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1.
Yakugaku Zasshi ; 144(7): 715-732, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38945846

RESUMO

An aqueous solution of 2,3-cis gallate type catechin (-)-epigallocatechin-3-O-gallate (EGCg) and caffeine afforded a precipitate of Creaming-down Phenomenon, which crystallized slowly for about three months to give a colorless block crystal. By X-ray crystallographic analysis, the crystal was determined to be a 2 : 2 complex of EGCg and caffeine, in which caffeine molecules were captured in a hydrophobic space formed with three aromatic A, B, and B' rings of EGCg. It was considered that the solubility of the 2 : 2 complex in water rapidly decreased and the 2 : 2 complex precipitated from aqueous solution. The hydrophobic spaces of EGCg captured a variety of heterocyclic compounds, and the molecular capture abilities of heterocyclic compounds using EGCg from the aqueous solutions were evaluated. Since the C ring of EGCg has two chiral carbon atoms, C2 and C3, the hydrophobic space of EGCg was a chiral space. EGCg captured diketopiperazine cyclo(Pro-Xxx) (Xxx=Phe, Tyr) and pharmaceuticals with a xanthine skeleton, proxyphylline and diprophylline, in the hydrophobic space, and recognized their chirality.


Assuntos
Cafeína , Catequina , Interações Hidrofóbicas e Hidrofílicas , Solubilidade , Chá , Catequina/química , Catequina/análogos & derivados , Chá/química , Cafeína/química , Cristalografia por Raios X , Estereoisomerismo , Água/química , Cristalização , Soluções , Compostos Heterocíclicos/química , Xantinas/química
2.
Molecules ; 29(11)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38893312

RESUMO

Gain-of-function mutations in the KCNT1 gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental and epileptic encephalopathy known as epilepsy of infancy with migrating focal seizures (EIMFS). The design of small molecule inhibitors of SLACK channels represents a potential therapeutic approach to the treatment of EIMFS, other childhood epilepsies, and developmental disorders. Herein, we describe a hit optimization effort centered on a xanthine SLACK inhibitor (8) discovered via a high-throughput screen. Across three distinct regions of the chemotype, we synthesized 58 new analogs and tested each one in a whole-cell automated patch-clamp assay to develop structure-activity relationships for inhibition of SLACK channels. We further evaluated selected analogs for their selectivity versus a variety of other ion channels and for their activity versus clinically relevant SLACK mutants. Selectivity within the series was quite good, including versus hERG. Analog 80 (VU0948578) was a potent inhibitor of WT, A934T, and G288S SLACK, with IC50 values between 0.59 and 0.71 µM across these variants. VU0948578 represents a useful in vitro tool compound from a chemotype that is distinct from previously reported small molecule inhibitors of SLACK channels.


Assuntos
Bloqueadores dos Canais de Potássio , Relação Estrutura-Atividade , Humanos , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Ativados por Sódio , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Xantina/química , Xantina/farmacologia , Técnicas de Patch-Clamp , Células HEK293 , Estrutura Molecular , Xantinas/química , Xantinas/farmacologia
3.
J Chromatogr A ; 1726: 464973, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38729044

RESUMO

Hydrophilic interaction chromatography (HILIC) offers different selectivity than reversed-phase liquid chromatography (RPLC). However, our knowledge of the driving force for selectivity is limited and there is a need for a better understanding of the selectivity in HILIC. Quantitative assessment of retention mechanisms makes it possible to investigate selectivity based on understanding the underlying retention mechanisms. In this study, selected model compounds from the Ikegami selectivity tests were evaluated on different polar stationary phases. The study results revealed significant insights into the selectivity in HILIC. First, hydroxy and methylene selectivity is driven by hydrophilic partitioning; but surface adsorption for 2-deoxyuridine or 5-methyluridine reduces the selectivity factor. Furthermore, the retention of 2-deoxyuridine or 5-methyluridine by surface adsorption in combination with the phase ratio explain the difference in hydroxy or methylene selectivity observed among different stationary phases. Investigations on xanthine positional isomers (1-methylxanthine/3-methylxanthine, theophylline/theobromine) indicate that isomeric selectivity is controlled by surface adsorption; however, hydrophilic partitioning may contribute to resolution by enhancing overall retention. In addition, two pairs of nucleoside isomers (adenosine/vidarabine, 2'-deoxy and 3'-deoxyguanosine) provide an example that isomeric selectivity can also be controlled by hydrophilic partitioning if their partitioning coefficients are significantly different in HILIC. Although more data is needed, the current study provides a mechanistic based understanding of the selectivity in HILIC and potentially a new way to design selectivity tests.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Adsorção , Cromatografia Líquida/métodos , Isomerismo , Nucleosídeos/química , Nucleosídeos/análise , Cromatografia de Fase Reversa/métodos , Xantinas/química
4.
Plant Sci ; 345: 112117, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38750798

RESUMO

Coffee plants contain well-known xanthines as caffeine. Three Coffea species grown in a controlled greenhouse environment were the focus of this research. Coffea arabica and C. canephora are two first principal commercial species and commonly known as arabica and robusta, respectively. Originating in Central Africa, C. anthonyi is a novel species with small leaves. The xanthine metabolites in flower, fruit and leaf extracts were compared using both targeted and untargeted metabolomics approaches. We evaluated how the xanthine derivatives and FQA isomers relate to the expression of biosynthetic genes encoding N- and O-methyltransferases. Theobromine built up in leaves of C. anthonyi because caffeine biosynthesis was hindered in the absence of synthase gene expression. Despite this, green fruits expressed these genes and they produced caffeine. Given that C. anthonyi evolved successfully over time, these findings put into question the defensive role of caffeine in leaves. An overview of the histolocalisation of xanthines in the different flower parts of Coffea arabica was also provided. The gynoecium contained more theobromine than the flower buds or petals. This could be attributed to increased caffeine biosynthesis before fructification. The presence of theophylline and the absence of theobromine in the petals indicate that caffeine is catabolized more in the petals than in the gynoecium.


Assuntos
Cafeína , Coffea , Metabolômica , Metiltransferases , Folhas de Planta , Coffea/genética , Coffea/metabolismo , Coffea/enzimologia , Metiltransferases/genética , Metiltransferases/metabolismo , Folhas de Planta/metabolismo , Folhas de Planta/genética , Cafeína/metabolismo , Flores/genética , Flores/metabolismo , Perfilação da Expressão Gênica , Xantinas/metabolismo , Frutas/genética , Frutas/metabolismo , Teobromina/metabolismo , Regulação da Expressão Gênica de Plantas
5.
Nat Commun ; 15(1): 3625, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38684649

RESUMO

Modern, highly evolved nucleoside-processing enzymes are known to exhibit perfect regioselectivity over the glycosylation of purine nucleobases at N9. We herein report an exception to this paradigm. Wild-type nucleoside phosphorylases also furnish N7-xanthosine, a "non-native" ribosylation regioisomer of xanthosine. This unusual nucleoside possesses several atypical physicochemical properties such as redshifted absorption spectra, a high equilibrium constant of phosphorolysis and low acidity. Ultimately, the biosynthesis of this previously unknown natural product illustrates how even highly evolved, essential enzymes from primary metabolism are imperfect catalysts.


Assuntos
Pentosiltransferases , Ribonucleosídeos , Xantinas , Glicosilação , Xantinas/metabolismo , Xantinas/química
6.
Eur J Med Chem ; 271: 116380, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38615410

RESUMO

Imaging of the A1 adenosine receptor (A1R) by positron emission tomography (PET) with 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propyl-xanthine ([18F]CPFPX) has been widely used in preclinical and clinical studies. However, this radioligand suffers from rapid peripheral metabolism and subsequent accumulation of radiometabolites in the vascular compartment. In the present work, we prepared four derivatives of CPFPX by replacement of the cyclopentyl group with norbornane moieties. These derivatives were evaluated by competition binding studies, microsomal stability assays and LC-MS analysis of microsomal metabolites. In addition, the 18F-labeled isotopologue of 8-(1-norbornyl)-3-(3-fluoropropyl)-1-propylxanthine (1-NBX) as the most promising candidate was prepared by radiofluorination of the corresponding tosylate precursor and the resulting radioligand ([18F]1-NBX) was evaluated by permeability assays with Caco-2 cells and in vitro autoradiography in rat brain slices. Our results demonstrate that 1-NBX exhibits significantly improved A1R affinity and selectivity when compared to CPFPX and that it does not give rise to lipophilic metabolites expected to cross the blood-brain-barrier in microsomal assays. Furthermore, [18F]1-NBX showed a high passive permeability (Pc = 6.9 ± 2.9 × 10-5 cm/s) and in vitro autoradiography with this radioligand resulted in a distribution pattern matching A1R expression in the brain. Moreover, a low degree of non-specific binding (5%) was observed. Taken together, these findings identify [18F]1-NBX as a promising candidate for further preclinical evaluation as potential PET tracer for A1R imaging.


Assuntos
Tomografia por Emissão de Pósitrons , Receptor A1 de Adenosina , Xantinas , Receptor A1 de Adenosina/metabolismo , Humanos , Animais , Xantinas/química , Xantinas/síntese química , Ratos , Células CACO-2 , Masculino , Estrutura Molecular , Relação Estrutura-Atividade , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/síntese química , Relação Dose-Resposta a Droga , Radioisótopos de Flúor/química
7.
Basic Clin Pharmacol Toxicol ; 134(6): 818-832, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38583870

RESUMO

BACKGROUND: Autophagy can have either beneficial or detrimental effects on various heart diseases. Pharmacological interventions improve cardiac function, which is correlated with enhanced autophagy. To assess whether a xanthine derivative (KMUP-3) treatment coincides with enhanced autophagy while also providing cardio-protection, we investigated the hypothesis that KMUP-3 treatment activation of autophagy through PI3K/Akt/eNOS signalling offered cardioprotective properties. METHODS: The pro-autophagic effect of KMUP-3 was performed in a neonatal rat model targeting cardiac fibroblasts and cardiomyocytes, and by assessing the impact of KMUP-3 treatment on cardiotoxicity, we used antimycin A-induced cardiomyocytes. RESULTS: As determined by transmission electron microscopy observation, KMUP-3 enhanced autophagosome formation in cardiac fibroblasts. Furthermore, KMUP-3 significantly increased the expressions of autophagy-related proteins, LC3 and Beclin-1, both in a time- and dose-dependent manner; moreover, the pro-autophagy and nitric oxide enhancement effects of KMUP-3 were abolished by inhibitors targeting eNOS and PI3K in cardiac fibroblasts and cardiomyocytes. Notably, KMUP-3 ameliorated cytotoxic effects induced by antimycin A, demonstrating its protective autophagic response. CONCLUSION: These findings enable the core pathway of PI3K/Akt/eNOS axis in KMUP-3-enhanced autophagy activation and suggest its principal role in safeguarding against cardiotoxicity.


Assuntos
Autofagia , Miócitos Cardíacos , Óxido Nítrico Sintase Tipo III , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Autofagia/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Sprague-Dawley , Animais Recém-Nascidos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Xantinas/farmacologia , Células Cultivadas , Cardiotônicos/farmacologia , Cardiotoxicidade/prevenção & controle , Proteína Beclina-1/metabolismo
8.
Chem Biodivers ; 21(7): e202400823, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38687255

RESUMO

The design of novel agrochemicals starting from bioactive natural products is one of the most effective ways in the discovery and development of new pesticidal agents. In this paper, a series of novel butenolide-containing methylxanthine derivatives (Ia-Ir) were designed based on natural methylxanthine caffeine and stemofoline, and the derivatized insecticide flupyradifurone of the latter. The structures of the synthesized compounds were confirmed via 1H-NMR, 13C NMR, HRMS and X-ray single crystal diffraction analyses. The biological activities of the compounds were evaluated against a variety of agricultural pests including oriental armyworm, bean aphid, diamondback moth, fall armyworm, cotton bollworm, and corn borer; the results indicated that some of them have favorable insecticidal potentials, particularly toward diamondback moth. Among others, Ic and Iq against diamondback moth possessed LC50 values of 6.187 mg ⋅ L-1 and 3.269 mg ⋅ L-1, respectively, - 2.5- and 4.8-fold of relative insecticidal activity respectively to that of flupyradifurone (LC50=15.743 mg ⋅ L-1). Additionally, both the DFT theoretical calculation and molecular docking with acetylcholine binding protein were conducted for the highly bioactive compound (Ic). Ic and Iq derived from the integration of caffeine (natural methylxanthine) and butenolide motifs can serve as novel leading insecticidal compounds for further optimization.


Assuntos
4-Butirolactona , Teoria da Densidade Funcional , Inseticidas , Simulação de Acoplamento Molecular , Mariposas , Inseticidas/química , Inseticidas/farmacologia , Inseticidas/síntese química , Animais , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/farmacologia , 4-Butirolactona/síntese química , Mariposas/efeitos dos fármacos , Cristalografia por Raios X , Estrutura Molecular , Xantinas/farmacologia , Xantinas/química , Xantinas/síntese química , Afídeos/efeitos dos fármacos , Relação Estrutura-Atividade
9.
Schweiz Arch Tierheilkd ; 166(4): 207-215, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38572822

RESUMO

INTRODUCTION: This case report describes the long-term success of a subcutaneous ureteral bypass device in a dog for treatment of a ureteral obstruction. The suspected xanthine urolithiasis was secondary to treatment with allopurinol for leishmaniasis. The dog presented initially with lethargy, anuria and abdominal pain. Mild azotemia was found on biochemical analysis and abdominal ultrasound revealed bilateral ureteral obstruction. A subcutaneous ureteral bypass was subsequently placed using a standard surgical technique. The dog recovered uneventfully and the azotemia resolved within days. Follow-up examinations were performed every trimester for over three years and no complications like obstruction of the bypass tubes, urinary tract infection or azotemia were recognized during this follow-up period. Allopurinol was replaced with domperidone as long-term treatment against Leishmaniasis which resulted in a mild increase of the leishmania serum antibody titer. The subcutaneous ureteral bypass placement was successful and safe in this dog and is a valuable alternative in cases of ureteral obstruction also in dogs.


INTRODUCTION: Ce rapport de cas décrit le succès à long terme d'une dérivation urétérale sous-cutanée chez un chien pour le traitement d'une obstruction urétérale. L'urolithiase xanthique suspectée était secondaire à un traitement à l'allopurinol contre la leishmaniose. Le chien a d'abord présenté une léthargie, une anurie et des douleurs abdominales. L'analyse biochimique a révélé une légère azotémie et l'échographie abdominale a révélé une obstruction urétérale bilatérale. Une dérivation urétérale sous-cutanée a été mise en place selon une technique chirurgicale standard. Le chien s'est rétabli sans incident et l'azotémie a disparu en quelques jours. Des examens de suivi ont été effectués tous les trimestres pendant plus de trois ans et aucune complication telle qu'une obstruction du tube de dérivation, une infection urinaire ou une azotémie n'a été constatée au cours de cette période de suivi. L'allopurinol a été remplacé par de la dompéridone dans le cadre d'un traitement à long terme contre la leishmaniose, ce qui a entraîné une légère augmentation du titre des anticorps sériques contre la leishmaniose. La mise en place d'une dérivation urétérale sous-cutanée s'est avérée efficace et sûre chez ce chien et constitue une alternative intéressante en cas d'obstruction urétérale, y compris chez les chiens.


Assuntos
Azotemia , Doenças do Gato , Doenças do Cão , Leishmaniose , Obstrução Ureteral , Urolitíase , Animais , Cães , Gatos , Obstrução Ureteral/etiologia , Obstrução Ureteral/cirurgia , Obstrução Ureteral/veterinária , Alopurinol/uso terapêutico , Azotemia/veterinária , Urolitíase/cirurgia , Urolitíase/veterinária , Leishmaniose/veterinária , Xantinas , Stents/veterinária , Doenças do Cão/tratamento farmacológico , Doenças do Cão/cirurgia
10.
Front Immunol ; 15: 1338714, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38469308

RESUMO

Background: Autoimmune encephalitis is a neurological condition caused by abnormal immune responses, manifesting as cognitive impairments, behavioral abnormalities, and seizures. Its diagnosis depends on the detecting neuronal surface antibodies in serum or cerebrospinal fluid. Despite recent advances in understanding, clinical recognition remains challenging, especially with rare antibodies such as anti-dopamine D2 receptor (D2R) and anti-dipeptidyl-peptidase-like protein 6 (DPPX) antibodies. Delayed diagnosis can lead to severe complications. This case presentation emphasizes the diagnostic intricacies and effective treatment of the anti-D2R and DPPX antibody-associated autoimmune encephalitis. Case description: The patient presented with a 3-day history of fatigue and limb soreness followed by a 3-h episode of confusion and limb convulsions. Upon admission to our facility, the initial diagnosis included status epilepticus, aspiration pneumonia, metabolic acidosis, respiratory alkalosis, and suspected encephalitis. Despite receiving antiepileptic, anti-infection, and antivirus therapy, the patient's condition deteriorated. Both computed tomography (CT) scan and magnetic resonance imaging (MRI) of the brain showed no significant abnormalities. No pathogen was identified in the cerebrospinal fluid (CSF). However, further CSF and serum examination revealed positive results of anti-D2R and anti-DPPX antibodies, confirming a diagnosis of anti-D2R and DPPX antibody-associated autoimmune encephalitis. The patient underwent a comprehensive treatment regimen, including high-dose methylprednisolone pulse therapy combined with intravenous immunoglobulin (IVIG), antiviral and anti-infection treatments, and antiepileptic medications. Significant clinical improvement was observed, and by the 18th day of admission, the patient was stable and coherent. Conclusions: The current patient represents the first reported case of double-positive autoimmune encephalitis for anti-D2R and DPPX antibodies, with epilepsy as a prominent feature. High-dose methylprednisolone pulse therapy combined with IVIG has shown significant safety and efficacy in treating anti-D2R and DPPX antibody-positive autoimmune encephalitis-associated epilepsy.


Assuntos
Doenças Autoimunes do Sistema Nervoso , Encefalite , Epilepsia , Doença de Hashimoto , Xantinas , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Metilprednisolona/uso terapêutico , Anticonvulsivantes , Encefalite/diagnóstico , Encefalite/tratamento farmacológico , Encefalite/etiologia , Anticorpos , Convulsões/complicações , Doenças Autoimunes do Sistema Nervoso/complicações
11.
Drug Res (Stuttg) ; 74(3): 133-144, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38350632

RESUMO

In this study, the protective efficacy of pentoxifylline (PTX) as a xanthine derivative against arsenic trioxide (ATO)-induced kidney and liver damage in mice was investigated. Thirty-six mice were divided into six groups, receiving intraperitoneal injections of saline, ATO, PTX, or a combination for four weeks. Blood samples were analyzed for serum biochemistry, while hepatic tissue underwent examination for histopathological changes and assessment of oxidative stress markers and antioxidant gene expression through Real-Time PCR. ATO exposure significantly increased serum markers (creatinine, ALT, BUN, ALP, AST) and induced histopathological changes in the liver. Moreover, it elevated renal and hepatic nitric oxide (NO) and lipid peroxidation (LPO) levels, and reduced antioxidant enzyme expression (CAT, GSR, GPx, MPO, SOD), total thiol groups (TTGs), and total antioxidant capacity (TAC). Conversely, PTX treatment effectively lowered serum hepatic and renal markers, improved antioxidant markers, and induced histopathological alterations. Notably, PTX did not significantly affect renal and hepatic NO levels. These findings suggest that PTX offers therapeutic potential in mitigating liver and acute kidney injuries induced by various insults, including exposure to ATO.


Assuntos
Alcaloides , Antioxidantes , Camundongos , Animais , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Trióxido de Arsênio/metabolismo , Trióxido de Arsênio/farmacologia , Fígado/metabolismo , Estresse Oxidativo , Alcaloides/farmacologia , Xantinas/metabolismo , Xantinas/farmacologia
12.
J Am Chem Soc ; 146(7): 4892-4902, 2024 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-38319883

RESUMO

Nidulaxanthone A is a dimeric, dihydroxanthone natural product that was isolated in 2020 from Aspergillus sp. Structurally, the compound features an unprecedented heptacyclic 6/6/6/6/6/6/6 ring system which is unusual for natural xanthone dimers. Biosynthetically, nidulaxanthone A originates from the monomer nidulalin A via stereoselective Diels-Alder dimerization. To expedite the synthesis of nidulalin A and study the proposed dimerization, we developed methodology involving the use of allyl triflate for chromone ester activation, followed by vinylogous addition, to rapidly forge the nidulalin A scaffold in a four-step sequence which also features ketone desaturation using Bobbitt's oxoammonium salt. An asymmetric synthesis of nidulalin A was achieved using acylative kinetic resolution (AKR) of chiral, racemic 2H-nidulalin A. Dimerization of enantioenriched nidulalin A to nidulaxanthone A was achieved using solvent-free, thermolytic conditions. Computational studies have been conducted to probe both the oxoammonium-mediated desaturation and (4 + 2) dimerization events.


Assuntos
Cetonas , Xantinas , Cloreto de Sódio , Dimerização
13.
Inorg Chem ; 63(7): 3366-3375, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38323570

RESUMO

Overcoming the intrinsic low activity of most peroxidase mimics under neutral pH is crucial but still extremely challenging for the detection of disease markers in biological samples. Here, we chose nanoclay (i.e., montmorillonite K10, MK10) as a carrier to modulate the structure of Fe1-xS nanozyme components through an interfacial modulation strategy, aiming at breaking the neutral pH limitation of Fe1-xS. MK10 with abundant hydroxyl groups on its surface acts as a carrier to increase the ratio of Fe(II) and S(II-) content in surface Fe1-xS. We verify that Fe(II)-promoted surface hydroxyl radical generation and S(II-)-promoted regeneration of Fe(II) play key roles in endowing peroxidase-like activity to Fe1-xS at neutral pH. As expected, Fe1-xS/MK10 exhibited 11-fold higher Vmax and 52-fold higher catalytic efficiency than bare Fe1-xS. As a proof of concept, the sensor constructed based on Fe1-xS/MK10 achieved colorimetric detection of xanthine under neutral conditions with a linear range of 5-300 µM and a limit of detection of 2.49 µM. Finally, we achieved highly sensitive detection of xanthine in serum using the constructed biosensor. Our contribution is the novel use of a nanoclay-mediated interfacial modulation strategy for boosting the peroxidase-mimicking activity and breaking the pH limitation, which contributes to the in situ detection of disease markers by nanozymes under physiological conditions.


Assuntos
Peroxidase , Peroxidases , Peroxidase/química , Peroxidases/química , Colorimetria , Concentração de Íons de Hidrogênio , Xantinas , Compostos Ferrosos , Peróxido de Hidrogênio
14.
J Agric Food Chem ; 71(49): 19343-19356, 2023 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-38047436

RESUMO

On the basis of the structures of natural methylxanthines and chalcone, a series of novel chalcone analogues containing a methylxanthine moiety, Ia-Ig, and their N-acyl pyrazoline derivatives IIa-IIz and IIaa-IIaf were synthesized and identified through melting points, 1H NMR, 13C NMR, and HRMS. The single crystal of compound IId was obtained, which further illustrated the structural characteristics of the methylxanthine-acylpyrazoline compounds. The biological tests showed that some of them displayed favorable insecticidal activities toward Plutella xylostella L. and were superior to the natural methylxanthine compound caffeine while being comparable with the insecticide triflumuron (e.g., compound Ic: LC50 = 16.8508 mg/L, IIf: LC50 = 1.5721 mg/L, against P. xylostella). Of these compounds, Ic, IIf, and IIu could serve as novel insecticidal leading structures for further study. Some of the compounds showed good fungicidal activities (e.g., compound Ig: EC50 = 14.74 µg/mL, against Rhizoctonia cerealis; IIf: EC50 = 7.06 µg/mL, against Physalospora piricola; IIac: EC50 = 5.37 and 8.19 µg/mL, against Phytophthora capsici and Sclerotinia sclerotiorum, respectively); Ic, Ig, IIa, IIf, IIr, IIs, IIv, IIac, and IIaf could be novel fungicidal leading compounds for further exploration. Furthermore, most of the tested compounds exhibited apparent herbicidal activities against Brassica campestris at a concentration of 100 µg/mL; among others, compound IIa was the best one both toward Brassica campestris and Echinochloa crusgalli and deserves further investigation. The structure-activity relationships of these compounds were also summarized and discussed in detail. The contrast experiment results of compounds C-1 and C-2 showed a positive effect on the biological activity enhancement from the combination of the methylxanthine moiety with the N-dichloroacetyl phenylpyrazoline skeleton. In addition, two 3D-QSAR models with predictive capability were constructed based on the insecticidal and fungicidal activities to afford deep insight into the bioactivity profiles of these compounds. This research provides useful guidance and reference for the discovery and development of novel xanthine natural product-based pesticides.


Assuntos
Chalconas , Fungicidas Industriais , Inseticidas , Fungicidas Industriais/química , Xantinas , Relação Estrutura-Atividade , Inseticidas/química , Relação Quantitativa Estrutura-Atividade
15.
J Med Chem ; 66(23): 15674-15698, 2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-37967029

RESUMO

The MAS-related Gq protein-coupled receptor X4 (MRGPRX4) is poorly investigated. MRGPRX4 has been proposed to be involved in pain transmission, itch, inflammation, wound healing, and cancer. However, so far only a few moderately potent, nonselective MRGPRX4 agonists have been described, most of which appear to preferably activate the minor receptor variant MRGPRX4-83L but not the main variant 83S. In the present study, we discovered a xanthine derivative bearing a phosphate substituent that activates the main variant of MRGPRX4. Optimization resulted in analogs with high potency and metabolic stability. The best compounds of the present series include 8-(m-methoxyphenethyl)-1-propargylxanthine substituted with a butyl linker in the 3-position containing a terminal phosphonate (30d, PSB-22034, EC50 Ca2+ assay/ß-arrestin assay, 11.2 nM/32.0 nM) and its N7-methyl derivative 31d (PSB-22040, EC50, 19.2/30.0 nM) showing high selectivity versus all other MRGPRX subtypes. They present promising tool compounds for exploring the potential of MRGPRX4 as a future drug target.


Assuntos
Receptores Acoplados a Proteínas G , Xantinas , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Prurido
16.
Pediatr Endocrinol Diabetes Metab ; 29(3): 143-155, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38031830

RESUMO

INTRODUCTION: Atherosclerosis, a precursor to cardiovascular disease (CVD), is deeply intertwined with lipid metabolism. The metabolic process in the Down syndrome (DS) population remain less explored. Aim of the study: This study examines the lipid profiles of DS in comparison to their siblings (CG), aiming to uncover potential atherosclerotic and CVD risks. MATERIAL AND METHODS: The study included 42 people with DS (mean age 14.17 years) and the CG - 20 individuals (mean age 15.92 years). Anthropometric measurements: BMI, BMI SDS, and TMI were calculated. Lipid profile (LP) and metabolomics were determined. RESULTS: LP: DS display significantly reduced HDL (DS vs. CG: 47±10 vs. 59 ±12 mg/dl; p = 0.0001) and elevated LDL (104 ±25 vs. 90 ±22 mg/dl; p = 0.0331). Triglycerides, APO A1, and APO B/APO A1 ratio corroborate with the elevated risk of CVD in DS. Despite no marked differences in: TCH and APO B, the DS group demonstrated a concerning BMI trend. Of 31 identified metabolites, 12 showed statistical significance (acetate, choline, creatinine, formate, glutamine, histidine, lysine, proline, pyroglutamate, threonine, tyrosine, and xanthine). However, only 8 metabolites passed the FDR validation (acetate, creatinine, formate, glutamine, lysine, proline, pyroglutamate, xanthine). CONCLUSIONS: Down syndrome individuals show distinct cardiovascular risks, with decreased HDL and increased LDL levels. Combined with metabolomic disparities and higher BMI and TMI, this suggests an increased atherosclerosis risk compared to controls.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Síndrome de Down , Humanos , Criança , Adulto , Adolescente , Apolipoproteína A-I , Fatores de Risco , Creatinina , Glutamina , Lisina , Ácido Pirrolidonocarboxílico , Doenças Cardiovasculares/epidemiologia , Aterosclerose/etiologia , Apolipoproteínas B , Xantinas , Acetatos , Formiatos , Prolina
17.
Food Funct ; 14(19): 8893-8902, 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37701930

RESUMO

Increasing evidence suggests that dietary (poly)phenols and methylxanthines have neuroprotective effects; however, little is known about whether they can cross the blood-brain barrier (BBB) and exert direct effects on the brain. We investigated the presence of (poly)phenol and methylxanthine metabolites in plasma and cerebrospinal fluid (CSF) from 90 individuals at risk of dementia using liquid chromatography-mass spectrometry and predicted their mechanism of transport across the BBB using in silico modelling techniques. A total of 123 and 127 metabolites were detected in CSF and plasma, respectively. In silico analysis suggests that 5 of the 20 metabolites quantified in CSF can cross the BBB by passive diffusion, while at least 9 metabolites require the aid of cell transporters to cross the BBB. Our results showed that (poly)phenols and methylxanthines are bioavailable, can cross the BBB via passive diffusion or transport carriers, and can reach brain tissues to exert neuroprotective effects.


Assuntos
Barreira Hematoencefálica , Fármacos Neuroprotetores , Fenóis , Xantinas , Humanos , Barreira Hematoencefálica/metabolismo , Fármacos Neuroprotetores/líquido cefalorraquidiano , Fármacos Neuroprotetores/metabolismo , Fenol , Fenóis/líquido cefalorraquidiano , Fenóis/metabolismo , Xantinas/líquido cefalorraquidiano , Xantinas/metabolismo
18.
Chem Commun (Camb) ; 59(72): 10809-10812, 2023 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-37599611

RESUMO

Xanthine derivatives were identified as inhibitors of the N6-methyladenosine (m6A) demethylase activity of fat-mass-and-obesity-associated protein (FTO) by activity-based high-throughput screening using the m6A-sensitive ribonuclease MazF. Pentoxifylline exhibited L-ascorbic acid concentration-dependent inhibitory activity against FTO, an unprecedented mode of inhibition, indicating that L-ascorbic acid is a promising key for designing FTO-specific inhibitors.


Assuntos
Alcaloides , Ácido Ascórbico/farmacologia , Ensaios de Triagem em Larga Escala , Ribonucleases , Xantinas/farmacologia
19.
Bioorg Med Chem Lett ; 94: 129461, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37652099

RESUMO

Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.


Assuntos
Alcaloides , Hepatopatia Gordurosa não Alcoólica , Humanos , Diuréticos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Triptofano Hidroxilase/antagonistas & inibidores , Xantinas/química , Xantinas/farmacologia
20.
Anal Bioanal Chem ; 415(24): 5949-5960, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37468755

RESUMO

The use of peroxidase mimics has great potential for various real applications due to their strong catalytic activity. Herein, a facile strategy was proposed to directly prepare CuO@g-C3N4 by Cu-MOF derivatization and demonstrated its efficacy in constructing a multiple enzymatic cascade system by loading protein enzymes onto it. The resulting CuO@g-C3N4 possessed high peroxidase-like activity, with a Michaelis constant (Km) of 0.25 and 0.16 mM for H2O2 and 3,3',5,5'-tetramethylbenzidine (TMB), respectively. Additionally, the high surface area of CuO@g-C3N4 facilitated the loading of protein enzymes and maintained their activity over an extended period, expanding the potential applications of CuO@g-C3N4. To test its feasibility, CuO@g-C3N4/protein oxidase complex was prepared and used to sense the ripeness and freshness of fruits and meat, respectively. The mechanism relied on the fact that the ripeness of fruits increased and freshness of food decreased with the release of marked targets, such as glucose and xanthine, which could produce H2O2 when digested by the corresponding oxidase. The peroxidase mimics of CuO@g-C3N4 could then sensitively colorimetric detect H2O2 in present of TMB. The obtained CuO@g-C3N4/oxidase complex exhibited an excellent linear response to glucose or xanthine in the range of 1.0-120 µmol/L or 8.0-350 µmol/L, respectively. Furthermore, accurate quantification of glucose and xanthine in real samples is achieved with spiked recoveries ranging from 80.2% to 120.0% and from 94.2% to 112.0%, respectively. Overall, this work demonstrates the potential of CuO@g-C3N4 in various practical applications, such as food freshness detection.


Assuntos
Colorimetria , Peróxido de Hidrogênio , Colorimetria/métodos , Glucose , Peroxidase/metabolismo , Peroxidases , Antioxidantes , Xantinas
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