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1.
Mol Cell Biol ; 39(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31501275

RESUMO

The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription. The MYC inhibitor Omomyc can reduce the ability of MYC to bind specific box sequences in promoters of MYC target genes by binding directly to E box sequences as demonstrated by chromatin immunoprecipitation (CHIP). Here, we demonstrate by both a proximity ligation assay (PLA) and double chromatin immunoprecipitation (ReCHIP) that Omomyc preferentially binds to Max, not Myc, to mediate inhibition of MYC-mediated transcription by replacing MYC/MAX heterodimers with Omomyc/MAX heterodimers. The formation of Myc/Max and Omomyc/Max heterodimers occurs cotranslationally; Myc, Max, and Omomyc can interact with ribosomes and Max RNA under conditions in which ribosomes are intact. Taken together, our data suggest that the mechanism of action of Omomyc is to bind DNA as either a homodimer or a heterodimer with Max that is formed cotranslationally, revealing a novel mechanism to inhibit the MYC oncogene. We find that in vivo, Omomyc distributes quickly to kidneys and liver and has a short effective half-life in plasma, which could limit its use in vivo.

2.
Virus Res ; 270: 197662, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301331

RESUMO

Human adenovirus type 4 (HAdV4) is an etiological agent of acute respiratory disease (ARD) in pediatric and adult patients. HAdV4 strains can be divided into two major genomic clusters, namely prototype (p)-like viruses and a-like viruses. Here, the complete genome sequence of HAdV4 strain GZ01, isolated from a child with ARD in southern China, is first reported and analyzed. This strain was determined to be of the 4a1 genome-type based on in silico restriction profiles. Then, a replication-competent rAd4DsRed virus, containing the HAdV4 GZ01 infectious genome and expressing the reporter molecule DsRed, was generated and characterized. Recombinant rAd4DsRed can infect AD293, hamster, and mouse cells in which DsRed protein was expressed. No changes in antigenicity and genome replication were detected for rAd4DsRed and wild-type HAdV4. Mice immunized with rAd4DsRed was elicited a marked antibody response to DsRed. A rapid method of testing neutralizing antibodies against HAdV3 and HAdV4 was also established using a mixture of rAd4DsRed and rAd3EGFP. Our results provide the foundation to develop HAdV4 vaccines, potential vector platforms for vaccine and gene therapy, and rapid methods for serological and antiviral screening.

3.
Molecules ; 24(12)2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226791

RESUMO

Stapled α-helical peptides represent an emerging superclass of macrocyclic molecules with drug-like properties, including high-affinity target binding, protease resistance, and membrane permeability. As a model system for probing the chemical space available for optimizing these properties, we focused on dual Mdm2/MdmX antagonist stapled peptides related to the p53 N-terminus. Specifically, we first generated a library of ATSP-7041 (Chang et al., 2013) analogs iteratively modified by L-Ala and D-amino acids. Single L-Ala substitutions beyond the Mdm2/(X) binding interfacial residues (i.e., Phe3, Trp7, and Cba10) had minimal effects on target binding, α-helical content, and cellular activity. Similar binding affinities and cellular activities were noted at non-interfacial positions when the template residues were substituted with their d-amino acid counterparts, despite the fact that d-amino acid residues typically 'break' right-handed α-helices. d-amino acid substitutions at the interfacial residues Phe3 and Cba10 resulted in the expected decreases in binding affinity and cellular activity. Surprisingly, substitution at the remaining interfacial position with its d-amino acid equivalent (i.e., Trp7 to d-Trp7) was fully tolerated, both in terms of its binding affinity and cellular activity. An X-ray structure of the d-Trp7-modified peptide was determined and revealed that the indole side chain was able to interact optimally with its Mdm2 binding site by a slight global re-orientation of the stapled peptide. To further investigate the comparative effects of d-amino acid substitutions we used linear analogs of ATSP-7041, where we replaced the stapling amino acids by Aib (i.e., R84 to Aib4 and S511 to Aib11) to retain the helix-inducing properties of α-methylation. The resultant analog sequence Ac-Leu-Thr-Phe-Aib-Glu-Tyr-Trp-Gln-Leu-Cba-Aib-Ser-Ala-Ala-NH2 exhibited high-affinity target binding (Mdm2 Kd = 43 nM) and significant α-helicity in circular dichroism studies. Relative to this linear ATSP-7041 analog, several d-amino acid substitutions at Mdm2(X) non-binding residues (e.g., d-Glu5, d-Gln8, and d-Leu9) demonstrated decreased binding and α-helicity. Importantly, circular dichroism (CD) spectroscopy showed that although helicity was indeed disrupted by d-amino acids in linear versions of our template sequence, stapled molecules tolerated these residues well. Further studies on stapled peptides incorporating N-methylated amino acids, l-Pro, or Gly substitutions showed that despite some positional dependence, these helix-breaking residues were also generally tolerated in terms of secondary structure, binding affinity, and cellular activity. Overall, macrocyclization by hydrocarbon stapling appears to overcome the destabilization of α-helicity by helix breaking residues and, in the specific case of d-Trp7-modification, a highly potent ATSP-7041 analog (Mdm2 Kd = 30 nM; cellular EC50 = 600 nM) was identified. Our findings provide incentive for future studies to expand the chemical diversity of macrocyclic α-helical peptides (e.g., d-amino acid modifications) to explore their biophysical properties and cellular permeability. Indeed, using the library of 50 peptides generated in this study, a good correlation between cellular permeability and lipophilicity was observed.


Assuntos
Aminoácidos/química , Peptídeos Penetradores de Células/química , Fragmentos de Peptídeos/química , Conformação Proteica , Sequência de Aminoácidos/genética , Substituição de Aminoácidos/genética , Aminoácidos/síntese química , Peptídeos Penetradores de Células/síntese química , Peptídeos Penetradores de Células/genética , Peptídeos Penetradores de Células/farmacologia , Dicroísmo Circular , Dipeptídeos/química , Humanos , Oligopeptídeos/química , Peptídeos Cíclicos/farmacologia , Permeabilidade/efeitos dos fármacos , Estrutura Secundária de Proteína , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/genética
4.
Bioorg Med Chem Lett ; 29(5): 700-706, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711390

RESUMO

A series of novel tetracyclic core-containing HCV NS5A inhibitors has been discovered. Incorporation of tetrahydropyran-substituted amino acid moiety improved their potency and yielded HCV NS5A inhibitors with a minimum potency shift from the GT1a strain compared to other genotypes and mutants. Compounds 53 and 54 showed the best potency profile and had reasonable half-times in rat PK studies. However, further optimization of their oral bioavailability is still needed in order to advance them for further development. [BMCL ABSTRACT] ©2000 Elsevier Science Ltd. All rights reserved.

5.
J Thorac Dis ; 10(Suppl 19): S2280-S2294, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30116607

RESUMO

Human mastadenovirus (HAdVs) can cause a broad spectrum of diseases in both children and adults, including acute respiratory infection, gastroenteritis, epidemic keratoconjunctivitis. Populations susceptible to adenovirus infection include children, immunocompromised patients and military recruits. To date, seven species (A-G) including more than 79 genotypes have been characterized, of which HAdV-B3, B4, B7 and the recently reemerged types 14 and 55 often lead to severe pneumonia. The live oral enteric-coated adenovirus type 4 and 7 vaccine, which was approved for use in US military personnel of 17 through 50 years of age, had been shown to be safe and highly effective in numerous clinical trials and by ongoing surveillance of febrile respiratory illness. However, there is currently no vaccine approved for general use in children and adults in any part of the world. This review article will summarize the epidemiological data available for adenovirus and the effectiveness of the adenovirus vaccine in the US military. It will also provide a brief overview of innovative vaccine strategies, animal models for vaccine evaluation, and issues regarding vaccine production.

6.
J Med Chem ; 61(9): 3984-4003, 2018 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29681153

RESUMO

We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Farmacorresistência Viral/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Cães , Genótipo , Hepacivirus/genética , Hepacivirus/metabolismo , Masculino , Ratos , Distribuição Tecidual
7.
BMC Cardiovasc Disord ; 18(1): 58, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29609545

RESUMO

BACKGROUND: The present study sought to explore the relationship of common cardiovascular disease risk factors and noncoding RNAs with essential hypertension (EH). METHODS: A total of 402 EH patients and 402 gender- and age-frequency matched healthy controls were enrolled in this study. Each participant received a questionnaire survey, physical examination and laboratory tests. Quantitative real-time polymerase chain reaction (qPCR) was performed to assess relative expression levels of six noncoding RNAs (NR_027032, NR_034083, NR_104181, miR-126, miR-143 and miR-145) in peripheral blood leucocytes. Multiple logistic regression analysis was used to estimate the risk of having EH between hypertensive and non-hypertensive patients. RESULTS: Analysis showed that participants with anxiety, high body mass index, abdominal obesity and family history of hypertension had higher risk for EH, whereas those with bland diet and occupational physical activities had lower risk for EH. qPCR assays showed that NR_027032 (P = 0.015) and NR_034083 (P = 0.004) were significantly reduced in EH patients compared with controls, whereas NR_104181 (P = 0.007), miR-143 (P = 0.005) and miR-145 (P = 0.015) were significantly elevated. After controlling the cardiovascular risk factors, multivariate analysis showed that lower expression levels of NR_034083 and higher expression levels of NR_104181 and miR-143 were risk factors for EH. CONCLUSIONS: EH is a result of environmental and epigenetic factors. Strikingly, NR_034083, NR_104181 and miR-143 may be correlated with the risk for EH development; therefore, epigenetic markers could be used to measure hypertension levels to help elucidate the pathogenesis of EH.


Assuntos
Hipertensão Essencial/genética , Leucócitos/química , RNA não Traduzido/genética , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Comorbidade , Epigênese Genética , Hipertensão Essencial/sangue , Hipertensão Essencial/diagnóstico , Hipertensão Essencial/epidemiologia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Estilo de Vida , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Fenótipo , Fatores de Proteção , RNA não Traduzido/sangue , Fatores de Risco
8.
Bioorg Med Chem ; 26(10): 2807-2815, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29598901

RESUMO

Macrocyclic α-helical peptides have emerged as a compelling new therapeutic modality to tackle targets confined to the intracellular compartment. Within the scope of hydrocarbon-stapling there has been significant progress to date, including the first stapled α-helical peptide to enter into clinical trials. The principal design concept of stapled α-helical peptides is to mimic a cognate (protein) ligand relative to binding its target via an α-helical interface. However, it was the proclivity of such stapled α-helical peptides to exhibit cell permeability and proteolytic stability that underscored their promise as unique macrocyclic peptide drugs for intracellular targets. This perspective highlights key learnings as well as challenges in basic research with respect to structure-based design, innovative chemistry, cell permeability and proteolytic stability that are essential to fulfill the promise of stapled α-helical peptide drug development.


Assuntos
Descoberta de Drogas/métodos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Animais , Humanos , Compostos Macrocíclicos/farmacocinética , Modelos Moleculares , Peptídeos/farmacocinética , Conformação Proteica em alfa-Hélice
9.
Bioorg Med Chem Lett ; 27(16): 3704-3708, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28711352

RESUMO

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.


Assuntos
Proteína ADAM17/antagonistas & inibidores , Hidantoínas/química , Hidantoínas/síntese química , Hidantoínas/farmacologia , Ácidos Pentanoicos/química , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Proteína ADAM17/metabolismo , Administração Oral , Animais , Área Sob a Curva , Cães , Ativação Enzimática/efeitos dos fármacos , Meia-Vida , Haplorrinos , Humanos , Hidantoínas/administração & dosagem , Hidantoínas/farmacocinética , Ácidos Pentanoicos/administração & dosagem , Ácidos Pentanoicos/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Curva ROC , Ratos , Relação Estrutura-Atividade
11.
Wei Sheng Yan Jiu ; 46(6): 905-912, 2017 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-29903198

RESUMO

OBJECTIVE: To understand the main environmental factors of hypertension, and to explore the relationship between hypertension and leukocyte long noncoding RNA. METHODS: A case-control study was conducted in a hospital in Fuzhou City by using stratified random sampling method between Nov. 2014 and Jun. 2015 including 382 essential hypertension patients and 382 control subjects. The related surveys included questionnaire investigation, physical examination and laboratory detection. Real-time PCR method was used to compare the expression of long non-coding RNA( NR_104181 and NR_027032) in the case group with that of in the control group. Multiple factor Logistic regression was used to analyze the association of environmental factors, long noncoding RNA and the risk of hypertension. RESULTS: Multiple factor Logistic regression analysis revealed that the main risk factors of hypertension included: salty diet( OR = 1. 732, 95% CI 1. 204-2. 493), anxiety( OR = 1. 746, 95% CI 1. 326-2. 298), BMI ≥ 24( OR = 1. 475, 95% CI 1. 030-2. 111), abdominal obesity( OR = 1. 836, 95% CI 1. 229-2. 742), family history of hypertension( OR = 3. 004, 95% CI 2. 118-4. 261). The main protective factor of hypertension included: physical activity( OR = 0. 776, 95% CI0. 620-0. 972). Wilcoxon rank sum test indicated that: The expression level of NR_104181 in hypertension was higher than that in control group, the difference was statistically significant( P < 0. 05). The expression level of NR_027032 in hypertension was lower than that in control health group, the difference was statistically significant( P < 0. 05). Multiple factor Logistic regression analysis showed that controlling for salty diet, anxiety, abdominal obesity and physical activity, peripheral blood leukocytes NR_104181 high expression( OR = 2. 658, 95% CI 1. 109-6. 370), NR_ 027032 low expression( OR = 0. 179, 95% CI 0. 057-0. 560) were possibly related to the risk of hypertension. CONCLUSION: Hypertension is the result of environmental factors and genetic factors, and lncRNA may be associated with the risk of hypertension.


Assuntos
Exposição Ambiental/efeitos adversos , Hipertensão/genética , Obesidade Abdominal/epidemiologia , RNA Longo não Codificante/genética , Estudos de Casos e Controles , China/epidemiologia , Humanos , Obesidade Abdominal/diagnóstico , Obesidade Abdominal/etnologia , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco
12.
J Med Chem ; 60(1): 290-306, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-27808515

RESUMO

We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.


Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Polimorfismo Genético , Pirrolidinas/química , Pirrolidinas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Linhagem Celular , Cães , Haplorrinos , Hepacivirus/genética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Humanos , Pirrolidinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Tiazóis/farmacocinética
13.
J Med Chem ; 59(22): 10228-10243, 2016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27792320

RESUMO

The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, we now describe the discovery of a novel series of chromane containing NS5A inhibitors. SAR studies around the "Z" group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the phenyl group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivatives as "Z" group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A inhibitors, such as compounds 14 and 25-28, with significantly improved potency against resistance-associated variants, such as GT2b, GT1a Y93H, and GT1a L31V. Compound 14 also showed reasonable PK exposures in preclinical species (rat and dog).


Assuntos
Antivirais/farmacologia , Cromanos/farmacologia , Descoberta de Drogas , Farmacorresistência Viral/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Cromanos/síntese química , Cromanos/química , Cães , Relação Dose-Resposta a Droga , Masculino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 26(19): 4851-4856, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27568086

RESUMO

As part of an ongoing effort in NS5A inhibition at Merck we now describe our efforts for introducing substitution around the tetracyclic indole core of MK-8742. Fluoro substitution on the core combined with the fluoro substitutions on the proline ring improved the potency against GT1a Y93H significantly. However, no improvement on GT2b potency was achieved. Limiting the fluoro substitution to C-1 of the tetracyclic indole core had a positive impact on the potency against the resistance associated variants, such as GT1a Y93H and GT2b, and the PK profile as well. Compounds, such as 62, with reduced potency shifts between wild type GT1a to GT2b, GT1a Y93H, and GT1a L31V were identified.


Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Imidazóis/farmacologia , Indóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacocinética , Benzofuranos/química , Benzofuranos/farmacocinética , Imidazóis/química , Imidazóis/farmacocinética , Indóis/química , Indóis/farmacocinética , Relação Estrutura-Atividade
16.
ACS Med Chem Lett ; 7(5): 498-501, 2016 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-27190600

RESUMO

In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.

17.
Arch Environ Occup Health ; 71(6): 330-337, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26654585

RESUMO

The present study was to evaluate workplace violence and examine its effect on job burnout and turnover attempt among medical staff in China. A total of 2,020 medical employees were selected from Fujian province by using stratified cluster sampling method. The Chinese version of the Workplace Violence Scale and the Maslach Burnout Inventory-General Survey were used to measure the workplace violence and job burnout, respectively. Other potential influencing factors for job burnout and turnover attempt were collected using a structured questionnaire. The incidence of workplace violence among medical staff was 48.0%. Workplace violence had a positive correlation with emotional exhaustion and cynicism and a negative correlation with professional efficacy. Workplace violence, marital status, employment type, working time (≥ 10 h/day), performance recognition, and life satisfaction were significant predictors for turnover attempt among Chinese medical staff.


Assuntos
Esgotamento Profissional/epidemiologia , Satisfação no Emprego , Corpo Clínico/psicologia , Reorganização de Recursos Humanos , Violência no Trabalho/psicologia , Local de Trabalho/psicologia , Adulto , Esgotamento Profissional/etiologia , China/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Reorganização de Recursos Humanos/estatística & dados numéricos , Prevalência , Violência no Trabalho/estatística & dados numéricos , Adulto Jovem
18.
Environ Sci Pollut Res Int ; 22(6): 4527-33, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25315932

RESUMO

In this study, 13 types of organic materials were oxidized using H2O2 in a continuous flow reactor under the condition of supercritical water. The effect of the operational parameters on the conversion of total organic carbon (TOC) and total nitrogen (TN) was investigated, and the resulting quality of treated water was analyzed. It was found that these materials were easily oxidized with a TOC conversion achieving 99% at temperature of 460 °C and TN conversion reaching 94% at temperature of 500 °C. Rice decomposition was rapid, with TOC and TN decomposition rates of 99% obtained within residence of 100 s at temperature of 460 °C. At temperature of 460 °C, pressure of 24 MPa, residence time of 100 s, and excess oxygen of 100%, the quality of treated water attained levels commensurate with China's Standards for Drinking Water Quality. Reaction rate equation parameters were obtained by fitting the experimental data to the differential equation obtained using the Runge-Kutta algorithm. The decrease of the TOC in water samples exhibited reaction orders of 0.95 for the TOC concentration and 0.628 for the oxygen concentration. The activation energy was 83.018 kJ/mol.


Assuntos
Ambiente Controlado , Alimentos , Resíduos de Alimentos , Eliminação de Resíduos/métodos , Navios , Purificação da Água/métodos , Carbono/análise , China , Peróxido de Hidrogênio/química , Cinética , Oxirredução , Oxigênio , Eliminação de Resíduos/instrumentação , Temperatura Ambiente , Purificação da Água/normas
19.
J Acoust Soc Am ; 131(6): 4399-408, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22712914

RESUMO

An acoustic method can provide a noninvasive, efficient and full-field reconstruction of aerodynamic fields in a furnace. A simple yet reasonable model is devised for reconstruction of a velocity field in a cross section of a tangential furnace from acoustic measurements based on typical physical characteristics of the field. The solenoidal component of the velocity field is modeled by a curved surface, derived by rotating a curve of Gaussian distribution, determined by six characteristic parameters, while the nonrotational component is governed by a priori knowledge. Thus the inverse problem is translated into determination of the characteristic parameters using a set of acoustic projection data. First numerical experiments were undertaken to simulate the acoustic measurement, so as to preliminarily validate the effectiveness of the model. Based on this, physical experiments under different operating conditions were performed in a pilot-scale setup to provide a further test. Hot-wire anemometry and strip floating were applied to compare with acoustic measurements. The acoustic measurements provided satisfactory consistency with both of these approaches. Nevertheless, for a field with a relatively large magnitude of air velocities, the acoustic measurement can give more reliable reconstructions. Extension of the model to measurements of hot tangential furnaces is also discussed.

20.
Bioorg Med Chem Lett ; 21(10): 3172-6, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21458257

RESUMO

TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Amidas/farmacologia , Inibidores Enzimáticos/farmacologia , Pirrolidinas/química , Tartaratos/química , Proteína ADAM17 , Amidas/síntese química , Amidas/química , Animais , Disponibilidade Biológica , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Ratos
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