RESUMO
8-Membered cyclic ethers are found in a wide range of natural products; however, they are challenging synthetic targets due to enthalpic and entropic barriers. The gold(I)-catalyzed intramolecular dehydrative alkoxylation of ω-hydroxy allylic alcohols was explored to stereoselectively construct α,α'-cis-oxocenes and further applied in a formal synthesis of (+)-laurencin. The gold(I)-catalyzed intramolecular dehydrative alkoxylation may constitute an alternative method for the synthesis of molecular building blocks and natural products that contain highly functionalized 8-membered cyclic ethers.
Assuntos
Produtos Biológicos/síntese química , Éteres Cíclicos/síntese química , Ouro/química , Oxocinas/síntese química , Produtos Biológicos/química , Catálise , Éteres Cíclicos/química , Oxocinas/química , Propanóis/síntese química , Propanóis/química , EstereoisomerismoRESUMO
BACKGROUND: Acute kidney injury (AKI) is common among intensive care unit (ICU) patients. AKI is highly heterogeneous, with variable links to poor outcomes. Current approaches to classify AKI severity and identify patients at highest risk for poor outcomes focus on the maximum change in serum creatinine (SCr) values. However, these scores are hampered by the need for a reliable baseline SCr value and the absence of a component differentiating transient from persistent rises in SCr. We hypothesized that identification of resolving or nonresolving AKI subphenotypes based on the early trajectory of SCr values in the ICU would better differentiate patients at risk of hospital mortality. METHODS: We performed a secondary analysis of two prospective studies of ICU patients admitted to a trauma ICU (group 1; n = 1914) or general medical-surgical ICUs (group 2; n = 1867). In group 1, we tested definitions for resolving and nonresolving AKI subphenotypes and selected the definitions resulting in subphenotypes with the greatest separation in risk of death relative to non-AKI controls. We applied this definition to group 2 and tested whether the subphenotypes were independently associated with hospital mortality after adjustment for AKI severity. RESULTS: AKI occurred in 46% and 69% of patients in groups 1 and 2, respectively. In group 1, a resolving AKI subphenotype (defined as a decrease in SCr of 0.3 mg/dl or 25% from maximum in the first 72 h of study enrollment) was associated with a low risk of death. A nonresolving AKI subphenotype (defined as all AKI cases not meeting the "resolving" definition) was associated with a high risk of death. In group 2, the resolving AKI subphenotype was not associated with increased mortality (relative risk [RR] 0.86, 95% CI 0.63-1.17), whereas the nonresolving AKI subphenotype was associated with higher mortality (RR 1.68, 95% CI 1.15-2.44) even after adjustment for AKI severity stage. CONCLUSIONS: The trajectory of SCr levels identifies AKI subphenotypes with different risks for death, even among AKI cases of similar severity. These AKI subphenotypes might better define the patients at risk for poor outcomes who might benefit from novel interventions.
Assuntos
Injúria Renal Aguda/sangue , Injúria Renal Aguda/mortalidade , Creatinina/sangue , Mortalidade Hospitalar/tendências , Unidades de Terapia Intensiva/tendências , Fenótipo , Injúria Renal Aguda/diagnóstico , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
INTRODUCTION: To determine whether single nucleotide polymorphisms (SNPs) in FAS and related genes are associated with acute kidney injury (AKI) in patients with acute respiratory distress syndrome (ARDS). METHODS: We studied 401 (Caucasian N = 310 and African-American N = 91) patients aged ≥ 13 years with ALI who enrolled in the Fluid and Catheter Treatment Trial (FACTT) between 2000 and 2005 from 20 North American centers. We genotyped 367 SNPs in 45 genes of the Fas/Fas ligand pathway to identify associations between SNPs in Fas pathway genes and the development of AKI by day 2 after enrollment in FACTT, adapting Acute Kidney Injury Network (AKIN) criteria. Written informed consent was obtained from participants or legally authorized surrogates in the original FACTT study and available to use for secondary analysis. RESULTS: In Caucasian patients, we identified associations between two SNPs and the incidence of AKI (stage 1 and above): rs1050851 and rs2233417; both are found within the gene for nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA). For rs1050851 and rs2233417, the odds ratios (ORs) were 2.34 (95 % confidence interval (CI) = 1.58-3.46, p = 1.06 × 10(-5), FDR = 0.003) and 2.46 (CI = 1.61-3.76, p = 1.81 × 10(-5), FDR = 0.003) for each minor allele, respectively. The associations were stronger still for AKIN stage 2-3 with respective ORs 4.00 (CI = 2.10-7.62, p = 1.05 × 10(-5), FDR = 0.003) and 4.03 (CI = 2.09-7.77, p = 1.88 × 10(-5), FDR = 0.003) for each minor allele homozygote. We observed no significant association between these SNPs and AKI in the smaller subset of African Americans. CONCLUSION: In Caucasian patients with ALI, the presence of minor alleles in two SNPs in NFKBIA was strongly associated with the development of AKI. TRIAL REGISTRATION: NCT00281268 . Registered 20/01/2006.
Assuntos
Injúria Renal Aguda/genética , Proteína Ligante Fas/genética , Polimorfismo de Nucleotídeo Único , Injúria Renal Aguda/etiologia , Negro ou Afro-Americano/genética , Alelos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Humanos , Proteínas I-kappa B/genética , Masculino , Pessoa de Meia-Idade , Inibidor de NF-kappaB alfa , Polimorfismo de Nucleotídeo Único/genética , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/genética , Transdução de Sinais/genética , População Branca/genéticaRESUMO
Nitric oxide (NO) is an important signaling molecule in the human body, playing a crucial role in cell and neuronal communication, regulation of blood pressure, and in immune activation. However, overproduction of NO by the neuronal isoform of nitric oxide synthase (nNOS) is one of the fundamental causes underlying neurodegenerative disorders and neuropathic pain. Therefore, developing small molecules for selective inhibition of nNOS over related isoforms (eNOS and iNOS) is therapeutically desirable. The aims of this review focus on the regulation and dysregulation of NO signaling, the role of NO in neurodegeneration and pain, the structure and mechanism of nNOS, and the use of this information to design selective inhibitors of this enzyme. Structure-based drug design, the bioavailability and pharmacokinetics of these inhibitors, and extensive target validation through animal studies are addressed.
Assuntos
Neuralgia/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Sítios de Ligação , Calmodulina/química , Calmodulina/metabolismo , Humanos , Simulação de Dinâmica Molecular , Neuralgia/metabolismo , Neuralgia/patologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Óxido Nítrico Sintase/metabolismo , Peptídeos/química , Peptídeos/uso terapêutico , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Estrutura Terciária de ProteínaRESUMO
A new genus, Neoschidium was erected with the type genus, Neoschidium phasma (Distant). It was earlier described under Ghilianella Spinola 1850 as G. phasma Distant and later under Schidium Bergroth 1916 as Schidium phasma (Distant) by Bergroth (1916). Because it exhibits characters not only of Ghilianella and Schidium but also intermediate specific characters that are not found in both the genera, the type genus Neoschidium phasma (Distant) is redescribed with additional taxonomic details, morphometrics, and illustrations. It is also recorded for the first time from India.
Assuntos
Biodiversidade , Reduviidae/classificação , Animais , Ecossistema , Índia , Masculino , Reduviidae/anatomia & histologiaRESUMO
We report the Pd-catalyzed amination of arenes to form N-aryl phthalimides with regioselectivity controlled predominantly by steric effects. Mono-, di-, and trisubstituted arenes lacking a directing group undergo amination reactions with moderate to high yields and high regioselectivities from sequential addition of PhI(OAc)2 as an oxidant in the presence of Pd(OAc)2 as catalyst. This sterically derived selectivity contrasts that for analogous arene acetoxylation.
Assuntos
Derivados de Benzeno/química , Compostos Organometálicos/química , Paládio/química , Ftalimidas/síntese química , Aminação , Catálise , Estrutura Molecular , Ftalimidas/química , EstereoisomerismoRESUMO
A 1:1 mixture of [AuCl(IPr)] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine) and AgClO(4) catalyzes the intermolecular dehydrative alkoxylation of primary and secondary allylic alcohols with aliphatic primary and secondary alcohols to form allylic ethers. These transformations are regio- and stereospecific with preferential addition of the alcohol nucleophile at the γ-position of the allylic alcohol syn to the departing hydroxyl group and with predominant formation of the E stereoisomer. The minor α regioisomer is formed predominantly through a secondary reaction manifold involving regioselective γ-alkoxylation of the initially formed allylic ether rather than by the direct α-alkoxylation of the allylic alcohol.
Assuntos
Compostos Alílicos/síntese química , Éteres/síntese química , Ouro/química , Metano/análogos & derivados , Propanóis/química , Compostos Alílicos/química , Catálise , Éteres/química , Metano/química , Estrutura Molecular , EstereoisomerismoRESUMO
Utilizing a phenotypic screen, we identified chemical matter that increased astrocytic apoE secretion in vitro. We designed a clickable photoaffinity probe based on a pyrrolidine lead compound and carried out probe-based quantitative chemical proteomics in human astrocytoma CCF-STTG1 cells to identify liver x receptor ß (LXRß) as the target. Binding of the small molecule ligand stabilized LXRß, as shown by cellular thermal shift assay (CETSA). In addition, we identified a probe-modified peptide by mass spectrometry and proposed a model where the photoaffinity probe is bound in the ligand-binding pocket of LXRß. Taken together, our findings demonstrated that the lead chemical matter bound directly to LXRß, and our results highlight the power of chemical proteomic approaches to identify the target of a phenotypic screening hit. Additionally, the LXR photoaffinity probe and lead compound described herein may serve as valuable tools to further evaluate the LXR pathway.
Assuntos
Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Receptores X do Fígado/metabolismo , Astrócitos/citologia , Linhagem Celular , Humanos , Ligantes , Ligação Proteica , ProteômicaRESUMO
Herein, we report the radiosynthesis of 18F-difluoromethylarenes via the assembly of three components, a boron reagent, ethyl bromofluoroacetate, and cyclotron-produced non-carrier added [18F]fluoride. The two key steps are a copper-catalysed cross-coupling reaction, and a Mn-mediated 18F-fluorodecarboxylation.
RESUMO
The design, synthesis, and application of [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis of sulfur(VI) fluorides, is described. The utility of AISF is demonstrated in the synthesis of a diverse array of aryl fluorosulfates and sulfamoyl fluorides under mild conditions. Additionally, a single-step preparation of AISF was developed that installed the bis(fluorosulfonyl)imide group on acetanilide utilizing an oxidative C-H functionalization protocol.
RESUMO
A method using calcium triflimide [Ca(NTf2)2] as a Lewis acid to activate sulfonyl fluorides toward nucleophilic addition with amines is described. The reaction converts a wide array of sterically and electronically diverse sulfonyl fluorides and amines into the corresponding sulfonamides in good yield.
RESUMO
The synthesis of a new trifluoromethyl oxetane was developed using a Corey-Chaykovsky epoxidation/ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displays a broad substrate scope. The trifluoromethyl oxetane was also evaluated as a tert-butyl isostere in the context of the γ-secretase modulator (GSM) program. We demonstrate that the trifluoromethyl oxetane-containing GSM has decreased lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-butyl GSM analogue, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-butyl isostere.
Assuntos
Éteres Cíclicos/química , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Cristalografia por Raios X , Éteres Cíclicos/síntese química , Éteres Cíclicos/metabolismo , Humanos , Cetonas/química , Microssomos/metabolismo , Conformação Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismoRESUMO
Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.
Assuntos
Aminoquinolinas/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Aminoquinolinas/síntese química , Animais , Células CACO-2 , Bovinos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ensaios Enzimáticos , Histidina/química , Humanos , Camundongos , Óxido Nítrico Sintase Tipo I/química , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , RatosRESUMO
γ-Secretase, a four-subunit transmembrane aspartic proteinase, is a highly valued drug target in Alzheimer's disease and cancer. Despite significant progress in structural studies, the respective molecular mechanisms and binding modes of γ-secretase inhibitors (GSIs) and modulators (GSMs) remain uncertain. Here, we developed biotinylated cleavable-linker photoprobes based on the BMS-708163 GSI to study its interaction with γ-secretase. Comparison of four cleavable linkers indicated that the hydrazine-labile N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) linker was cleaved most efficiently to release photolabeled and affinity-captured presenilin-1 (PS1), the catalytic subunit of γ-secretase. Peptide mapping showed that the BMS-708163-based probe photoinserted at L282 of PS1. This insertion site was consistent with the results of molecular dynamics simulations of the γ-secretase complex with inhibitor. Taken together, this work reveals the binding site of a GSI and offers insights into the mechanism of action of this class of inhibitors.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Sondas Moleculares/farmacologia , Oxidiazóis/farmacologia , Sulfonamidas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Sítios de Ligação/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Simulação de Dinâmica Molecular , Sondas Moleculares/síntese química , Sondas Moleculares/química , Estrutura Molecular , Oxidiazóis/química , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
A new species from India, Physomerus centralis sp. nov. (Hemiptera: Heteroptera: Coreidae) is described and illustrated with both male and female genitalia. Morphological measurements and their ratios were taken as additional diagnostic characters. A key to the Indian species of the genus Physomerus Burmeister is provided.
Assuntos
Heterópteros/anatomia & histologia , Heterópteros/classificação , Distribuição Animal , Animais , Feminino , Índia , Masculino , Especificidade da EspécieRESUMO
A new stenopodaine reduviid, Aulacogenia darjeelingensis sp. nov. belonging to the "corniculata species group" from India is described and illustrated. A key to the Indian species of the genus Aulacogenia Stål is provided.
Assuntos
Reduviidae/classificação , Distribuição Animal , Estruturas Animais/anatomia & histologia , Estruturas Animais/crescimento & desenvolvimento , Animais , Tamanho Corporal , Ecossistema , Feminino , Índia , Masculino , Tamanho do Órgão , Reduviidae/anatomia & histologia , Reduviidae/crescimento & desenvolvimentoRESUMO
A new species of Stenolemus Signoret, 1858, Stenolemus annulatus sp. nov. (Reduviidae: Emesinae) is described from India. This new species is closely related to S. susainathani Wygodzinsky from Nilgiri Hills, South India and S. larat Wygodzinsky from Moluccas, Larat, by sharing common characteristics such as the ratio of distance between eyes and their width, long antennal first segment, slightly elevated postocular region of head and sharply divided pronotum into three parts, but can be easily separated by the following diagnostic characteristics: pronotum with petiole about as long as forelobe and 1.3 times shorter than hindlobe, first antennal segment with five annulations, rostrum creamy white and luteous at apex, basal and lateral areas of second segment; hind lobe of pronotum with 1+1 submedian conical rounded projections; forecoxa shorter than hind lobe of pronotum, foretibia with one subbasal and one submedian annulation and hind femora reaching apex of forewings. A key to Indian species of the genus Stenolemus is given.
Assuntos
Reduviidae/classificação , Distribuição Animal , Estruturas Animais/anatomia & histologia , Estruturas Animais/crescimento & desenvolvimento , Animais , Tamanho Corporal , Ecossistema , Feminino , Índia , Masculino , Tamanho do Órgão , Reduviidae/anatomia & histologia , Reduviidae/crescimento & desenvolvimentoRESUMO
Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure-activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes.
Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico Sintase Tipo I/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
A 1:1 mixture of (1)AuCl [1 = P(t-Bu)(2)o-biphenyl] and AgSbF(6) catalyzes the intramolecular amination of allylic alcohols with alkylamines to form substituted pyrrolidine and piperidine derivatives. Gold(I)-catalyzed cyclization of (R,Z)-8-(N-benzylamino)-3-octen-2-ol (96% ee, 95% de) led to isolation of (R,E)-1-benzyl-2-(1-propenyl)piperidine in 99% yield with 96% ee, consistent with the net syn addition of the amine relative to the departing hydroxyl group.