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1.
Genome Med ; 10(1): 74, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30266093

RESUMO

BACKGROUND: Exome sequencing is now being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. One reason for this is the paucity of information about the clinical utility of exome sequencing in the prenatal setting. METHODS: We retrospectively reviewed indications, results, time to results (turnaround time, TAT), and impact of exome results for 146 consecutive "fetal exomes" performed in a clinical diagnostic laboratory between March 2012 and November 2017. We define a fetal exome as one performed on a sample obtained from a fetus or a product of conception with at least one structural anomaly detected by prenatal imaging or autopsy. Statistical comparisons were performed using Fisher's exact test. RESULTS: Prenatal exome yielded an overall molecular diagnostic rate of 32% (n = 46/146). Of the 46 molecular diagnoses, 50% were autosomal dominant disorders (n = 23/46), 41% were autosomal recessive disorders (n = 19/46), and 9% were X-linked disorders (n = 4/46). The molecular diagnostic rate was highest for fetuses with anomalies affecting multiple organ systems and for fetuses with craniofacial anomalies. Out of 146 cases, a prenatal trio exome option designed for ongoing pregnancies was performed on 62 fetal specimens, resulting in a diagnostic yield of 35% with an average TAT of 14 days for initial reporting (excluding tissue culture time). The molecular diagnoses led to refined recurrence risk estimates, altered medical management, and informed reproductive planning for families. CONCLUSION: Exome sequencing is a useful diagnostic tool when fetal structural anomalies suggest a genetic etiology, but other standard prenatal genetic tests did not provide a diagnosis.

2.
Biomark Res ; 6: 28, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30237882

RESUMO

Background: Metabolic syndrome is a cluster of abnormalities that increases the risk for type 2 diabetes and atherosclerosis. Plasma and serum water T2 from benchtop nuclear magnetic resonance relaxometry are early, global and practical biomarkers for metabolic syndrome and its underlying abnormalities. In a prior study, water T2 was analyzed against ~ 130 strategically selected proteins and metabolites to identify associations with insulin resistance, inflammation and dyslipidemia. In the current study, the analysis was broadened ten-fold using a modified aptamer (SOMAmer) library, enabling an unbiased search for new proteins correlated with water T2 and thus, metabolic health. Methods: Water T2 measurements were recorded using fasting plasma and serum from non-diabetic human subjects. In parallel, plasma samples were analyzed using a SOMAscan assay that employed modified DNA aptamers to determine the relative concentrations of 1310 proteins. A multi-step statistical analysis was performed to identify the biomarkers most predictive of water T2. The steps included Spearman rank correlation, followed by principal components analysis with variable clustering, random forests for biomarker selection, and regression trees for biomarker ranking. Results: The multi-step analysis unveiled five new proteins most predictive of water T2: hepatocyte growth factor, receptor tyrosine kinase FLT3, bone sialoprotein 2, glucokinase regulatory protein and endothelial cell-specific molecule 1. Three of the five strongest predictors of water T2 have been previously implicated in cardiometabolic diseases. Hepatocyte growth factor has been associated with incident type 2 diabetes, and endothelial cell specific molecule 1, with atherosclerosis in subjects with diabetes. Glucokinase regulatory protein plays a critical role in hepatic glucose uptake and metabolism and is a drug target for type 2 diabetes. By contrast, receptor tyrosine kinase FLT3 and bone sialoprotein 2 have not been previously associated with metabolic conditions. In addition to the five most predictive biomarkers, the analysis unveiled other strong correlates of water T2 that would not have been identified in a hypothesis-driven biomarker search. Conclusions: The identification of new proteins associated with water T2 demonstrates the value of this approach to biomarker discovery. It provides new insights into the metabolic significance of water T2 and the pathophysiology of metabolic syndrome.

3.
Genet Med ; 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30158690

RESUMO

PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective. METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization. RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS. CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

4.
Am J Hum Genet ; 103(1): 154-162, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29961569

RESUMO

TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.

5.
J Transl Med ; 15(1): 258, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258604

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is a highly prevalent condition that identifies individuals at risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Prevention of these diseases relies on early detection and intervention in order to preserve pancreatic ß-cells and arterial wall integrity. Yet, the clinical criteria for MetS are insensitive to the early-stage insulin resistance, inflammation, cholesterol and clotting factor abnormalities that characterize the progression toward type 2 diabetes and atherosclerosis. Here we report the discovery and initial characterization of an atypical new biomarker that detects these early conditions with just one measurement. METHODS: Water T2, measured in a few minutes using benchtop nuclear magnetic resonance relaxometry, is exquisitely sensitive to metabolic shifts in the blood proteome. In an observational cross-sectional study of 72 non-diabetic human subjects, the association of plasma and serum water T2 values with over 130 blood biomarkers was analyzed using bivariate, multivariate and logistic regression. RESULTS: Plasma and serum water T2 exhibited strong bivariate correlations with markers of insulin, lipids, inflammation, coagulation and electrolyte balance. After correcting for confounders, low water T2 values were independently and additively associated with fasting hyperinsulinemia, dyslipidemia and subclinical inflammation. Plasma water T2 exhibited 100% sensitivity and 87% specificity for detecting early insulin resistance in normoglycemic subjects, as defined by the McAuley Index. Sixteen normoglycemic subjects with early metabolic abnormalities (22% of the study population) were identified by low water T2 values. Thirteen of the 16 did not meet the harmonized clinical criteria for metabolic syndrome and would have been missed by conventional screening for diabetes risk. Low water T2 values were associated with increases in the mean concentrations of 6 of the 16 most abundant acute phase proteins and lipoproteins in plasma. CONCLUSIONS: Water T2 detects a constellation of early abnormalities associated with metabolic syndrome, providing a global view of an individual's metabolic health. It circumvents the pitfalls associated with fasting glucose and hemoglobin A1c and the limitations of the current clinical criteria for metabolic syndrome. Water T2 shows promise as an early, global and practical screening tool for the identification of individuals at risk for diabetes and atherosclerosis.


Assuntos
Biomarcadores/sangue , Espectroscopia de Ressonância Magnética , Síndrome Metabólica/sangue , Água/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Sanguíneas/metabolismo , Análise por Conglomerados , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Curva ROC , Sensibilidade e Especificidade , Adulto Jovem
6.
Org Lett ; 19(23): 6368-6371, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29135268

RESUMO

Functionalized bicyclic amino-azaheterocycles are rapidly accessed in a one-pot cross-coupling/reduction sequence enabled by the use of COware. Incompatible reagents are physically separated in a single reaction vessel to effect two chemoselective transformations-Suzuki-Miyaura cross-coupling and heteroarene reduction. The developed method allows access to novel heterocyclic templates, including semisaturated Hedgehog and dual PI3K/mTOR inhibitors, which show enhanced physicochemical properties compared to their unsaturated counterparts.

7.
Biochim Biophys Acta Proteins Proteom ; 1865(10): 1274-1286, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28698152

RESUMO

BACKGROUND: Three NPXY motifs and one FERM domain in CCM1 makes it a versatile scaffold protein for tethering the signaling components together within the CCM signaling complex (CSC). The cellular role of CCM1 protein remains inadequately expounded. Both phosphotyrosine binding (PTB) and pleckstrin homology (PH) domains were recognized as structurally related but functionally distinct domains. METHODS: By utilizing molecular cloning, protein binding assays and RT-qPCR to identify novel cellular partners of CCM1 and its cellular expression patterns; by screening candidate PTB/PH proteins and subsequently structurally simulation in combining with current X-ray crystallography and NMR data to defined the essential structure of PTB/PH domain for NPXY-binding and the relationship among PTB, PH and FERM domain(s). RESULTS: We identified a group of 28 novel cellular partners of CCM1, all of which contain either PTB or PH domain(s), and developed a novel classification system for these PTB/PH proteins based on their relationship with different NPXY motifs of CCM1. Our results demonstrated that CCM1 has a wide spectrum of binding to different PTB/PH proteins and perpetuates their specificity to interact with certain PTB/PH domains through selective combination of three NPXY motifs. We also demonstrated that CCM1 can be assembled into oligomers through intermolecular interaction between its F3 lobe in FERM domain and one of the three NPXY motifs. Despite being embedded in FERM domain as F3 lobe, F3 module acts as a fully functional PH domain to interact with NPXY motif. The most salient feature of the study was that both PTB and PH domains are structurally and functionally comparable, suggesting that PTB domain is likely evolved from PH domain with polymorphic structural additions at its N-terminus. CONCLUSIONS: A new ß1A-strand of the PTB domain was discovered and new minimum structural requirement of PTB/PH domain for NPXY motif-binding was determined. Based on our data, a novel theory of structure, function and relationship of PTB, PH and FERM domains has been proposed, which extends the importance of the NPXY-PTB/PH interaction on the CSC signaling and/or other cell receptors with great potential pointing to new therapeutic strategies. GENERAL SIGNIFICANCE: The study provides new insight into the structural characteristics of PTB/PH domains, essential structural elements of PTB/PH domain required for NPXY motif-binding, and function and relationship among PTB, PH and FERM domains.


Assuntos
Proteínas Sanguíneas/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fosfoproteínas/metabolismo , Fosfotirosina/metabolismo , Domínios de Homologia à Plecstrina/fisiologia , Domínios Proteicos/fisiologia , Motivos de Aminoácidos , Sítios de Ligação , Ligação Proteica
8.
ACS Med Chem Lett ; 8(1): 43-48, 2017 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-28105273

RESUMO

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

9.
J Med Chem ; 59(23): 10738-10749, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27933945

RESUMO

Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.


Assuntos
Inibidores Enzimáticos/farmacologia , Lactamas/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Lactamas/administração & dosagem , Lactamas/síntese química , Lactamas/química , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Distribuição Tecidual
10.
Adv Exp Med Biol ; 924: 165-169, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27753038

RESUMO

Circulating cell-free DNA (ccfDNA) is a promising diagnostic tool and its size fractionation is of interest. However, kits for isolation of ccfDNA available on the market are designed for small volumes hence processing large sample volumes is laborious. We have tested a new method that enables enrichment of ccfDNA from large volumes of plasma and subsequently allows size-fractionation of isolated ccfDNA into two fractions with individually established cut-off levels of ccfDNA length. This method allows isolation of low-abundant DNA as well as separation of long and short DNA molecules. This procedure may be important e.g., in prenatal diagnostics and cancer research that have been already confirmed by our primary experiments. Here, we report the results of selective separation of 200- and 500-bp long synthetic DNA fragments spiked in plasma samples. Furthermore, we size-fractionated ccfDNA from the plasma of pregnant women and verified the prevalence of fetal ccfDNA in all fractions.


Assuntos
DNA/sangue , DNA/isolamento & purificação , Biologia Molecular/métodos , Diagnóstico Pré-Natal/métodos , Sistema Livre de Células , DNA/genética , Feminino , Humanos , Reação em Cadeia da Polimerase/métodos , Gravidez , Reprodutibilidade dos Testes
11.
J Med Chem ; 59(11): 5356-67, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27167608

RESUMO

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Tiazóis/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
12.
J Neuroimmune Pharmacol ; 11(2): 279-93, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26829944

RESUMO

The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients with effective suppression of virus replication by combination antiretroviral therapy (cART). Several neurotransmitter systems were reported to be abnormal in HIV-infected patients, including the inhibitory GABAergic system, which mediates fine-tuning of neuronal processing and plays an essential role in cognitive functioning. To elucidate the role of abnormal GABAergic transmission in HAND, the expression of GABAergic markers was measured in 449 human brain specimens from HIV-infected patients with and without HAND. Using real-time polymerase chain reaction, immunoblotting and immunohistochemistry we found that the GABAergic markers were significantly decreased in most sectors of cerebral neocortex, the neostriatum, and the cerebellum of HIV-infected subjects. Low GABAergic expression in frontal neocortex was correlated significantly with high expression of endothelial cell markers, dopamine receptor type 2 (DRD2L), and preproenkephalin (PENK) mRNAs, and with worse performance on tasks of verbal fluency. Significant associations were not found between low GABAergic mRNAs and HIV-1 RNA concentration in the brain, the history of cART, or HIV encephalitis. Pathological evidence of neurodegeneration of the affected GABAergic neurons was not present. We conclude that abnormally low expression of GABAergic markers is prevalent in HIV-1 infected patients. Interrelationships with other neurotransmitter systems including dopaminergic transmission and with endothelial cell markers lend added support to suggestions that synaptic plasticity and cerebrovascular anomalies are involved with HAND in virally suppressed patients.


Assuntos
Complexo AIDS Demência/metabolismo , Neurônios GABAérgicos/metabolismo , Infecções por HIV/metabolismo , HIV-1 , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica/fisiologia , Complexo AIDS Demência/imunologia , Complexo AIDS Demência/psicologia , Estudos de Coortes , Neurônios GABAérgicos/imunologia , Glutamato Descarboxilase/biossíntese , Infecções por HIV/imunologia , Infecções por HIV/psicologia , Humanos , Neuroimunomodulação/fisiologia , Testes Neuropsicológicos , Córtex Pré-Frontal/imunologia
13.
Org Biomol Chem ; 13(40): 10131-5, 2015 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-26411833

RESUMO

Efficient conversion of ketones into kinetic enol phosphates under mild and accessible conditions has been realised using the developed methods with di-tert-butylmagnesium and bismesitylmagnesium. Optimisation of the quench protocol resulted in high yields of enol phosphates from a range of cyclohexanones and aryl methyl ketones, with tolerance of a range of additional functional units.


Assuntos
Carbono/química , Magnésio/química , Fosfatos/síntese química , Cetonas/química , Cinética , Estrutura Molecular , Fosfatos/química
14.
J Magn Reson Imaging ; 42(6): 1560-71, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25920095

RESUMO

PURPOSE: To quantify the change in cerebral spinal fluid (CSF) production rate and maximum systolic velocity in astronauts before and after exposure to microgravity and identify any physiologic trend and/or risk factor related to intracranial hypertension. MATERIALS AND METHODS: Following Institutional Review Board (IRB) approval, with waiver of informed consent, a retrospective review of 27 astronauts imaged at 3T was done. Qualitative analysis was performed on T2 -weighted axial images through the orbits for degree of flattening of the posterior globe according to the following grades: 0 = none, 1 = mild, 2 = moderate, and 3 = severe. One grade level change postflight was considered significant for exposure to intracranial hypertension. CSF production rate and maximum systolic velocity was calculated from cine phase-contrast magnetic resonance imaging and compared to seven healthy controls. RESULTS: Fourteen astronauts were studied. The preflight CSF production rate in astronauts was similar to controls (P = 0.83). Six astronauts with significant posterior globe flattening demonstrated a 70% increase in CSF production rate postflight compared to baseline (P = 0.01). There was a significant increase in CSF maximum systolic velocity in the subgroup without posterior globe flattening (P = 0.01). CONCLUSION: The increased postflight CSF production rate in astronauts with positive flattening is compatible with the hypothesis of microgravity-induced intracranial hypertension inferring downregulation in CSF production in microgravity that is upregulated upon return to normal gravity. Increased postflight CSF maximum systolic velocity in astronauts with negative flattening suggests increased craniospinal compliance and a potential negative risk factor to microgravity-induced intracranial hypertension.


Assuntos
Astronautas , Líquido Cefalorraquidiano/fisiologia , Hipertensão Intracraniana/etiologia , Hipertensão Intracraniana/patologia , Imagem por Ressonância Magnética/métodos , Ausência de Peso/efeitos adversos , Biomarcadores/líquido cefalorraquidiano , Líquido Cefalorraquidiano/citologia , Método Duplo-Cego , Humanos , Hidrodinâmica , Hipertensão Intracraniana/líquido cefalorraquidiano , Pressão Intracraniana , Masculino , Pessoa de Meia-Idade
15.
J Magn Reson Imaging ; 39(6): 1374-83, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24243801

RESUMO

PURPOSE: To implement high resolution diffusion tensor imaging (DTI) for visualization and quantification of peripheral nerves in human forearm. MATERIALS AND METHODS: This HIPAA-compliant study was approved by our Institutional Review Board and written informed consent was obtained from all the study participants. Images were acquired with T1 -and T2 -weighted turbo spin echo with/without fat saturation, short tau inversion recovery (STIR). In addition, high spatial resolution (1.0 × 1.0 × 3.0 mm(3) ) DTI sequence was optimized for clearly visualizing ulnar, superficial radial and median nerves in the forearm. Maps of the DTI derived indices, fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity (λ// ) and radial diffusivity (λ⊥ ) were generated. RESULTS: For the first time, the three peripheral nerves, ulnar, superficial radial, and median, were visualized unequivocally on high resolution DTI-derived maps. DTI delineated the forearm nerves more clearly than other sequences. Significant differences in the DTI-derived measures, FA, MD, λ// and λ⊥ , were observed among the three nerves. A strong correlation between the nerve size derived from FA map and T2 -weighted images was observed. CONCLUSION: High spatial resolution DTI is superior in identifying and quantifying the median, ulnar, and superficial radial nerves in human forearm. Consistent visualization of small nerves and nerve branches is possible with high spatial resolution DTI. These normative data could potentially help in identifying pathology in diseased nerves. J. Magn. Reson. Imaging 2014;39:1374-1383. © 2013 Wiley Periodicals, Inc.


Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Imagem de Tensor de Difusão/métodos , Antebraço/inervação , Nervo Mediano/anatomia & histologia , Nervo Radial/anatomia & histologia , Nervo Ulnar/anatomia & histologia , Adulto , Anisotropia , Feminino , Antebraço/anatomia & histologia , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Nervos Periféricos/anatomia & histologia , Valores de Referência , Adulto Jovem
16.
Drug Discov Today ; 18(23-24): 1158-72, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24051399

RESUMO

In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.


Assuntos
Química Farmacêutica/educação , Desenho de Drogas , Descoberta de Drogas/métodos , Classe Ia de Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Currículo , Indústria Farmacêutica/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Solubilidade
17.
Chemistry ; 19(29): 9655-62, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23765429

RESUMO

The direct microwave-mediated condensation between 3-oxetanone and primary amides and thioamides has delivered moderate to good yields of (hydroxymethyl)oxazoles and (hydroxymethyl)thiazoles. The reactions use a sustainable solvent and only require short reaction times. These are highly competitive methods for the construction of two classes of valuable heteroarenes, which bear a useful locus for further elaboration. Electronic structure calculations have shown that the order of events involves chalcogen atom attack at sp(3) carbon and alkyl-oxygen cleavage. The critical role of acid catalysis was shown clearly, and the importance of acid strength was demonstrated. The calculated barriers were also fully consistent with the observed order of thioamide and amide reactivity. Spontaneous ring opening involves a modest degree of C-O cleavage, moderating the extent of strain relief. On the acid-catalysed pathway, C-O cleavage is less extensive still, but proton transfer to the nucleofuge is well advanced with the carboxylic acid catalysts, and essentially complete with methanesulfonic acid.


Assuntos
Carbono/química , Calcogênios/química , Éteres Cíclicos/química , Oxazóis/síntese química , Oxigênio/química , Tiazóis/síntese química , Tioamidas/síntese química , Catálise , Computadores Moleculares , Micro-Ondas , Oxazóis/química , Solventes , Tiazóis/química , Tioamidas/química
18.
J Magn Reson Imaging ; 36(4): 920-7, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22689475

RESUMO

PURPOSE: To implement a diffusion tensor imaging (DTI) protocol for visualization of peripheral nerves in human forearm. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant study was approved by our Institutional Review Board and written informed consent was obtained from 10 healthy participants. T(1) - and T(2) -weighted turbo spin echo with fat saturation, short tau inversion recovery (STIR), and DTI sequences with 21 diffusion-encoding directions were implemented to acquire images of the forearm nerves with an 8 channel knee coil on a 3T MRI scanner. Identification of the nerves was based on T(1) -weighted, T(2) -weighted, STIR, and DTI-derived fractional anisotropy (FA) images. Maps of the DTI-derived indices, FA, mean diffusivity (MD), longitudinal diffusivity (λ(//) ), and radial diffusivity (λ(⟂) ) along the length of the nerves were generated. RESULTS: DTI-derived maps delineated the forearm nerves more clearly than images acquired with other sequences. Only ulnar and median nerves were clearly visualized on the DTI-derived FA maps. No significant differences were observed between the left and right forearms in any of the DTI-derived measures. Significant variation in the DTI measures was observed along the length of the nerve. Significant differences in the DTI measures were also observed between the median and ulnar nerves. CONCLUSION: DTI is superior in visualizing the median and ulnar nerves in the human forearm. The normative data could potentially help distinguish normal from diseased nerves.


Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Antebraço/inervação , Nervo Mediano/anatomia & histologia , Nervo Ulnar/anatomia & histologia , Adulto , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
19.
Bioorg Med Chem Lett ; 21(20): 6188-94, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21903390
20.
J Med Chem ; 52(20): 6257-69, 2009 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-19772287

RESUMO

p38alpha MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNFalpha and IL-1beta at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38alpha/beta inhibitors using crystal structures of our inhibitors bound to p38alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.


Assuntos
Amidas/química , Amidas/farmacologia , Compostos de Bifenilo/química , Descoberta de Drogas , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Amidas/administração & dosagem , Amidas/uso terapêutico , Animais , Artrite Experimental/tratamento farmacológico , Humanos , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/química , Modelos Moleculares , Conformação Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Ratos
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