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1.
ChemMedChem ; 17(1): e202100544, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34595843

RESUMO

Eleven small-molecular-weight compounds and three cyclic peptides were synthesized and evaluated for binding to hypoxia-inducible factor-1α (HIF-1α). Microscale thermophoresis analysis identified peptide [19 F]SFB-link-c-(Ppg)LLFVY 3 and small-molecule inhibitor 5 as potent HIF-1α binding compounds with KD values of 0.46±0.2 µM and 7.8±3.4 µM, respectively. Both compounds represent novel HIF-1α-targeting compounds that are predicted to interact with the PAS-B region of HIF-1α, as confirmed with molecular docking studies. Lead structures 3 and 5 were further radiolabelled with fluorine-18 for positron emission tomography (PET) imaging agents targeting HIF-1α in vivo.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Peptídeos Cíclicos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Radioisótopos de Flúor , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Estrutura Molecular , Peso Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
2.
J Med Chem ; 64(21): 15671-15689, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34672630

RESUMO

Positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) with gallium-68 (68Ga) and fluorine-18 (18F) radiotracers has aroused tremendous interest over the past few years. The use of organosilicon-[18F]fluoride acceptors (SiFA) conjugated to urea-based peptidomimetic PSMA inhibitors provides a "kit-like" multidose synthesis technology. Nine novel 18F-labeled SiFA-bearing PSMA inhibitors with different linker moieties were synthesized and analyzed for their in vitro binding against [125I]I-TAAG-PSMA in LNCaP cells. IC50 values ranged from 58-570 nM. Among all compounds, [18F]SiFA-Asp2-PEG3-PSMA (IC50 = 125 nM) showed the highest tumor uptake in LNCaP tumors (SUV60min 0.73). A substantial increase in molar activity (Am) (from 7.5 ± 0.5 to 86 ± 3 GBq/µmol) led to a significant increase in LNCaP tumor uptake (SUV60min 1.18; Δ 0.45 corresponding to +62%). In vivo blocking with DCFPyL resulted in -32% uptake after 60 min. The SiFA-isotopic exchange chemistry offers a method that is readily adaptable for a "kit-type" labeling procedure and clinical translation.


Assuntos
Tomografia por Emissão de Pósitrons , Antígeno Prostático Específico/antagonistas & inibidores , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos/farmacologia , Ureia/análogos & derivados , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Radioisótopos de Flúor , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Antígeno Prostático Específico/análise , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/química , Ureia/farmacologia
3.
ACS Omega ; 6(30): 19983-19994, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34337272

RESUMO

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the coronavirus disease of 2019 (COVID-19). Its genome encodes two open reading frames for two large proteins, PP1a and PP1ab. Within the two polypeptide stretches, there are two proteases that process the large proteins into 15 discrete proteins essential for the assembly of the virion during its replication. We describe herein the cloning of the genes for these discrete proteins optimized for expression in Escherichia coli, production of the proteins, and their purification to homogeneity. These included all but six: NSP6, which possesses eight transmembrane regions, and five that are small proteins/peptides (E, ORF3b, ORF6, ORF7b, and ORF10). These proteins are intended for experimental validation of small-molecule binders as molecular template hits. The proof of concept was established with the ADP-ribosylhydrolase (ARH) domain of NSP3 in discovery of small-molecule templates that could serve as the basis for further optimization. The hit molecules include one submicromolar and a few low-micromolar binders to the ARH domain. Availability of these proteins in soluble forms opens up the opportunity for discoveries of novel templates with the potential for anti-COVID-19 pharmaceuticals.

4.
ACS Med Chem Lett ; 12(5): 798-804, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34055228

RESUMO

Recent experimental evidence demonstrated an aberrant overexpression of cyclooxygenase-1 (COX-1) in various cancers, which has stimulated the development of COX-1-selective inhibitors as promising anticancer drugs and cancer imaging agents. Herein we describe the synthesis and validation of 3-(furan-2-yl)-N-aryl 5-amino-pyrazoles as a novel class of COX-1 inhibitors, including molecular docking studies. Among all tested compounds, 4-(5-azido-3-(furan-2-yl)-1H-pyrazol-1-yl)benzoic 17 displayed a favorable COX-1 inhibition and selectivity profile (COX-1 IC50 = 0.1 µM, SI >1000 over COX-2). Compound 17 was selected as a lead structure for developing the novel COX-1-selective fluorescent probe 22. Fluorescent probe 22 was prepared via click chemistry by installing a nitro-benzoxadiazole motif as a fluorophore into the 3-(furan-2-yl)-N-aryl 5-amino-pyrazole scaffold. Fluorescence probe 22 was tested in ovarian cancer cell line OVCAR-3, confirming its usefulness for targeting and visualizing COX-1 in living cells with confocal microscopy.

5.
J Am Chem Soc ; 143(14): 5497-5507, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33784084

RESUMO

Genetically encoded macrocyclic peptide libraries with unnatural pharmacophores are valuable sources for the discovery of ligands for many targets of interest. Traditionally, generation of such libraries employs "early stage" incorporation of unnatural building blocks into the chemically or translationally produced macrocycles. Here, we describe a divergent late-stage approach to such libraries starting from readily available starting material: genetically encoded libraries of peptides. A diketone linchpin 1,5-dichloropentane-2,4-dione converts peptide libraries displayed on phage to 1,3-diketone bearing macrocyclic peptides (DKMP): shelf-stable precursors for Knorr pyrazole synthesis. Ligation of diverse hydrazine derivatives onto DKMP libraries displayed on phage that carries silent DNA-barcodes yields macrocyclic libraries in which the amino acid sequence and the pharmacophore are encoded by DNA. Selection of this library against carbonic anhydrase enriched macrocycles with benzenesulfonamide pharmacophore and nanomolar Kd. The methodology described in this manuscript can graft diverse pharmacophores into many existing genetically encoded phage libraries and significantly increase the value of such libraries in molecular discoveries.


Assuntos
Compostos Macrocíclicos/química , Biblioteca de Peptídeos , Sequência de Aminoácidos , Descoberta de Drogas , Ligantes , Compostos Macrocíclicos/metabolismo
6.
Chemistry ; 27(10): 3326-3337, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32786126

RESUMO

Live-cell imaging with fluorescent probes is an essential tool in chemical biology to visualize the dynamics of biological processes in real-time. Intracellular disease biomarker imaging remains a formidable challenge due to the intrinsic limitations of conventional fluorescent probes and the complex nature of cells. This work reports the in cellulo assembly of a fluorescent probe to image cyclooxygenase-2 (COX-2). We developed celecoxib-azide derivative 14, possessing favorable biophysical properties and excellent COX-2 selectivity profile. In cellulo strain-promoted fluorogenic click chemistry of COX-2-engaged compound 14 with non/weakly-fluorescent compounds 11 and 17 formed fluorescent probes 15 and 18 for the detection of COX-2 in living cells. Competitive binding studies, biophysical, and comprehensive computational analyses were used to describe protein-ligand interactions. The reported new chemical toolbox enables precise visualization and tracking of COX-2 in live cells with superior sensitivity in the visible range.


Assuntos
Química Click , Corantes Fluorescentes/química , Azidas , Ciclo-Oxigenase 2 , Diagnóstico por Imagem
7.
J Org Chem ; 86(2): 1612-1621, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33369429

RESUMO

The development of new chemical tools with improved properties is essential to chemical and cell biology. Of particular interest is the development of mimics of small molecules with important cellular function that allow the direct observation of their trafficking in a cell. To this end, a novel 15-azasterol has been designed and synthesized as a luminescent cholesterol mimic for the monitoring of cholesterol trafficking. The brightness of this probe, which is ∼32-times greater than the widely used dehydroergosterol probe, is combined with resistance to photobleaching in solution and in human fibroblasts and an exceptionally large Stokes-like shift of ∼150-200 nm. The photophysical properties of the probe have been studied experimentally and computationally, suggesting an intersystem crossing to the triplet excited state with subsequent phosphorescent decay. Molecular dynamics simulations show a similar binding mode of cholesterol and the azasterol probe to NPC proteins, demonstrating the structural similarity of the probe to cholesterol.


Assuntos
Colesterol , Fluorescência , Humanos
8.
J Med Chem ; 63(17): 9540-9562, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787141

RESUMO

Vancomycin-resistant enterococci (VRE) are the second leading cause of hospital-acquired infections (HAIs) attributed to a drug-resistant bacterium in the United States, and resistance to the frontline treatments is well documented. To combat VRE, we have repurposed the FDA-approved carbonic anhydrase drug acetazolamide to design potent antienterococcal agents. Through structure-activity relationship optimization we have arrived at two leads possessing improved potency against clinical VRE strains from MIC = 2 µg/mL (acetazolamide) to MIC = 0.007 µg/mL (22) and 1 µg/mL (26). Physicochemical properties were modified to design leads that have either high oral bioavailability to treat systemic infections or low intestinal permeability to treat VRE infections in the gastrointestinal tract. Our data suggest the intracellular targets for the molecules are putative α-carbonic and γ-carbonic anhydrases, and homology modeling and molecular dynamics simulations were performed. Together, this study presents potential anti-VRE therapeutic options to provide alternatives for problematic VRE infections.


Assuntos
Acetazolamida/química , Acetazolamida/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Desenho de Fármacos , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Acetazolamida/farmacocinética , Acetazolamida/toxicidade , Animais , Antibacterianos/farmacocinética , Antibacterianos/toxicidade , Células CACO-2 , Anidrases Carbônicas/química , Anidrases Carbônicas/metabolismo , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade , Distribuição Tecidual
9.
J Family Med Prim Care ; 9(1): 243-246, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32110598

RESUMO

AIMS: The present study was conducted to determine correlation between peri-implantitis and periodontitis in adjacent teeth. MATERIALS AND METHODS: The present study was conducted on 58 patients with 84 dental implants. They were divided into two groups, group I (50) was with peri-implantitis and group II (34) was without it. In all patients, probing depth (PD), gingival recession (GR), and clinical attachment loss (CAL) was calculated around implant, adjacent to implant and on contralateral side. Obtained data were statistically analyzed using statistical software IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp with one-way analysis of variance. RESULTS: Males were 30 with 52 dental implants and females were 28 with 32 dental implants. CAL was 5.82 ± 0.52 in group I and 3.62 ± 0.63 in group II (P = 0.001) around implants. PD was 4.28 ± 1.26 in group I and 2.20 ± 0.52 in group II around adjacent teeth (P = 0.002). PD around contralateral teeth was significant (P = 0.05) in group I (3.18 ± 1.01) and group II (2.71 ± 0.73). CONCLUSION: Periodontitis has negative effect on implant success. Teeth adjacent to dental implant plays an important role in deciding the success or failure of implant. Maintenance of periodontal health is of paramount importance for successful implant therapy.

10.
Synth Commun ; 49(11): 1436-1443, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-33093687

RESUMO

AT13387 is an orally bioavailable clinical candidate developed to inhibit theheat shock protein 90 (Hsp90). This article describes a modified synthetic route for the multi-gram production of AT13387 in 46% overall yield. The modified synthetic route is short, avoids stringent reaction conditions and difficult purifications, which led to increase in an overall yield.

11.
Bioorg Med Chem Lett ; 29(3): 420-423, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30587447

RESUMO

Proteasome-mediated degradation of proteins is a vital cellular process and is performed by the ubiquitin-dependent proteasome system (UPS) and the ubiquitin-independent proteasome system (UIPS). While both systems are necessary to maintain healthy cell function, many disease states are characterized by reduced activity of the UPS, and the UIPS cannot by itself maintain proper protein levels. It has been suggested that the 20S core particle (20S CP), the isoform of the proteasome in the UIPS that can degrade proteins without a ubiquitin tag, can be stimulated with a small molecule to assist the 20S CP to accept and hydrolyze substrates more rapidly. Several small molecule stimulators of the 20S CP have since been discovered, including AM-404, an arachidonic acid derivative. AM-404 has previously been shown to inhibit fatty acid amide hydrolase activity. We wished to evaluate what structural components of AM-404 are required to stimulate the 20S CP with the long-term goal of using this information to design a stimulator with better drug-like qualities. We synthesized numerous derivatives of AM-404, varying the chain length, substitutions, and degree of unsaturation. Through this endeavor, we obtained several molecules capable of stimulating the 20S CP to various degrees. We discovered that though chain length is important, the presence of a cis-alkene in a specific location in the aliphatic chain has the greatest impact on the ability to stimulate the 20S CP. Two of the derivatives maintain modest stimulatory activity, and have improved toxicity over AM-404.


Assuntos
Ácidos Araquidônicos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ácidos Araquidônicos/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
12.
J Med Chem ; 61(5): 1833-1844, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29420887

RESUMO

A group of glutathione S-transferase π (GSTπ) activatable O2-(sulfonylethyl derived) diazeniumdiolates 5-12 were designed and synthesized. These compounds could be activated by GSTπ to initiate the ß-elimination reaction, liberating an active vinyl sulfone-based GSH derivative and a diazeniumdiolate anion which subsequently releases NO in situ. The most active compound 6 released relatively high levels of NO and inhibited proliferation of melanoma B16 cells, superior to a diazeniumdiolate-based anticancer agent JS-K (1). Importantly, 6 had 8-fold less inhibitory activity against normal epithelial JB6 Cl 30-7b cells. The inhibitory activity of 6 could be diminished by an NO scavenger or GSTπ inhibitor. Furthermore, 6 induced nitration of mitochondrial tyrosine in B16 cells and inoculated B16 tumors in mice, which might be responsible for oxidation of protein leading to tumor suppression. Finally, 6 significantly retarded the B16 cells growth in a mouse xenograft model. These findings suggest that 6 may have a potential to treat melanoma.


Assuntos
Compostos Azo/farmacologia , Glutationa S-Transferase pi/farmacologia , Melanoma Experimental/tratamento farmacológico , Animais , Antineoplásicos , Compostos Azo/síntese química , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Células Epiteliais , Xenoenxertos , Humanos , Melanoma Experimental/patologia , Camundongos , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico
13.
J Contemp Dent Pract ; 18(6): 479-483, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28621278

RESUMO

INTRODUCTION: One of the common findings encountered by the clinician at the end of orthodontic treatment is the apical root resorption. Root resorption occurs to various degrees. A severe form of root resorption is characterized by shortening of root for more than 4 mm or more than one-third of the total tooth length. A low incidence rate of resorption is observed based on radiographic findings for the diagnosis of root resorption, panoramic radiography, and periapical radiography. Hence, we evaluated the accuracy of panoramic radiographic films for assessing the root resorption in comparison with the periapical films. MATERIALS AND METHODS: This study included the assessment of all the cases in which pre- and post-treatment radiographs were available for analysis of the assessment of the amount of root resorption. Complete records of 80 patients were analyzed. Examination of a total of 900 teeth was done. Mean age of the patients in this study was 21 years ranging from 11 to 38 years. The majority of the patients in the present study were females. All the treatments were carried out by registered experienced orthodontists having minimum experience of more than 10 years. All the cases were divided into two study groups. Group I comprised panoramic radiographic findings, while group II consisted of periapical radiographic findings. For the measurement of crown portion, root portion, and the complete root length, magnification loops of over 100 powers with parallax correction with inbuilt grids were used. Assessment of the tooth length and the crown length was done by the same observers. All the results were analyzed by Statistical Package for the Social Sciences software version 6.0. RESULTS: Maximum amount of root resorption was observed in case of maxillary central incisors and canines among group I and II cases respectively. However, nonsignificant difference was obtained while comparing the mean root resorption in relation to maxillary incisors and canines among the two study groups. While comparing the overall value of root resorption among the two study groups, a significant difference was obtained. The maximum value of tooth length in both the groups was observed in cases of maxillary canines. Significant differences were observed while comparing the tooth length of various teeth among the two study groups. Among the deviated forms of root shape, dilacera-tion was the most common form of root shape detected in both the study groups. CONCLUSION: Periapical radiographs are more efficient in the assessment of the shape and resorption of the root. CLINICAL SIGNIFICANCE: Thorough evaluation of periapical radiographs is necessary for detection of even minute levels of root resorption.


Assuntos
Radiografia Dentária/métodos , Radiografia Panorâmica , Reabsorção da Raiz/diagnóstico por imagem , Ápice Dentário/diagnóstico por imagem , Raiz Dentária/diagnóstico por imagem , Adolescente , Adulto , Criança , Dente Canino/diagnóstico por imagem , Humanos , Incisivo/diagnóstico por imagem , Ortodontia Corretiva/efeitos adversos , Adulto Jovem
14.
J Forensic Dent Sci ; 9(1): 20-23, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28584470

RESUMO

CONTEXT: Forensic odontology is one of the branches of dentistry, which played a very important role in identification of individuals in accident, natural and mass disaster, and civil unrest and in genocide crimes. In the absence of natural teeth, marking or labeling of denture plays a vital role in the personal identification. BACKGROUND: Various types of marking or labeling methods are reported. However, many are not according to the criteria put forth by American Dental Association or other professional association. Majority of these techniques may be time consuming and expansive, may not be standardized, long lasting and do not permit the incorporation of a large amount of information. AIM: The aim of this study is to find out a denture identification technique that should be easy, less expensive, long lasting, and standardized. MATERIALS AND METHODS: This article illustrates an inclusion denture casted metal technique of the individual national identification number printed in the patient's residence number or iquama or national identity card issued by the ministry of interior, Kingdom of Saudi Arabia is used as a denture marker in the lingual surface of mandibular denture. RESULTS: The label in this method is durable and can withstand high temperature, less chances of deterioration, visible radiographically, and provide all important information about individual that is standardized, reliable, and also accessible from any remote location. CONCLUSION: Hence, the proposed technique is an easy, less expensive, long lasting, radiographically visible, and standardized method of identification.

15.
Hip Pelvis ; 29(1): 1-14, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28316957

RESUMO

In total hip arthroplasty (THA), the accurate positioning of implants is the key to achieve a good clinical outcome. Computer-assisted orthopaedic surgery (CAOS) has been developed for more accurate positioning of implants during the THA. There are passive, semi-active, and active systems in CAOS for THA. Navigation is a passive system that only provides information and guidance to the surgeon. There are 3 types of navigation: imageless navigation, computed tomography (CT)-based navigation, and fluoroscopy-based navigation. In imageless navigation system, a new method of registration without the need to register the anterior pelvic plane was introduced. CT-based navigation can be efficiently used for pelvic plane reference, the functional pelvic plane in supine which adjusts anterior pelvic plane sagittal tilt for targeting the cup orientation. Robot-assisted system can be either active or semi-active. The active robotic system performs the preparation for implant positioning as programmed preoperatively. It has been used for only femoral implant cavity preparation. Recently, program for cup positioning was additionally developed. Alternatively, for ease of surgeon acceptance, semi-active robot systems are developed. It was initially applied only for cup positioning. However, with the development of enhanced femoral workflows, this system can now be used to position both cup and stem. Though there have been substantial advancements in computer-assisted THA, its use can still be controversial at present due to the steep learning curve, intraoperative technical issues, high cost and etc. However, in the future, CAOS will certainly enable the surgeon to operate more accurately and lead to improved outcomes in THA as the technology continues to evolve rapidly.

16.
Nat Commun ; 8(1): 1, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28232747

RESUMO

Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Química Click/métodos , Inibidores de Ciclo-Oxigenase 2/síntese química , Ciclo-Oxigenase 2/química , Edema/tratamento farmacológico , Pirazóis/síntese química , Triazóis/síntese química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Carragenina , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Edema/induzido quimicamente , Edema/enzimologia , Edema/patologia , Feminino , Expressão Gênica , Membro Posterior , Humanos , Cinética , Simulação de Acoplamento Molecular , Estrutura Secundária de Proteína , Pirazóis/farmacologia , Ratos , Relação Estrutura-Atividade , Termodinâmica , Triazóis/farmacologia
17.
Org Biomol Chem ; 14(30): 7250-7, 2016 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-27383140

RESUMO

The cyclooxygenase-2 (COX-2) enzyme is overexpressed in a variety of cancers and mediates inflammatory processes that aid the growth and progression of malignancies. Three novel and selective fluorescent COX-2 inhibitors have been designed and synthesized on the basis of previously reported pyrimidine-based COX-2 inhibitors and the 7-nitrobenzofurazan fluorophore. In vitro evaluation of COX-1/COX-2 isozyme inhibition identified N-(2-((7-nitro-benzo[c][1,2,5]oxadiazol-4-yl)amino)propyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoro-methyl)-pyrimidin-2-amine (6) as a novel potent and selective COX-2 inhibitor (IC50 = 1.8 µM). Lead compound (6) was further evaluated for its ability to selectively visualize COX-2 isozyme in COX-2 expressing human colon cancer cell line HCA-7 using confocal microscopy experiments.


Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Corantes Fluorescentes/síntese química , Oxidiazóis/síntese química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Humanos , Estrutura Molecular , Imagem Óptica/métodos , Oxidiazóis/farmacologia , Relação Estrutura-Atividade
18.
J Contemp Dent Pract ; 17(5): 408-13, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27443368

RESUMO

BACKGROUND: Some relation exists between oral and general health with progressive aging. Certain risk factors are common between oral and systemic diseases. Absence of teeth also affects the oral health by altering the quality of life. Hence, the nutritional changes occurring in elderly patients following prosthodontic rehabilitation are evaluated. MATERIALS AND METHODS: A total of 250 patients who underwent prosthodontic treatment for missing teeth were included for the study. Twice measurement of nutritional parameters was done: Initially at the time of diagnosis and then 5 months following commencement of the prosthodontic treatment. Dental analysis, evaluation of the diet, anthropometric assessment, and analysis of serum biochemical values were done in all the patients and tabulated records were maintained. Independent Student's t test and Tukey's test were done to assess the level of significance. RESULTS: A total of 250 patients were included for the study. The complete denture (CD) group showed the highest alteration in the mean values of the nutritional parameters followed by the removable partial denture group. A significant change was seen in the body mass index, protein, carbohydrate, and iron levels among the different patients who were grouped based on the mode of treatment modality. The CD group showed significantly higher mean change in carbohydrates value compared with mean change in patients receiving fixed treatment. CONCLUSION: Both nutrition and diet form an integral part of the prosthodontic treatment to maintain the health of elderly population. CLINICAL SIGNIFICANCE: With the advancement in the level of edentulism, rehabilitation by prosthetic treatment has become progressively important to restore and improve dietary parameters.


Assuntos
Arcada Edêntula , Estado Nutricional , Prostodontia , Qualidade de Vida , Idoso , Prótese Total , Prótese Parcial Fixa , Prótese Parcial Removível , Feminino , Avaliação Geriátrica , Nível de Saúde , Humanos , Arcada Edêntula/reabilitação , Arcada Parcialmente Edêntula/reabilitação , Masculino , Mastigação , Saúde Bucal , Perda de Dente
19.
Bioorg Med Chem Lett ; 26(6): 1516-1520, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26898334

RESUMO

Cyclooxygenase-2 (COX-2) is the key enzyme in the prostaglandin synthesis pathway which is involved in various pathophysiological conditions. The enzyme is membrane bound and located inside of the endoplasmic reticulum and nuclear membrane. Effective perfusion of inhibitors to the active site requires lipophilic drugs, which consequently display high unspecific background accumulation, for example, in fatty tissues. The objective of this work was the development of a small molecule radiolabeled with a long-lived iodine radioisotope to enable longer imaging times and better target-to-background ratios. A group of iodinated compounds (8-10) was synthesized and identified as selective COX-2 inhibitors (COX-2 IC50=0.85-13 µM). Molecular docking results provided the theoretical support for the experimental COX-2 inhibition data. Furthermore, a novel (125)I-containing trifluoro-pyrimidine compound ([(125)I]Pyricoxib) was prepared via radioiododestannylation reaction as potent and selective COX-2 inhibitor. Radiosynthesis of [(125)I]Pyricoxib was accomplished with innovative fluorous chemistry using fluorous chloroamine-T (F-CAT) as novel oxidizing agent in high radiochemical yields of 91 ± 4%.


Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Sulfonas/síntese química , Sulfonas/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Humanos , Radioisótopos do Iodo , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/química , Relação Estrutura-Atividade , Sulfonas/química
20.
J Enzyme Inhib Med Chem ; 31(6): 1018-28, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26403939

RESUMO

The carboxylic acid group (-COOH) present in classical NSAIDs is partly responsible for the gastric toxicity associated with the administration of these drugs. This concept has been extensively proven using NSAID prodrugs. However, the screening of NSAIDs with no carboxylic acid at all has been neglected. The goal of this work was to determine if new NSAID derivatives devoid of acidic moieties would retain the anti-inflammatory activity of the parent compound, without causing gastric toxicity. To test this concept, we replaced the carboxylic acid group in ibuprofen, flurbiprofen, and naproxen with three ammonium moieties. We tested the resulting water-soluble NSAID derivatives for anti-inflammatory and ulcerogenic activity in vitro and in vivo. In this regard, we observed that all non-acidic NSAIDs exerted a potent anti-inflammatory activity, suggesting that the acid group in commercial 2-phenylpropionic acid NSAIDs not be an essential requirement for anti-inflammatory activity. These data provide complementary evidence supporting the discontinuation of ulcerogenic acidic NSAIDs.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios/farmacologia , Ácidos Carboxílicos/química , Anti-Inflamatórios/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
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