data, and all six analogues displayed an improved potency for inhibiting IN binding to LEDGF/p75 in vitro to respect to the parent compound Lavendustin B. Additionally, these analogs show to inhibit weakly LEDGF/p75-independent IN catalytic activity suggesting a multimodal allosteric mechanism of action. Nevertheless, for the synthesized compounds similar profiles for HIV-1 inhibition and cytoxicity were highlighted. Taken together, our studies elucidated the mode of action of Lavendustin B analogs and provided a path for their further development as a new promising class of HIV-1 integrase inhibitors.


Assuntos
Desenho de Fármacos , Integrase de HIV/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Salicilatos/síntese química , Salicilatos/farmacologia , meta-Aminobenzoatos/síntese química , meta-Aminobenzoatos/farmacologia , Regulação Alostérica/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Técnicas de Química Sintética , Integrase de HIV/química , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Células HeLa , Humanos , Conformação Proteica , Salicilatos/química , Salicilatos/metabolismo , meta-Aminobenzoatos/química , meta-Aminobenzoatos/metabolismo
17.
Cell Rep ; 16(1): 28-36, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27320923

RESUMO

The Wnt/ß-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of ß-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic ß-catenin pathway for cancer therapy, the development of specific inhibitors remains insufficient. Using a T cell factor (TCF)-dependent luciferase-reporter system, we screened for small-molecule compounds that act against Wnt/ß-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate) as a selective inhibitor of Wnt/ß-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to ß-catenin, promoting its degradation, and specifically downregulates Wnt/ß-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/ß-catenin signaling pathway.


Assuntos
Benzoatos/farmacologia , Oncogenes , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , meta-Aminobenzoatos/farmacologia , Animais , Benzoatos/química , Linhagem Celular Tumoral , Camundongos , Sulfonamidas/química , Ensaios Antitumorais Modelo de Xenoenxerto , meta-Aminobenzoatos/química
18.
Biotechnol J ; 11(7): 981-7, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27168529

RESUMO

3-amino-benzoic acid (3AB) is an important building block molecule for production of a wide range of important compounds such as natural products with various biological activities. In the present study, we established a microbial biosynthetic system for de novo 3AB production from the simple substrate glucose. First, the active 3AB biosynthetic pathway was reconstituted in the bacterium Escherichia coli, which resulted in the production of 1.5 mg/L 3AB. In an effort to improve the production, an E. coli-E. coli co-culture system was engineered to modularize the biosynthetic pathway between an upstream strain and an downstream strain. Specifically, the upstream biosynthetic module was contained in a fixed E. coli strain, whereas a series of E. coli strains were engineered to accommodate the downstream biosynthetic module and screened for optimal production performance. The best co-culture system was found to improve 3AB production by 15 fold, compared to the mono-culture approach. Further engineering of the co-culture system resulted in biosynthesis of 48 mg/L 3AB. Our results demonstrate co-culture engineering can be a powerful new approach in the broad field of metabolic engineering.


Assuntos
Técnicas de Cocultura/métodos , Escherichia coli/genética , meta-Aminobenzoatos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Reatores Biológicos , Vias Biossintéticas , Escherichia coli/metabolismo , Engenharia Metabólica/métodos
19.
J Cardiovasc Pharmacol Ther ; 21(1): 70-81, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25868658

RESUMO

Myocardial ischemia has become one of the main causes of sudden cardiac death worldwide. Autophagy has been demonstrated to protect cardiomyocytes from ischemia/reperfusion (I/R)-induced damage. A novel small molecule compound 2-Chloro-5-[[5-[[5-(4,5-Dimethyl-2-nitrophenyl)-2-furanyl]methylene]-4,5-dihydro-4-oxo-2-thiazolyl]amino]benzoic acid (PT1) has been previously shown to specifically activate 5'-adenosine monophosphate-activated protein kinase (AMPK). Because AMPK activation effectively induces autophagy, we tested the protective efficacy of PT1 on cardiomyocytes after oxygen glucose deprivation/reoxygenation (OGD/R) in vitro. Mouse neonatal cardiomyocytes were treated with PT1 after OGD/R. 3-[4-(1,3-benzodioxol-5-yl)-2-oxo-3-buten-1-yl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (3HOI-BA-01), a novel small compound showing potent inhibitory effect on mammalian target of rapamycin (mTOR) activation, was also tested for its cardioprotective effect, based on the established relationship between mTOR signaling and autophagy. Cell survival and autophagy-related signal pathways were examined after treatment with these agents. Our data indicate that both PT1 and 3HOI-BA-01 enhance cell survival after OGD/R. As expected, both PT1 and 3HOI-BA-01 induced autophagy in cardiomyocytes through activating AMPK pathway and inhibiting mTOR signaling, respectively. Induction of autophagy by PT1 and 3HOI-BA-01 was responsible for their cardioprotective effect, since inhibition of autophagy abolished the protective efficacy. Furthermore, simultaneous administration of PT1 and 3HOI-BA-01 profoundly upregulated autophagy after OGD/R and significantly promoted survival of cardiomyocytes. In vivo administration of PT1 and 3HOI-BA-01 in a murine myocardial (I/R injury model remarkably reduced infarct size and induced autophagy. Taken together, our research suggests that PT1 and 3HOI-BA-01 could be promising therapeutic agents for myocardial ischemia.


Assuntos
Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Benzodioxóis/farmacologia , Indóis/farmacologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tiazóis/farmacologia , meta-Aminobenzoatos/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Hipóxia Celular , Células Cultivadas , Citoproteção , Modelos Animais de Doenças , Glucose/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
20.
Chembiochem ; 16(17): 2484-90, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26426567

RESUMO

Mutational analysis of the pyridoxal 5'-phosphate (PLP)-dependent enzyme PctV was carried out to elucidate the multi-step reaction mechanism for the formation of 3-aminobenzoate (3-ABA) from 3-dehydroshikimate (3-DSA). Introduction of mutation K276R led to the accumulation of a quinonoid intermediate with an absorption maximum at 580 nm after the reaction of pyridoxamine 5'-phosphate (PMP) with 3-DSA. The chemical structure of this intermediate was supported by X-ray crystallographic analysis of the complex formed between the K276R mutant and the quinonoid intermediate. These results clearly show that a quinonoid intermediate is involved in the formation of 3-ABA. They also indicate that Lys276 (in the active site of PctV) plays multiple roles, including acid/base catalysis during the dehydration reaction of the quinonoid intermediate.


Assuntos
Oxirredutases/metabolismo , Pactamicina/biossíntese , Sítios de Ligação , Biocatálise , Domínio Catalítico , Cristalografia por Raios X , Cinética , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Oxirredutases/química , Oxirredutases/genética , Pactamicina/química , Fosfato de Piridoxal/química , Ácido Chiquímico/análogos & derivados , Ácido Chiquímico/química , Ácido Chiquímico/metabolismo , Espectrofotometria Ultravioleta , meta-Aminobenzoatos/química , meta-Aminobenzoatos/metabolismo
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