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The performance of gold nanospheres as substrates for surface-enhanced Raman spectroscopy (SERS) investigation has been compromised by their low adsorption efficiency, high colloidal dispersibility, and diminishing hot spots. However, gold nanosphere substrates modified using aryldiazonium gold(III) chemistry via durable gold-carbon bonds are promising for SERS enhancement due to their controlled organic layer density. In this study, arylated gold nanospheres AuNSs-COOH have shown SERS enhancement when incorporated into graphene oxide (GO) to form nanocomposites (NCs) labeled AuNSs-COOH/GO (AuNCs). Our investigation using X-ray photoelectron spectroscopy (XPS) surface analysis showed that the gold-aryl nanospheres reached their maximum SERS enhancement with an optimal coating. The evaluation included the Au 4f chemical environment and compact graphitic layers for the SERS substrate optimization. The fabricated AuNC substrates demonstrated superior efficiency and reproducibility. A broad linear range of 10-3-10-7 M 4-nitrophenol detection was obtained with exceptional repeatability, as evidenced by the relative standard deviation (RSD) of 9.32%. A detailed investigation of the energy profiles, particularly the valence band maximum (VBM) and band gap values of the substrate and analyte, depicted the electromagnetic (EM) and charge-transfer-induced enhancement and the role of GO inclusion in substrate efficiency in SERS enhancement mechanisms. The finite-difference time domain (FDTD) simulation results revealed that AuNCs incorporated with graphitic nanostructures exhibited the most substantial SERS effect through an EM field enhancement mechanism. This study demonstrated significant SERS enhancement using gold-aryl nanospheres when modified with GO, in contrast to the typical reliance on anisotropic nanostructures.
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In this study, we report the modification of flexible copper films via the spontaneous reduction of aryldiazonium gold salts [X-4-C6H4N≡N]AuCl4 (XâCOOH, NO2). The electroless modification involves dipping of flexible copper films in the aryldiazonium gold solutions for a few seconds, under ambient conditions, followed by a washing step with deionized water to obtain a mechanically robust gold-aryl coating. The chemical composition, morphology, electronic structure, and optical properties of the gold-aryl layer and the flexibility of the modified copper films are supported by the results from X-ray photoelectron spectroscopy (XPS), electrochemistry, contact angle, scanning electron microscopy (SEM), and ultraviolet photoelectron spectroscopy (UPS). XPS surface analysis showed metallic gold in addition to C-C, C-O/C-N, and CâO functional groups from the grafted aryls. Cu 2p showed metallic copper as a major component and a small amount of Cu(II) ions. Wettability studies showed that Au-COOH@Cu increased the contact angle of the bare copper films from 68.0 ± 0.7° to 82.0° ± 0.7°, while Au-NO2@Cu increased the contact angle to 134.0° ± 0.3°. UPS energy profile analysis of [HOOC-4-C6H4N≡N]AuCl4 (valence band maximum = 1.91 eV) exhibited greater reducibility than [O2N-4-C6H4N≡N]AuCl4 (valence band maximum = 2.91 eV). The lower ionization potential of [HOOC-4-C6H4N≡N]AuCl4 (IP = 4.33 eV) enhanced the reactivity upon copper film contact, potentially inducing efficient energy level alignment, compared with [O2N-4-C6H4N≡N]AuCl4 (IP = 5.62 eV). UPS results were further supported by electrochemistry investigation which revealed that [HOOC-4-C6H4N≡N]AuCl4 is easily reducible compared with [O2N-4-C6H4N≡N]AuCl4. The findings presented here hold significant implications for developing flexible copper films and pave the way for future advancements in electronic material modification for industrial applications.
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Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds-4a, 4f, 4l, and 4r-demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 µM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77-66.22 µM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 µM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.
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Antineoplásicos , Benzotiazóis , Proliferação de Células , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Tiadiazóis , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Humanos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Benzotiazóis/química , Benzotiazóis/farmacologia , Benzotiazóis/síntese química , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Desenho de Fármacos , Relação Estrutura-Atividade , Sorafenibe/farmacologia , Sorafenibe/química , Estrutura Molecular , Simulação por Computador , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
PURPOSE OF REVIEW: This review aims to offer an up-to-date evaluation of Inclisiran's (a small interfering RNA treatment) ability to decrease low-density lipoprotein cholesterol (LDL-C), as well as its safety and potential effects on decreasing cardiovascular risk. RECENT FINDINGS: Inclisiran significantly lowers LDL-C levels, as shown by phase III studies, by inhibiting hepatic synthesis of proprotein convertase subtilisin kexin 9 (PCSK-9), a protein implicated in the degradation of LDL receptors. Inclisiran has the benefit of subcutaneous injection twice a year, which may reduce patient nonadherence when compared with other LDL-C reducing therapies such as statins and ezetimibe, which require daily dosing. When added on top of statins, a greater proportion of patients achieved recommended cholesterol goals. It has also demonstrated a good safety profile with few adverse effects. SUMMARY: Inclisiran is a promising treatment for lowering LDL-C levels in people at high risk of atherosclerotic cardiovascular disease. It is a practical and well tolerated option for those who struggle to stick to medication regimes because of its twice-yearly dosage schedule and a good safety profile. Although it has been demonstrated to be effective in decreasing LDL-C, further research is needed to determine its impact on reducing cardiovascular events. Nonetheless, Inclisiran is a significant advancement in lipid-lowering medication and could improve patient outcomes.
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Anticolesterolemiantes , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , LDL-Colesterol , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Colesterol , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/tratamento farmacológico , Pró-Proteína Convertase 9/metabolismo , Anticolesterolemiantes/uso terapêuticoRESUMO
In the present work, the anti-inflammatory effect of 30 compounds containing 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole was investigated. All final target compounds showed significant Inhibitory effect on p38α. P38α is considered one of the key kinases in the inflammatory process due to its regulatory effect on pro-inflammatory mediators. The final target compounds divided into four group based on the type of terminal moiety (amide and sulfonamide) and the linker between pyrimidine ring and terminal moiety (ethyl and propyl). Most compounds with terminal sulfonamide moiety and propyl linker between the sulfonamide and pyrimidine ring were the most potent among all synthesized final target compounds with sub-micromolar IC50s. Compound 24g (with p-Cl benzene sulfonamide and propyl linker) exhibited the highest activity over P38α with IC50 0.68 µM. All final target compounds were tested for their ability to inhibit nitric oxide release and prostaglandin E2 production. Compounds having amide terminal moiety with ethyl linker showed higher inhibitory activity for nitric oxide release and compound 21d exhibited the highest activity for nitric oxide release with IC50 1.21 µM. Compounds with terminal sulfonamide moiety and propyl linker showed the highest activity for inhibiting PGE2 production and compounds 24i and 24g had the lowest IC50s with value 0.87 and 0.89 µM, respectively. Compounds 21d, 22d and 24g were tested for their ability to inhibit over expression of iNOS, COX1, and COX2. In addition the ability of compounds 21d, 22d and 24g to inhibit inflammatory cytokines were determined. Finally molecular docking of the three compounds were performed on P38α crystal structure to expect their mode of binding.
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Óxido Nítrico , Tiazóis , Tiazóis/farmacologia , Simulação de Acoplamento Molecular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Sulfonamidas/química , Amidas , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
A new series of 2-aminobenzothiazole hybrids linked to thiazolidine-2,4-dione 4a-e, 1,3,4-thiadiazole aryl urea 6a-d, and cyanothiouracil moieties 8a-d was synthesised. The in vitro antitumor effect of the new hybrids was assessed against three cancer cell lines, namely, HCT-116, HEPG-2, and MCF-7 using Sorafenib (SOR) as a standard drug. Among the tested compounds, 4a was the most potent showing IC50 of 5.61, 7.92, and 3.84 µM, respectively. Furthermore, compounds 4e and 8a proved to have strong impact on breast cancer cell line with IC50 of 6.11 and 10.86 µM, respectively. The three compounds showed a good safety profile towards normal WI-38 cells. Flow cytometric analysis of the three compounds in MCF-7 cells revealed that compounds 4a and 4c inhibited cell population in the S phase, whereas 8a inhibited the population in the G1/S phase. The most promising compounds were subjected to a VEGFR-2 inhibitory assay where 4a emerged as the best active inhibitor of VEGFR-2 with IC50 91 nM, compared to 53 nM for SOR. In silico analysis showed that the three new hybrids succeeded to link to the active site like the co-crystallized inhibitor SOR.
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Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
A novel series of 12 antipyrine derivatives containing 1,3,4-oxadiazoles (4a-d), 1,3,4-thiadiazoles (6a-d), and pyrimidines (8a-d), was preparedand assessed for its potential in vitro COX-2 inhibitors. Compared to Celecoxib, compounds 4b-d and 8d were the most potent derivatives c with a half-maximal inhibitory concentration range of 53-69 nM. Considering COX-2 selectivity index, compounds 4 b and 4c were chosen among these most potent derivatives for further investigation. The in vivo ability of compounds 4 b and 4c to counteract carrageenan-induced paw edoema has been assessed and their potential underlying mechanisms have been elucidated and the results have been further validated using molecular docking simulations.
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Anti-Inflamatórios , Antipirina , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antipirina/farmacologia , Celecoxib/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Edema/tratamento farmacológico , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications.
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Aldeído Redutase , Hipoglicemiantes , Animais , Camundongos , Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Cinética , Simulação de Acoplamento Molecular , Tiazolidinas/farmacologiaRESUMO
Polychlorinated dibenzofurans (PCDFs) are persistent toxic compounds that are ubiquitous in the environment. Nanocomposites of titanium(IV) oxide-vanadium(III) oxide (Ti3V2O7) and titanium(IV) oxide-silicon dioxide (Ti2Si7O30) were prepared and spectroscopically analyzed as potential decontaminants for dioxin-like materials. The analysis confirmed a homogeneous morphology with nanoscale particle size. The Ti-Si sample was found to have a high surface area compared to the Ti-V composite. Vanadium(III) oxide (V2O5) and silicon dioxide (SiO2) were chosen as materials for the formation of heterogeneous compounds with titanium(IV) oxide (TiO2) because they possess a suitable band alignment with TiO2, thus forming effective photocatalysts. This study evaluated the photodegradation of 2,3,7,8-tetrachlorodibenzo-furan (TCDF) in the presence of Ti-Si and Ti-V oxide composites, which was tested using high- (254 nm) and midenergy (302 nm) UV irradiation sources. While Ti-Si showed success in the photodegradation of 2,3,7,8-TCDF dissolved in a (1:1) methanol-tetrahydrofuran (MeOH-THF) solution, the Ti-V composite proved to be a powerful material in adsorbing TCDF with a high capacity immediately upon mixing. Ti-Si oxide was found to decompose TCDF under the two irradiation sources with 98-99% degradation occurring after 70 min. The use of 254 nm as an irradiation source in the presence of Ti-Si was 4.3 times faster than the analogue reaction irradiated without a catalyst. Byproducts of the degradation were evaluated using gas chromatography-mass spectrometry (GC-MS), resulting in a lower chlorinated congener and less toxicity, as the main degradation product.
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We carried out this study to validate the use of ultrasound sliding sign to predict intraperitoneal adhesions in women undergoing repeated caesarean section (CS). A cross-section study was performed in women with at least one CS scheduled for an elective CS. We used the sliding sign of the uterus against the anterior abdominal wall to assess intraperitoneal adhesions, positive sliding sign if uterus moved freely and a negative sliding sign if limited mobility. The obstetrician was blind to the ultrasound results, asked to report if adhesions were absent or present during CS to validate accuracy of the sliding sign. We examined 120 women, negative sliding was reported in 54 patients, positive sliding in 66 women. The presence of intra-abdominal adhesions was confirmed in 44/54 cases assigned to the high-risk group, while the prediction of low risk for adhesions confirmed in 66/66 patients with a sensitivity of 100%, specificity of 86.84%. Sliding sign is an effective method to detect intra-abdominal adhesions in women with a history of repeated caesarean delivery.Impact statementWhat is already known on this subject? There has been a dramatic increase in the caesarean section (CS) rate worldwide; repeated CSs may be associated with intraperitoneal adhesions that result in difficulty during the procedure and may be related to bowel or bladder injuries and neonatal morbidities.What do the results of this study add? The sliding sign by ultrasound has a sensitivity of 100%, specificity of 86.84%, a positive predictive value of 81.5, a negative predictive value of 100, and accuracy of 91.67, considering it rapid, easy and reliable method for prediction of intraperitoneal adhesions.What are the implications of these findings for clinical practice and/or future research? The use of sliding sign by ultrasound in cases with repeated CSs offers a good predictor tool for presence of intraperitoneal adhesions and subsequently avoid severe sequels during surgery and good preparation.
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Recesariana , Cesárea , Recém-Nascido , Humanos , Feminino , Gravidez , Cesárea/efeitos adversos , Recesariana/efeitos adversos , Ultrassonografia , Valor Preditivo dos Testes , Útero , Aderências Teciduais/diagnóstico por imagem , Aderências Teciduais/etiologiaRESUMO
The current study investigates the anti-inflammatory and hepatoprotective effects of selenium (Se) formulated as nanoparticles (SeNPs) and in combination with quercetin (QCT) against thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) in rats. ââââââSeventy-two male Sprague-Dawley rats were divided into six groups (n = 12). Three control groups; normal, SeNPs; group received SeNPs only and HCC; group received TAA. In addition, three preventive groups; SeNPs + TAA, QCT + TAA, and QCT + SeNPs + TAA. Induction of HCC was detected histopathologically and by the raise of the serum level of alpha-fetoprotein (AFP). Oxidative stress was evaluated by the hepatic levels of reduced glutathione (GSH), glutathione peroxidase (GPx), and malondialdehyde (MDA) spectrophotometrically. The oncogenic pathway of p53/ß-catenin/cyclin D1 was assessed by immunohistochemistry. The inflammatory markers; interleukin-33 (IL-33), IL-6, and IL-1ß were assessed by enzyme-linked immune sorbent assay. SeNPs prevented the elevation of serum AFP and hepatic IL-33, IL-1ß, and IL-6 in comparison to HCC or QCT + TAA groups. SeNPs + TAA exhibited a lower positive hepatic staining of p53, ß-catenin, and cyclin D1 in comparison to HCC or QCT + TAA groups. Moreover, SeNPs improved the overall oxidative balance indicated by low hepatic MDA and enhanced GSH and GPx when compared to HCC or QCT + TAA groups. ââSeNPs alone and in combination with QCT were found to suppress the progression of HCC in rats via the enhancement of the oxidative stress and then inflammatory status and the prevention of the deregulation of the oncogenic axis pathway of p53/ß-catenin/cyclin D.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Selênio , Animais , Carcinoma Hepatocelular/metabolismo , Ciclina D1/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Interleucina-6/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Estresse Oxidativo , Quercetina/farmacologia , Ratos , Ratos Sprague-Dawley , Selênio/farmacologia , Tioacetamida/toxicidade , Proteína Supressora de Tumor p53/metabolismo , alfa-Fetoproteínas , beta Catenina/metabolismoRESUMO
Galvanic replacement reaction was used in the synthesis of bimetallic gold-silver alloy nanoparticles (Au-Ag NPs), where pre-synthesized Ag nanoparticles-polyvinylpyrrolidone (AgNPs-PVP) were used to reduce the aryldiazonium tetrachloroaurate(III) salt in water. TEM images and EDS elemental analysis showed the formation of spherical Au-Ag NPs with sizes of 12.8 ± 4.9 nm and 25.6 ± 14.4 nm for corresponding Au-Ag ratios and termed as Au0.91Ag0.09 and Au0.79Ag0.21, respectively, with different concentrations of the gold precursor. The hydrodynamic sizes measured using dynamic light scattering are 46.4 nm and 74.8 nm with corresponding zeta potentials of - 44.56 and - 25.09 mV in water, for Au0.91Ag0.09 and Au0.79Ag0.21 respectively. Oxidative leachability of Ag ion studies from the starting AgNPs-PVP in 1 M NaCl showed a significant decrease in the plasmon peak after 8 h, indicating the complete dissolution of Ag ions, however, there is enhanced oxidation resistivity of Ag from Au-Ag NPs even after 24 h. Electrochemical studies on glassy carbon electrodes displayed a low oxidation peak in aqueous solutions of 20 mM KCl at 0.16 V and KNO3 at 0.33 V vs. saturated calomel electrode (SCE). We studied the antibacterial activity of Au-Ag alloy nanoparticles against gram-positive Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and gram-negative Escherichia coli, Salmonella typhimurium, and Pseudomonas aeruginosa. Our findings demonstrated superior antibacterial activity of Au-Ag NPs compared with AgNPs-PVP. Moreover, the nanoparticles inhibited the S. epidermidis biofilm formation.
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Nanopartículas Metálicas , Prata , Prata/farmacologia , Prata/química , Ouro/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Ligas/farmacologia , Ligas/química , Ligas de Ouro , Antibacterianos/farmacologia , Antibacterianos/química , ÁguaRESUMO
Two biologically active adamantane-linked hydrazine-1-carbothioamide derivatives, namely 2-(adamantane-1-carbonyl)-N-(tert-butyl)hydrazine-1-carbothioamide) 1 and 2-(adamantane-1-carbonyl)-N-cyclohexylhydrazine-1-carbothioamide 2, have been synthesized. X-ray analysis was conducted to study the effect of the t-butyl and cyclohexyl moieties on the intermolecular interactions and conformation of the molecules in the solid state. X-ray analysis reveals that compound 1 exhibits folded conformation, whereas compound 2 adopts extended conformation. The Hirshfeld surface analysis indicates that the contributions of the major intercontacts involved in the stabilization of the crystal structures do not change much as a result of the t-butyl and cyclohexyl moieties. However, the presence and absence of these contacts is revealed by the 2D-fingerprint plots. The CLP-Pixel method was used to identify the energetically significant molecular dimers. These dimers are stabilized by different types of intermolecular interactions such as N-H···S, N-H···O, C-H···S, C-H···O, H-H bonding and C-H···π interactions. The strength of these interactions was quantified by using the QTAIM approach. The results suggest that N-H···O interaction is found to be stronger among other interactions. The in vitro assay suggests that both compounds 1 and 2 exhibit urease inhibition potential, and these compounds also display moderate antiproliferative activities. Molecular docking analysis shows the key interaction between urease enzyme and title compounds.
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Adamantano , Ligação de Hidrogênio , Adamantano/farmacologia , Cristalografia por Raios X , Simulação de Acoplamento Molecular , Raios X , UreaseRESUMO
Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N-Mannich bases (1-3) are presented. Compounds 1, 2 and 3 crystallized in the monoclinic P21/c, P21 and P21/n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-Hâ¯O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-Hâ¯N, C-Hâ¯S and C-Hâ¯π interactions. The energy frameworks for crystal structures of 1-3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1-3 were determined using in silico techniques. Molecular docking of the compounds into the 11ß-HSD1 active site showed comparable binding affinity scores (-7.50 to -8.92 kcal/mol) to the 11ß-HSD1 co-crystallized ligand 4YQ (-8.48 kcal/mol, 11ß-HSD1 IC50 = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential.
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11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Adamantano , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adamantano/química , Simulação de Acoplamento Molecular , Bases de Mannich , Inibidores Enzimáticos/farmacologiaRESUMO
Because of the scale of the novel coronavirus (COVID-19) pandemic and the swift transmission of this highly contagious respiratory virus, repurposing existing drugs has become an urgent treatment approach. The objective of our study is to unravel the binding mechanism of the Food and Drug Administration (FDA)-approved dexamethasone (Dex) and boceprevir (Boc) drugs with selected COVID-19 protein targets SARS-CoV-2 spike protein C-terminal domain (spike-CTD), main protease (Mpro), and interleukin-6 (IL-6). Another objective is to analyze the effects of binding Dex and Boc drugs on the interactions of viral spike protein to human angiotensin-converting enzyme 2 (hACE2). Molecular docking and one-microsecond-long molecular dynamics simulations of each of the six protein-drug complexes along with steered molecular dynamics (SMD) and umbrella sampling (US) methods have revealed the binding mode interactions and the physicochemical stability of the three targeted proteins with two drugs. Results have shown that both drugs bind strongly with the three protein targets through hydrogen bonding and hydrophobic interactions. A major finding from this study is how the binding of the drugs with viral spike protein affects its interactions at the binding interface with hACE2 protein. Simulations of drug-bound spike-CTD with hACE2 show that due to the presence of a drug at the binding interface of spike-CTD, hACE2 is being blocked from making putative interactions with viral protein at such interface. These important findings regarding the binding affinity and stability of the two FDA-approved drugs with the main targets of COVID-19 along with the effect of drugs on hACE2 interactions would contribute to COVID-19 drug discovery and development. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-021-01843-0.
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Modified colloids and flat surfaces occupy an important place in materials science research due to their widespread applications. Interest in the development of modifiers that adhere strongly to surfaces relates to the need for stability under ambient conditions in many applications. Diazonium salts have evolved as the primary choice for the modification of surfaces. The term "diazonics" has been introduced in the literature to describe "the science and technology of aryldiazonium salt-derived materials". The facile reduction of diazonium salts via chemical or electrochemical processes, irradiation stimuli, or spontaneously results in the efficient modification of gold surfaces. Robust gold-aryl nanoparticles, where gold is connected to the aryl ring through bonding to carbon and films modified by using diazonium salts, are critical in electronics, sensors, medical implants, and materials for power sources. Experimental and theoretical studies suggest that gold-carbon interactions constructed via chemical reactions with diazonium salts are stronger than nondiazonium surface modifiers. This invited feature article summarizes the conceptual development of recent studies of diazonium salts in our laboratories and others with a focus on the surface modification of gold nanostructures, flat surfaces and gratings, and their applications in nanomedicine engineering, sensors, energy, forensic science, and catalysis.
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Compostos de Diazônio , Sais , Ouro , Coloide de Ouro , Propriedades de SuperfícieRESUMO
Biocompatible and luminescent nanostructures synthesized by capping gold-carbon nanoparticles (HOOC-4-C6H4-AuNPs) with amino acids tyrosine, tryptophan, and cysteine were used for the quantitative estimation of ranitidine (RNH), a peptic ulcer and gastroesophageal reflux drug. We applied a fluorescence quenching mechanism to investigate the viability of the energy transfer based on gold-carbon nanosensors. Förster resonance energy transfer (FRET) calculations showed a donor-acceptor distance of 1.69 nm (Tyr@AuNPs), 2.27 nm (Trp@AuNPs), and 2.32 nm (Cys@AuNPs). The constant time-resolved fluorescence lifetime measurements supported the static quenching nature. This method was successfully utilized in the detection and quantification of RNH, with a limit of detection (LOD) of 0.174, 0.56, and 0.332 µM for Tyr@AuNP, Trp@AuNP, and Cys@AuNP bioconjugates, respectively. This approach was also successful in the quantification of RNH in spiked serum samples.
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Aminoácidos/química , Antiulcerosos/sangue , Corantes Fluorescentes/química , Ouro/química , Nanopartículas/química , Ranitidina/sangue , Carbono/química , Transferência Ressonante de Energia de Fluorescência/métodos , Humanos , Limite de DetecçãoRESUMO
INTRODUCTION: Diabetic retinopathy (DR) is one of the major vision-threatening causes worldwide. Searching for an individualized therapeutic strategy to prevent its progress is challenging. OBJECTIVE: This work aimed to investigate the association of angiogenesis-inducer vascular endothelial growth factor (VEGF) gene family and related receptor variants (rs833069, rs12366035, rs7664413, rs7993418, and rs2305948) with susceptibility of DR and the response to 1 dose of aflibercept treatment in type 2 diabetes mellitus (T2DM). METHODS: Consecutive eligible patients with T2DM (n = 125) and 110 unrelated controls were enrolled in this preliminary prospective case-controlled study. Genotyping was identified using TaqMan real-time PCR. Adjusted odds ratio (OR) with 95% confidence interval (CI) was applied to assess the strength of the association with the clinical/ophthalmological characteristics and early response to intravitreal aflibercept treatment in terms of improved visual acuity (BCVA) and central macular thickness (CMT). RESULTS: We found that both VEGFB rs12366035 and VEGFC rs7664413 conferred higher risk for DR progression under allelic (OR [95% CI]: 1.71 [1.07-2.74]), homozygote comparison (3.55 [1.32-9.57]), and recessive (3.77 [1.43-9.93]) models for the former and under allelic (2.09 [1.25-3.490, homozygote comparison (2.76 [1.02-7.45]), and recessive (2.62 [0.98-6.98] models for the latter. In contrast, VEGFR1 rs7993418 conferred protection against DR under heterozygote comparison and dominant models. The rs12366035*T/T genotype showed the worst pretreatment BCVA score (0.35 ± 0.24) compared to other corresponding genotypes (0.66 ± 0.26 in C/T and 0.54 ± 0.25 in C/C carriers) (p = 0.008). Meanwhile, patients with rs7993418*G/G of VEGFR1 exhibited a significant reduction in CMT after aflibercept injection (12.26 ± 35.43 µ in G/G vs. 3.57 ± 8.74 µ in A/A) (p = 0.037). CONCLUSIONS: Polymorphisms of the studied VEGF/receptors could be considered as genetic risk factors of DM/DR development and could play an important role in aflibercept early response for DR patients in the study population.
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Retinopatia Diabética/genética , Macula Lutea/patologia , Edema Macular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Acuidade Visual , Inibidores da Angiogênese/administração & dosagem , Estudos de Casos e Controles , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/tratamento farmacológico , Feminino , Humanos , Injeções Intravítreas , Edema Macular/diagnóstico , Edema Macular/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Tomografia de Coerência Óptica/métodos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
A new series of 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine linked sulfonamide derivatives 12a-n was designed and synthesized according to the structure of well-established V600EBRAF inhibitors. The terminal sulfonamide moiety was linked to the pyrimidine ring via either ethylamine or propylamine bridge. The designed series was tested at fixed concentration (1 µM) against V600EBRAF, finding that 12e, 12i and 12l exhibited the strongest inhibitory activity among all target compounds and 12l had the lowest IC50 of 0.49 µM. They were further screened on NCI 60 cancer cell lines to reveal that 12e showed the most significant growth inhibition against multiple cancer cell lines. Therefore, cell cycle analysis of 12e was conducted to investigate the effect on cell cycle progression. Finally, virtual docking studies was performed to gain insights for the plausible binding modes of vemurafenib, 12i, 12e and 12l.
Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Simulação de Acoplamento Molecular , Mutação de Sentido Incorreto , Neoplasias , Proteínas Proto-Oncogênicas B-raf , Sulfonamidas , Substituição de Aminoácidos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
Patients with limited English proficiency (LEP) have disproportionately lower rates of cancer screening than English-proficient patients. Given the multifactorial nature of screening disparities, strategies to improve screening rates must address barriers within and outside of the clinic setting. The objectives of this study were to understand local barriers from multiple stakeholder perspectives, to identify potential multilevel intervention approaches, and to mobilize community-engaged intervention decision making and planning. This participatory formative evaluation approach employed needs assessment and user engagement in order to enhance intervention usefulness and relevance. The study took place in several stages and involved clinic and community partners in a small metropolitan area of the Midwest USA. Interviews were conducted with LEP patients (n = 9) who had not completed three recommended screenings (breast, cervical, and colorectal), primary care providers (n = 5), medical interpreter (n = 5), and community members (n = 3). These highlighted multilevel barriers including limited patient understanding of preventive health, time and cost constraints, and variable roles of language interpreters. The literature was also reviewed to identify interventions used with similar populations. Findings from this review suggest that interventions are largely focused on single population groups or address single screening barriers. Finally, a community-academic summit (n = 48 participants) was held to review results and develop recommendations for community and clinic interventions. Findings from this study indicate that it is possible to engage a diverse group of stakeholders in strategies that are responsive to health care providers and patients, including LEP patients from heterogeneous backgrounds.