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1.
J Chromatogr A ; 1621: 461089, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32362360

RESUMO

Given the increasing need for analyzing natural or contaminating compounds in complex food matrices in a simple and automated way, coupling miniaturized sample preparation techniques with chromatographic systems have become a growing field of research. In this regard, given the low extraction efficiency of conventional sorbent phases, the development of materials with enhanced extraction capabilities is of particular interest. Here we present several synthesized graphene-based materials supported on aminopropyl silica as sorbents for the extraction of xanthines. The synthesized materials were characterized by infrared spectroscopy and scanning electron microscopy. Aminopropyl silica coated with graphene oxide and functionalized with octadecylsilane/end-capped (SiGOC18ecap) showed the best performance for xanthines extraction. Hence, this material was employed as an in-tube solid phase microextraction (in-tube SPME) device coupled online with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and applied for the analysis of xanthines in roasted coffee samples. Extraction parameters and detection conditions were optimized. The method showed low limits of quantification (0.3-1.0 µg L-1), precision as relative standard deviation (RSD) values lower than 10%, recoveries between 73 and 109%, and pre-concentration factors from 5.6 to 7.2. Caffeine was determined in all ground roasted and instant coffee samples, in a wide range (0.9 to 36.8 mg g-1), and small amounts of theobromine and theophylline were also detected in some samples. This work demonstrated that functionalized graphene-based materials represent a promising new sorbent class for in-tube SPME, showing improved extraction capacity. The method was efficient, simple, and fast for the analysis of xanthines, demonstrating an excellent potential to be applied in other matrices.


Assuntos
Cromatografia Líquida/métodos , Café/química , Grafite/química , Dióxido de Silício/química , Microextração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Xantinas/análise , Adsorção , Cromatografia Líquida de Alta Pressão/métodos , Íons , Limite de Detecção , Xantinas/química
2.
Org Biomol Chem ; 18(16): 3104-3116, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32253415

RESUMO

Eph receptor tyrosine kinases, particularly EphA2 and EphB4, represent promising candidates for molecular imaging due to their essential role in cancer progression and therapy resistance. Xanthine derivatives were identified to be potent Eph receptor inhibitors with IC50 values in the low nanomolar range (1-40 nm). These compounds occupy the hydrophobic pocket of the ATP-binding site in the kinase domain. Based on lead compound 1, we designed two fluorine-18-labelled receptor tyrosine kinase inhibitors ([18F]2/3) as potential tracers for positron emission tomography (PET). Docking into the ATP-binding site allowed us to find the best position for radiolabelling. The replacement of the methyl group at the uracil residue ([18F]3) rather than the methyl group of the phenoxy moiety ([18F]2) by a fluoropropyl group was predicted to preserve the affinity of the lead compound 1. Herein, we point out a synthesis route to [18F]2 and [18F]3 and the respective tosylate precursors as well as a labelling procedure to insert fluorine-18. After radiolabelling, both radiotracers were obtained in approximately 5% radiochemical yield with high radiochemical purity (>98%) and a molar activity of >10 GBq µmol-1. In line with the docking studies, first cell experiments revealed specific, time-dependent binding and uptake of [18F]3 to EphA2 and EphB4-overexpressing A375 human melanoma cells, whereas [18F]2 did not accumulate at these cells. Since both tracers [18F]3 and [18F]2 are stable in rat blood, the novel radiotracers might be suitable for in vivo molecular imaging of Eph receptors with PET.


Assuntos
Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Receptores da Família Eph/análise , Xantinas/química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Efrina-A2/análise , Humanos , Melanoma/diagnóstico por imagem , Melanoma/patologia , Imagem Molecular/métodos , Ratos , Receptor EphB4/análise , Receptores da Família Eph/antagonistas & inibidores
3.
Biomed Chromatogr ; 34(1): e4712, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31633799

RESUMO

Coffee and tea are the most widely consumed beverages worldwide. However, the consumer may be unaware of the exact amount of methyl xanthine (MX, i.e. caffeine [C], theobromine [TB] and theophylline [TH]) consumed, as most of the products do not list the proper amounts. This may lead to serious risks including cardiovascular, kidney and stimulant effects. The aim of the study was to determine the MX amount in ready-to-use beverages (coffee and tea) collected from various outlets in the city of Al-Khobar, Saudi Arabia. Forty different samples of espresso, black coffee and red tea were collected. A fast, reliable and efficient UHPLC-DAD method was developed and validated for MX determination. Total lipids were extracted and fractionated in order to determine glycolipids, phospholipids and neutral lipids. The r2 value for the method was 0.980-0.988 in a linearity range of 0.5-200 ppm. The range for MX (C [0.02-2.39 mg/ml], TB [0.00-0.10 mg/ml] and TH [0.00-0.004 mg/ml]) and total lipids was 1-5 g. The amount of glycolipids (3.1 g) was higher among the lipid fractions followed by phospholipids (1.8 g) and neutral lipids (0.25 g). In general, espresso beverages (20-30 ml) contained high amounts of MX whereas black coffee beverages contained high amount of lipids. Most of the beverages expressed C, TB, TH, lipids or their fractions; however, the product with high amounts of MX and lipids at the same time was espresso (brands Chemistry and Wogard). Although the MX and lipid levels in these beverages well below the allowed limits, care must still be taken, especially when using the beverages with high serving volumes (200-250 ml) or coffee prepared via the filter method i.e. black coffee, using a high temperature for a longer time.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Café/química , Chá/química , Xantinas , Culinária , Temperatura Alta , Lipídeos/análise , Reprodutibilidade dos Testes , Arábia Saudita , Xantinas/análise , Xantinas/química , Xantinas/isolamento & purificação
4.
Sci Rep ; 9(1): 16015, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690793

RESUMO

Here in this study regarding the over expression of TP, which causes some physical, mental and socio problems like psoriasis, chronic inflammatory disease, tumor angiogenesis and rheumatoid arthritis etc. By this consideration, the inhibition of this enzyme is vital to secure life from serious threats. In connection with this, we have synthesized twenty derivatives of isoquinoline bearing oxadiazole (1-20), characterized through different spectroscopic techniques such as HREI-MS, 1H- NMR and 13C-NMR and evaluated for thymidine phosphorylase inhibition. All analogues showed outstanding inhibitory potential ranging in between 1.10 ± 0.05 to 54.60 ± 1.50 µM. 7-Deazaxanthine (IC50 = 38.68 ± 1.12 µM) was used as a positive control. Through limited structure activity relationships study, it has been observed that the difference in inhibitory activities of screened analogs are mainly affected by different substitutions on phenyl ring. The effective binding interactions of the most active analogs were confirmed through docking study.


Assuntos
Inibidores Enzimáticos/síntese química , Isoquinolinas/química , Simulação de Acoplamento Molecular , Oxidiazóis/química , Timidina Fosforilase/metabolismo , Sítios de Ligação , Inibidores Enzimáticos/metabolismo , Escherichia coli/enzimologia , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Oxidiazóis/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Timidina Fosforilase/química , Xantinas/química , Xantinas/metabolismo
5.
Phys Chem Chem Phys ; 21(48): 26430-26437, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31774088

RESUMO

We explore the influence of the relative position of the methyl substituent on the photophysics of theophylline and theobromine, two molecules that are structurally related to the DNA bases. Using a combination of spectroscopic techniques and quantum mechanical calculations, we show that moving the methyl group from N1 in theophylline to N7 in theobromine causes significant differences in their excited state properties, i.e., it produces pyramidalization of N7 in the excited state of the latter. Paradoxically, this modification seems to have little effect on the structural properties of the cation and the ionization process. It is suggested that similar effects may exist in the excited state properties of DNA bases.


Assuntos
Teobromina/química , Teofilina/química , Xantinas/química , Espectroscopia Fotoeletrônica , Espectrofotometria
6.
Molecules ; 24(23)2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31766549

RESUMO

Natural methylxanthines, caffeine, theophylline and theobromine, are widespread biologically active alkaloids in human nutrition, found mainly in beverages (coffee, tea, cocoa, energy drinks, etc.). Their detection is thus of extreme importance, and many studies are devoted to this topic. During the last decade, graphene oxide (GO) and reduced graphene oxide (RGO) gained popularity as constituents of sensors (chemical, electrochemical and biosensors) for methylxanthines. The main advantages of GO and RGO with respect to graphene are the easiness and cheapness of synthesis, the notable higher solubility in polar solvents (water, among others), and the higher reactivity towards these targets (mainly due to - interactions); one of the main disadvantages is the lower electrical conductivity, especially when using them in electrochemical sensors. Nonetheless, their use in sensors is becoming more and more common, with the obtainment of very good results in terms of selectivity and sensitivity (up to 5.4 × 10-10 mol L-1 and 1.8 × 10-9 mol L-1 for caffeine and theophylline, respectively). Moreover, the ability of GO to protect DNA and RNA from enzymatic digestion renders it one of the best candidates for biosensors based on these nucleic acids. This is an up-to-date review of the use of GO and RGO in sensors.


Assuntos
Grafite/química , Xantinas/análise , Xantinas/isolamento & purificação , Adsorção , Humanos , Xantinas/química
7.
J Org Chem ; 84(24): 15767-15776, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31738556

RESUMO

Molecules containing trifluoromethoxyaryl groups are of interest in pharmaceutical, agrochemical, and materials science research, due to their unique physical and electronic properties. Many of the known methods to synthesize aryl trifluoromethyl ethers require harsh reagents and highly controlled reaction conditions and rarely occur when heteroaromatic units are present. The two-step O-trifluoromethylation of phenols via aryl xanthates is one such method that suffers from these drawbacks. Herein, we report a method for the synthesis of aryl trifluoromethyl ethers from phenols by the facile conversion of the phenol to the corresponding aryl and heteroaryl xanthates with newly synthesized imidazolium methylthiocarbonothioyl salts and conversion of these xanthates to the trifluoromethyl ethers under mild reaction conditions.


Assuntos
Éteres/síntese química , Hidrocarbonetos Fluorados/síntese química , Fenóis/química , Xantinas/química , Éteres/química , Hidrocarbonetos Fluorados/química , Estrutura Molecular
8.
Sci Rep ; 9(1): 13941, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558747

RESUMO

Methylxanthines, purine alkaloids found in plants, are found in beverages (coffee, tea, cocoa) and foods (chocolate and other cocoa-containing foods) commonly consumed worldwide. Members of this family include caffeine, theophylline and theobromine. Methylxanthines have a variety of pharmacological effects, and caffeine and theophylline are used as pharmaceuticals. Methylxanthines are metabolized in the liver predominantly by the enzyme CYP1A2. Their co-administration with CYP1A2 inhibitors may lead to pharmacokinetic interactions. Little is known about the possible drug interactions between caffeine and substrates of other CYP450 enzymes. In our study, methylxanthine fractions inhibited CYP3A4 in a concentration-dependent manner. Concomitant consumption of green tea with CYP3A4 substrates could increase the possibility of interactions, and this requires further clarification. The inhibition of CYP3A4 is not only due to the presence of catechin derivatives but methylxanthines may also contribute to this effect.


Assuntos
Camellia sinensis/química , Inibidores do Citocromo P-450 CYP3A/química , Chá/química , Xantinas/química , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacologia , Humanos , Xantinas/farmacologia
9.
J Food Biochem ; 43(2): e12697, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31353656

RESUMO

Methylxanthines are among the most widely consumed drugs in the world and evidence of their health benefits has been growing in recent years. Primary Amine Oxidase (PrAO) has been recognized as a therapeutic target for the amelioration of inflammatory, vascular, and neurodegenerative diseases. Previous work in our laboratories showed that caffeine inhibited Bovine PrAO with a Ki of 1.0 mM using benzylamine as substrate. This study aimed to extend our previous work and explore the possibility that related methylxanthines might influence PrAO activity. While paraxanthine, theophylline, and 7-methylxanthine had little effect on PrAO, theobromine was a noncompetitive inhibitor with a Ki of 276 ± 44 µM. The specific structural elements of methylxanthines that are required for inhibition allow us to suggest that their binding site on PrAO may be a target for therapeutics. The health benefits associated with dietary methylxanthine consumption could involve PrAO inhibition. PRACTICAL APPLICATIONS: Inhibition of PrAO by methylxanthines may be significant in conferring health benefits. The design of PrAO inhibitors based on the structural motifs identified in this study (N-methylation at specific locations) is indicated. Existing therapeutics based on a core xanthine structure can be evaluated for their effects on PrAO. PrAO inhibition must be considered as a potential mediator of the beneficial health effects of some methylxanthines. If inhibition in human tissues is comparable to, or greater than, that found in these studies it points to an important role for these compounds in human health.


Assuntos
Inibidores Enzimáticos/química , Oxirredutases atuantes sobre Doadores de Grupo CH-NH2/antagonistas & inibidores , Teobromina/química , Xantinas/química , Animais , Bovinos , Cinética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH2/química , Oxirredutases atuantes sobre Doadores de Grupo CH-NH2/metabolismo
10.
J Agric Food Chem ; 67(34): 9501-9509, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31334642

RESUMO

Composition of bioactive compounds in cocoa beans is critical to the sensory and nutritional quality of cocoa based products. Twenty-six cocoa bean genotypes were freshly collected from the same plantation location in Indonesia. The bioactive compounds in these raw cocoa genotypes were identified and quantified. The results showed a great diversity in the composition of bioactive compounds among the 26 cocoa samples. The concentrations of methylxanthines, epicatechin, proanthocyanidin (PA) B-type oligomers, clovamide, and anthocyanins were important variables that differentiated these genotypes. MCC 01, SUL 3, ICCRI 03, and ICS 60 genotypes had the highest contents of flavan-3-ols including PAs and have the potential to be developed for "healthy" product formulations. Some genotypes such as DR 1, DR 2, DR 38, ICS 13, KPC 1, KW 617, RCC 71, and TSH 858 could be favored by industries due to the potential to be made into end-products with brighter appearance.


Assuntos
Cacau/química , Cacau/genética , Extratos Vegetais/química , Cacau/classificação , Catequina/química , Flavonoides , Genótipo , Indonésia , Proantocianidinas/química , Sementes/química , Sementes/genética , Xantinas/química
11.
J Pharmacol Exp Ther ; 370(3): 350-359, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31201216

RESUMO

Glucose-stimulated insulin secretion from pancreatic ß-cells is controlled by ATP-regulated potassium (KATP) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits. The KATP channel-opener diazoxide is FDA-approved for treating hyperinsulinism and hypoglycemia but suffers from off-target effects on vascular KATP channels and other ion channels. The development of more specific openers would provide critically needed tool compounds for probing the therapeutic potential of Kir6.2/SUR1 activation. Here, we characterize a novel scaffold activator of Kir6.2/SUR1 that our group recently discovered in a high-throughput screen. Optimization efforts with medicinal chemistry identified key structural elements that are essential for VU0071063-dependent opening of Kir6.2/SUR1. VU0071063 has no effects on heterologously expressed Kir6.1/SUR2B channels or ductus arteriole tone, indicating it does not open vascular KATP channels. VU0071063 induces hyperpolarization of ß-cell membrane potential and inhibits insulin secretion more potently than diazoxide. VU0071063 exhibits metabolic and pharmacokinetic properties that are favorable for an in vivo probe and is brain penetrant. Administration of VU0071063 inhibits glucose-stimulated insulin secretion and glucose-lowering in mice. Taken together, these studies indicate that VU0071063 is a more potent and specific opener of Kir6.2/SUR1 than diazoxide and should be useful as an in vitro and in vivo tool compound for investigating the therapeutic potential of Kir6.2/SUR1 expressed in the pancreas and brain.


Assuntos
Ativação do Canal Iônico/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores Sulfonilureia/metabolismo , Xantinas/farmacologia , Xantinas/farmacocinética , Animais , Canal Arterial/efeitos dos fármacos , Canal Arterial/fisiologia , Glucose/farmacologia , Células HEK293 , Humanos , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Camundongos , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacos , Xantinas/química
12.
Molecules ; 24(12)2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31212849

RESUMO

In earlier studies, we generated concentration-response (E/c) curves with CPA (N6-cyclopentyladenosine; a selective A1 adenosine receptor agonist) or adenosine, in the presence or absence of S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine (NBTI, a selective nucleoside transport inhibitor), and with or without a pretreatment with 8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)-benzoyloxy)propyl]-N1-propylxanthine (FSCPX, a chemical known as a selective, irreversible A1 adenosine receptor antagonist), in isolated, paced guinea pig left atria. Meanwhile, we observed a paradoxical phenomenon, i.e. the co-treatment with FSCPX and NBTI appeared to enhance the direct negative inotropic response to adenosine. In the present in silico study, we aimed to reproduce eight of these E/c curves. Four models (and two additional variants of the last model) were constructed, each one representing a set of assumptions, in order to find the model exhibiting the best fit to the ex vivo data, and to gain insight into the paradoxical phenomenon in question. We have obtained in silico evidence for an interference between effects of FSCPX and NBTI upon our ex vivo experimental setting. Regarding the mechanism of this interference, in silico evidence has been gained for the assumption that FSCPX inhibits the effect of NBTI on the level of endogenous (but not exogenous) adenosine. As an explanation, it may be hypothesized that FSCPX inhibits an enzyme participating in the interstitial adenosine formation. In addition, our results suggest that NBTI does not stop the inward adenosine flux in the guinea pig atrium completely.


Assuntos
Antagonistas do Receptor A1 de Adenosina/química , Proteínas de Transporte de Nucleobases/química , Receptor A1 de Adenosina/química , Xantinas/química , Adenosina/química , Adenosina/farmacologia , Antagonistas do Receptor A1 de Adenosina/farmacologia , Animais , Relação Dose-Resposta a Droga , Cobaias , Proteínas de Transporte de Nucleobases/antagonistas & inibidores , Xantinas/farmacologia
13.
Eur J Med Chem ; 176: 117-128, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31108261

RESUMO

A series of novel xanthine/NO donor hybrids containing 1,3,8-trisubstituted or 1,8-disubstituted xanthine derivatives were designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 90% cell viability at a concentration of 50 µM. The oxime containing compounds 7a-b and 17-24 were more active as antiproliferative agents than their non-oxime congeners 6a-b and 9-16. Hydroxyimino-phenethyl scaffold compounds 17-24 were more active than the hydroxyimino-ethyl phenyl acetamide 7a-b derivatives. Compounds 18-20 and 22-24 exhibited inhibition of EGFR with IC50 ranging from 0.32 to 2.88 µM. Compounds 18-20 and 22-24 increased the level of active caspase 3 by 4-8 folds, compared to the control cells in Panc-1 cell lines compared to doxorubicin as a reference drug. Compounds 18, 22 and 23 were the most caspase-3 inducers. Compounds 22 and 23 increased the levels of caspase-8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of cytochrome c levels in Panc-1 human pancreas cancer cells. Compound 23 exhibited mainly cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of Panc-1 cell line. The drug likeness profiles of compounds 18-20 and 22-24 were predicted to have good to excellent drug likeness profiles specially compounds 18-20 and 23. Finally molecular docking study was performed at the EGFR active site to suggest thier possible binding mode. The hydroxyimino-phenethyl scaffold compounds 17-24 represent an interesting starting point to optimize their pharmacokinetics and pharmacodynamics profiles.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Oximas/farmacologia , Xantinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/síntese química , Oximas/química , Oximas/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Xantinas/síntese química , Xantinas/química , Xantinas/toxicidade , Proteína X Associada a bcl-2/metabolismo
14.
Biomolecules ; 9(5)2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137572

RESUMO

This paper presents an analysis of the molecular mechanisms involved in the formation of inclusion complexes together with some structural interpretation of drug-carrier molecule interactions in aqueous multicomponent systems comprising methylxanthines and cyclodextrins. The determination of apparent partial molar volumes (Φv) from experimental density measurements, both for binary and ternary aqueous solutions of cyclodextrins and methylxanthines, was performed at low concentration range to be consistent with their therapeutic uses in the drug-releasing field. The estimation of the equilibrium constant for inclusion complexes of 1:1 stoichiometry was done through the mathematical modelling of this apparent molar property. The examination of the volume changes offered information about the driving forces for the insertion of the xanthine into the cyclodextrin molecule. The analysis on the volumes of transfer, Δ, Φv,c and the viscosity B-coefficients of transfer, ΔB, for the xanthine from water to the different aqueous solutions of cyclodextrin allowed evaluating the possible interactions between aqueous solutes and/or solute-solvent interactions occurring in the solution. Mutual diffusion coefficients for binary, and ternary mixtures composed by xanthine, cyclodextrin, and water were measured with the Taylor dispersion technique. The behavior diffusion of these multicomponent systems and the coupled flows occurring in the solution were analyzed in order to understand the probable interactions between cyclodextrin-xanthine by estimating their association constants and leading to clearer insight of these systems structure. The measurements were performed at the standard (298.15 ± 0.01) K and physiological (310.15 ± 0.01) K temperatures.


Assuntos
Ciclodextrinas/química , Portadores de Fármacos/química , Xantinas/química , Difusão , Termodinâmica , Viscosidade
15.
Bioorg Chem ; 87: 601-612, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30933785

RESUMO

In the present study, an attempt has been made to develop a new series of 1,3,7,8-tetrasubstituted xanthine based potent and selective AR ligands for the treatment of Parkinson's disease. Antagonistic interactions between dopamine and A2A adenosine receptors serve as the basis for the development of AR antagonists as potential drug candidates for PD. All the synthesized compounds have been evaluated for their affinity toward AR subtypes using in vitro radioligand binding assays. 1,3-Dipropylxanthine 7a with a methyl substituent at N-7 position represents the most potent compound of the series and displayed highest affinity (A2A, Ki = 0.108 µM), however incorporation of a propargyl group at 7-positon of the xanthine nucleus seems to be the most appropriate substitution to improve selectivity towards the A2A subtype along with reasonable potency. Antiparkinsonian activity has been evaluated using perphenazine induced catatonia in rats. Most of the synthesized xanthines significantly lowered the catatonic score as compared to control and displayed antiparkinsonian effects comparable to standard drug. All the synthesized compounds were subjected to grid-based molecular docking studies to understand the key structural requirements for the development of new molecules well-endowed with intrinsic efficacy and selectivity as adenosine receptor ligands. In silico studies carried out on newly synthesized xanthines provided further support to the pharmacological results.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Antiparkinsonianos/farmacologia , Modelos Animais de Doenças , Doença de Parkinson/tratamento farmacológico , Receptor A2A de Adenosina/metabolismo , Xantinas/farmacologia , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Animais , Antiparkinsonianos/síntese química , Antiparkinsonianos/química , Células Cultivadas , Ligantes , Modelos Moleculares , Estrutura Molecular , Doença de Parkinson/metabolismo , Ratos , Xantinas/síntese química , Xantinas/química
16.
FEBS Open Bio ; 9(4): 717-727, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30984545

RESUMO

In eukaryotic cells, cytoplasmic mRNA is characterised by a 3' poly(A) tail. The shortening and removal of poly(A) tails (deadenylation) by the Ccr4-Not nuclease complex leads to reduced translational efficiency and RNA degradation. Using recombinant human Caf1 (CNOT7) enzyme as a screening tool, we recently described the discovery and synthesis of a series of substituted 1-hydroxy-3,7-dihydro-1H-purine-2,6-diones (1-hydroxy-xanthines) as inhibitors of the Caf1 catalytic subunit of the Ccr4-Not complex. Here, we used a chemiluminescence-based AMP detection assay to show that active 1-hydroxy-xanthines inhibit both isolated Caf1 enzyme and human Caf1-containing complexes that also contain the second nuclease subunit Ccr4 (CNOT6L) to a similar extent, indicating that the active site of the Caf1 nuclease subunit does not undergo substantial conformational change when bound to other Ccr4-Not subunits. Using differential scanning fluorimetry, we also show that binding of active 1-hydroxy-xanthines requires the presence of Mg2+ ions, which are present in the active site of Caf1.


Assuntos
Magnésio/química , Ribonucleases/metabolismo , Fatores de Transcrição/metabolismo , Xantinas/química , Exorribonucleases , Humanos , Íons/química , Proteínas Repressoras , Ribonucleases/química , Fatores de Transcrição/química
17.
J Med Chem ; 62(8): 4032-4055, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-30835463

RESUMO

The A2B adenosine receptor (A2BAR) was proposed as a novel target for the (immuno)therapy of cancer since A2BAR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established, which facilitated the synthesis of the target compounds. Many of the new compounds exhibited subnanomolar affinity for the A2BAR combined with high selectivity. Functional groups were introduced, which will allow the attachment of dyes and other reporter groups. 8-(4-((4-(4-Bromophenyl)piperazin-1-yl)sulfonyl)phenyl)-1-propylxanthine (34, PSB-1901) was the most potent A2B-antagonist ( Ki 0.0835 nM, KB 0.0598 nM, human A2BAR) with >10 000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse A2BAR, making it a promising tool for preclinical studies. Computational studies predicted halogen bonding to contribute to the outstanding potency of 34.


Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Piperazinas/química , Receptor A2B de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/metabolismo , Animais , Sítios de Ligação , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Piperazinas/metabolismo , Piperazinas/farmacologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Receptor A2B de Adenosina/metabolismo , Relação Estrutura-Atividade , Xantinas/química , Xantinas/metabolismo
18.
Anticancer Drugs ; 30(4): 347-355, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30875347

RESUMO

Methylxanthine derivatives, such as caffeine and theophylline, enhance cell apoptosis and autophagy and reportedly induce the activity of phosphatase and tensin homologue (PTEN) and inhibit the mammalian target of rapamycin (mTOR). This study investigated the impacts of caffeine and theophylline on gastric cancer cell apoptosis and autophagy using a gastric cancer cell line (MGC-803) and a nude mouse model. Peritumoural and tumour tissues were collected from five patients diagnosed with gastric carcinoma who underwent laparoscopic radical gastrectomy at our hospital. Autophagy was suppressed in gastric cancer tumour tissue compared with peritumoural tissue. In vitro, both caffeine and theophylline effectively suppressed MGC-803 cell proliferation and migration and induced autophagy. To assess the involvement of PTEN in caffeine-mediated and theophylline-mediated gastric cancer cell death, we transiently transfected MGC-803 cells with an siRNA targeting PTEN. PTEN knockdown impaired the methylxanthine derivative-mediated inhibition of PI3K/Akt/mTOR signalling. In nude mice treated with caffeine or theophylline, MGC-803 cell tumours injected with siPTEN were larger than those injected with negative control siRNA. These results show that the methylxanthine derivatives (caffeine and theophylline) effectively induce gastric cancer cell apoptosis and autophagy by PTEN activation and PI3K/Akt/mTOR pathway suppression and strongly support the use of methylxanthine derivatives as potential anticancer therapeutics.


Assuntos
Autofagia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Neoplasias Gástricas/patologia , Xantinas/química , Xantinas/farmacologia , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Biomol Struct Dyn ; 37(13): 3467-3481, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30175951

RESUMO

Adenosine is a ubiquitous endogenous nucleoside that controls numerous physiological functions via interacting with its specific G-coupled receptors. Activation of adenosine receptors (AdoRs), particularly A2B AdoRs promotes the release of inflammatory cytokines; reduces vascular permeabilization and induces angiogenesis, thereby making A2B AdoR becomes a potentially pharmacological target for drug development. Presently, for investigating the structural determinants of 164 xanthine derivatives as A2B AdoR antagonists, we performed an in silico study integrating with 3D-QSAR, docking and molecular dynamics (MD) simulation. The obtained optimal model shows strong predictability (Q2 = 0.647, R2ncv = 0.955, and R2pred = 0.848). Additionally, to explore the binding mode of the ligand with A2B AdoR and to understand their binding mechanism, docking analysis, MD simulations (20 ns), and the calculation of binding free energy were also carried out. Finally, the structural determinants of these xanthine derivatives were identified and a total of 20 novel A2B AdoR antagonists with improved potency were computationally designed, and their synthetic feasibility and selectivity were also evaluated. The information derived from the present study offers a better appreciation for exploring the interaction mechanism of the ligand with A2B AdoR, which could be helpful for designing novel potent A2B AdoR antagonists. Communicated by Ramaswamy H. Sarma.


Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptor A2B de Adenosina/química , Receptor A2B de Adenosina/metabolismo , Xantinas/química , Humanos , Conformação Proteica , Relação Quantitativa Estrutura-Atividade
20.
J Biomol Struct Dyn ; 37(16): 4200-4214, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30366512

RESUMO

Lysine-specific demethylase 1 (LSD1) has been reported to connect with a range of solid tumors. Thus, the exploration of LSD1 inhibitors has emerged as an effective strategy for cancer treatment. In this study, we constructed a pharmacophore model based on a series of flavin adenine dinucleotide (FAD)-competing inhibitors bearing triazole - dithiocarbamate scaffold combining docking, structure-activity relationship (SAR) study, and molecular dynamic (MD) simulation. Meanwhile, another pharmacophore model was also constructed manually, relying on several speculated substrate-competing inhibitors and reported putative vital interactions with LSD1. On the basis of the two pharmacophore models, multi-step virtual screenings (VSs) were performed against substrate-binding pocket and FAD-binding pocket, respectively, combining pharmacophore-based and structure-based strategy to exploit novel LSD1 inhibitors. After bioassay evaluation, four compounds among 21 hits with diverse and novel scaffolds exhibited inhibition activity at the range of 3.63-101.43 µM. Furthermore, substructure-based enrichment was performed, and four compounds with a more potent activity were identified. After that, the time-dependent assay proved that the most potent compound with IC50 2.21 µM inhibits LSD1 activity in a manner of time-independent. In addition, the compound exhibited a cellular inhibitory effect against LSD1 in MGC-803 cells and may inhibit cell migration and invasion by reversing EMT in cultured gastric cancer cells. Considering the binding mode and SAR of the series of compounds, we could roughly deem that these compounds containing 3-methylxanthine scaffold act through occupying substrate-binding pocket competitively. This study presented a new starting point to develop novel LSD1 inhibitors.


Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Histona Desmetilases/antagonistas & inibidores , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas/métodos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Flavina-Adenina Dinucleotídeo/química , Flavina-Adenina Dinucleotídeo/metabolismo , Histona Desmetilases/química , Histona Desmetilases/metabolismo , Histonas/química , Histonas/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Químicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/enzimologia , Relação Estrutura-Atividade , Triazóis/química , Xantinas/química , Xantinas/metabolismo
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