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A new family of 16-membered macrocycles comprising two indole (In) and two quinoline (Q) units, coined In2Q2, was synthesized. Each unit is diagonally located and concatenated in a head-to-tail fashion, furnishing a non-flat saddle-shaped architecture with C2 symmetry. The synthetic protocol utilizing macrocyclic diamide as a pivotal precursor allowed us to access a series of In2Q2 derivatives bearing various substituents on the periphery. The In2Q2 derivatives and their Zn2+ complexes were emissive in both solution phase and solid state. While the entire architecture of In2Q2 is similar to that of quinoline tetramer TEtraQuinoline, a couple of contrasting physicochemical properties were revealed.
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Patients with secondary adrenal insufficiency can present with impaired free water excretion and hyponatremia, which is due to the enhanced secretion of vasopressin (AVP) despite increased total body water. AVP is produced in magnocellular neurons in the paraventricular nucleus of the hypothalamus (PVH) and supraoptic nucleus and in parvocellular corticotropin-releasing factor (CRF) neurons in the PVH. This study aimed to elucidate whether magnocellular AVP neurons or parvocellular CRF neurons coexpressing AVP are responsible for the pathogenesis of hyponatremia in secondary adrenal insufficiency. The number of CRF neurons expressing copeptin, an AVP gene product, was significantly higher in adrenalectomized AVP-floxed mice (AVPfl/fl) than in sham-operated controls. Adrenalectomized AVPfl/fl mice supplemented with aldosterone showed impaired water diuresis under ad libitum access to water or after acute water loading. They became hyponatremic after acute water loading, and it was revealed under such conditions that aquaporin-2 (AQP2) protein levels were increased in the kidney. Furthermore, translocation of AQP2 to the apical membrane was markedly enhanced in renal collecting duct epithelial cells. Remarkably, all these abnormalities observed in the mouse model for secondary adrenal insufficiency were ameliorated in CRF-AVP-/- mice that lacked AVP in CRF neurons. Our study demonstrates that CRF neurons in the PVH are responsible for the pathogenesis of impaired water excretion in secondary adrenal insufficiency.
Assuntos
Insuficiência Adrenal , Hiponatremia , Camundongos , Animais , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Hormônios Liberadores de Hormônios Hipofisários/metabolismo , Hiponatremia/metabolismo , Aquaporina 2/genética , Aquaporina 2/metabolismo , Arginina Vasopressina/metabolismo , Hipotálamo/metabolismo , Vasopressinas/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Neurônios/metabolismo , DiureseRESUMO
A new 15-membered-macrocyclic molecular entity, oxa-TriQuinoline (o-TQ), was designed and synthesized. In o-TQ, three oxygen atoms were joined onto three quinoline units at the 2- and 8-positions in a head-to-tail fashion by three-fold SN Ar reactions, giving rise to the characteristic N3 O3 aza-oxa-crown architecture. o-TQ can serve as a new tridentate nitrogen ligand to capture a CuI cation and adopt a bowl shape, before supramolecular complexation with corannulene and [12]cycloparaphenylene (CPP) occurs through π-π and CH-π interactions. In the presence of the CuI cation, the non-emissive o-TQ becomes a highly emissive material in the solid state, whereby the emission wavelengths depend on the ancillary ligand on the CuI cation. The o-TQ/CuI complex is able to promote carbene catalysis to provide a range of enamines with a gem-difluorinated terminus.
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DATB (1,3-dioxa-5-aza-2,4,6-triborinane) is a unique six-membered heterocycle exhibiting proficient catalytic activity in direct dehydrative amidation. Reported herein is an improved synthetic protocol for DATB derivatives featuring a concise two-step chromatography-free process. Suzuki-Miyaura coupling assembled 2,6-dibromoaniline derivatives and 1,2-phenylenediboronic acid to afford dimeric B-spiroborate salts. Acidic untying of the spiroborates gave rise to the DATB ring system with various substituents.
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The C4N4 fluorophore is an intense fluorescence emitter featuring a 2,5-diaminopyrimidine core comprising four carbon and four nitrogen atoms. A series of C4N4 derivatives was photochemically dimerized at the 5-amino group, furnishing overcrowded ortho-tetraaryl-substituted diaryl azo compounds with a characteristic skewed structure revealed by X-ray crystallography. The photoquenched azo-C4N4s are useful for fluorescently visualizing cells under hypoxic conditions.
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Diboron substructures have emerged as a promising scaffold for the catalytic dehydrative amidation of carboxylic acids and amines. This Letter describes the design, synthesis, and evaluation of the first isolable N(BOH)2 compound as an amidation catalyst. The new catalyst outperforms the previously reported B3NO2 heterocycle catalyst, with respect to turnover frequency, albeit the former gradually decomposes upon exposure to amines. This work opens up an avenue for designing a better catalyst for direct amidation.
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Porphyrin contains four inwardly oriented nitrogen atoms. It is arguably the most ubiquitous multifunctional naturally occurring macrocycle that has inspired the design of novel nitrogen-containing heterocycles for decades. While cyclic tetramers of pyrrole, indole, and pyridine have been exploited as macrocycles in this category, quinoline has been largely neglected as a synthon. Herein, we report the synthesis of TEtraQuinoline (TEQ) as a 'missing link' in this N4 macrocycle family. In TEQs, four quinoline units are concatenated to produce an S4-symmetric architecture. TEQs are characterized by a highly rigid saddle shape, wherein the lone-pair orbitals of the four nitrogen atoms are not aligned in a planar fashion. Nevertheless, TEQs can coordinate a series of transition-metal cations (Fe2+, Co2+, Ni2+, Cu2+, Zn2+, and Pd2+). TEQs are inherently fluorescence-silent but become strongly emissive upon protonation or complexation of Zn(II) cations (Ï = 0.71). TEQ/Fe(II) complexes can catalyze dehydrogenation and oxygenation reactions with catalyst loadings as low as 0.1 mol %.
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An iterative hydride reduction/oxidation process was promoted under ambient conditions by a quasi-planar iminium cation rigidified by two concatenated quinoline units. The iminium proton was fixed by hydrogen bonding from neighboring quinoline nitrogen atoms, rendering the imine highly susceptible to hydride reduction with weak reductants, e.g., 1,4-dihydropyridines. The thus-formed amine was readily oxidized by molecular oxygen to regenerate the quasi-planar iminium cation under ambient conditions. This process was exploited for catalytic oxidation of 1,4-dihydropyridines as well as 9,10-dihydroacridine to highlight an intriguing rigidity-driven catalysis.
Assuntos
Di-Hidropiridinas , Quinolinas , Catálise , Modelos Moleculares , Oxirredução , Óxidos , Oxigênio , PrótonsRESUMO
RATIONALE AND OBJECTIVES: We evaluated the availability of cytological diagnosis with outer cannula washing solution (C-OCWS) as a clinical diagnostic tool for computed tomography (CT)-guided needle biopsy. MATERIALS AND METHODS: We retrospectively assessed 109 consecutive patients (71 males, 38 females; median age 68 years), who underwent CT-guided needle biopsy. In all patients, the specimens sampled by the inner needle were used for histological diagnosis, and those taken from the outer cannula were rinsed with 0.9% saline solution: outer cannula washing solution for cytological diagnosis. The accuracy of C-OCWS in addition to histological diagnosis were compared with that of histological diagnosis alone. We used binary logistic regression analysis to determine the variables associated with diagnostic accuracy for malignancy and lesion characteristics. RESULTS: The C-OCWS method precisely diagnosed 7 (6.4%) malignant lesions (i.e., effective cases) in the 109 patients characterized as "negative for malignancy" via histological diagnosis alone. The accuracy of the combination of C-OCWS and histological diagnoses was significantly higher than that of histological diagnosis alone (0.95 vs. 0.89, respectively; pâ¯=â¯0.023). Multivariate logistic regression analysis showed that increasing only a marginal ratio (failure rate for proper position of biopsy needle within the tumor) was independently associated with a high rate of effective cases (pâ¯=â¯0.003). CONCLUSION: C-OCWS may be helpful for improving the quality of CT-guided needle biopsy, and is a simple method that may not necessarily increase the patients' physical burden.
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Cânula , Biópsia Guiada por Imagem , Idoso , Biópsia por Agulha/métodos , Feminino , Humanos , Biópsia Guiada por Imagem/métodos , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X/métodosRESUMO
A direct catalytic asymmetric addition of acetonitrile to aldehydes that realizes over 90 % ee is the ultimate challenge in alkylnitrile addition chemistry. Herein, we report achieving high enantioselectivity by the strategic use of a sterically demanding NiII pincer carbene complex, which afforded highly enantioenriched ß-hydroxynitriles. This highly atom-economical process paves the way for exploiting inexpensive acetonitrile as a promising C2 building block in a practical synthetic toolbox for asymmetric catalysis.
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A fluorine-containing tetrasubstituted stereogenic center is a highly valued structural feature in medicinal chemistry. Herein, we describe the direct coupling of racemic α-fluoronitriles and aldehydes promoted by a chiral CuI /Barton's base catalytic system, delivering α-tetrasubstituted α-fluoro-ß-hydroxynitriles with satisfactory stereoselection. The stereochemical course was positively biased by the combined use of asymmetrical achiral thiourea as a supplementary ligand for CuI , which significantly enhanced the stereoselectivity. Both aromatic and aliphatic aldehydes were implemented to provide densely and stereoselectively functionalized chiral building blocks with aliphatic and aromatic tails.
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A cascade alkene sulfonylation that simultaneously forges C-S and C-C bonds is a highly efficient and powerful approach for directly accessing structurally diverse sulfonylated compounds in a single operation. The reaction was enabled by visible-light-mediated regioselective radical addition of sulfonyl chlorides to 2-arylstyrenes using fac[Ir(ppy)3] as a photocatalyst, demonstrating its unique role in a photocascade process to execute atom transfer radical addition (ATRA) followed by photocyclization. A new class of sulfonyl-substituted fluorenes and pyrroloindoles, which are useful in the field of photoelectronic materials and medicinal chemistry, was produced in excellent yields by this photocascade reaction. In contrast, the cyclization was interrupted when using the [Ru(bpy)3Cl2] catalyst having lower reduction potential, leading only to the formation of a C-S bond and the production of acyclic sulfonylated 2-arylstyrenes under identical reaction conditions. The synthetic utility of the present room-temperature photocatalysis is enhanced by the broad availability of bench-stable sulfonyl chlorides and unactivated olefins, thereby providing a cost-effective and broad-scope protocol.
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α,ß-Unsaturated amides were incorporated as viable dipolarophiles in a catalytic asymmetric 1,3-dipolar cycloaddition of azomethine imines. The use of a 7-azaindoline auxiliary was essential to acquire sufficient reactivity with excellent diastereoselectivity, likely due to the chelating activation of the amide by the In(III)/bishydroxamic acid complex. Although the enantioselectivity remains unsatisfactory, this work is an important step toward the development of an asymmetric catalysis utilizing stable and low-reactive substrates.
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Amidas/química , Compostos Azo/química , Iminas/química , Compostos Organometálicos/química , Tiossemicarbazonas/química , Catálise , Reação de Cicloadição , Ácidos Hidroxâmicos/química , Índio/química , Estrutura Molecular , EstereoisomerismoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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A 3-year-old boy was clinically diagnosed with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis. We identified EBV-infected CD8-positive T-lymphocytes by cytologic double staining of the peripheral blood for EBV-encoded small RNA and cell surface markers. The patient was subsequently administered immunosuppressive therapy with a reduced dose of etoposide because of previous organ damage. EBV clearance was confirmed by serial quantification of cell-fractionated EBV-DNA, whereas EBV-DNA persisted in the plasma for 18 weeks. Immunochemotherapy with low-dose etoposide combined with serial viral load monitoring is a potential therapeutic option for severe EBV-hemophagocytic lymphohistiocytosis cases with organ damage.
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Biomarcadores/análise , Citodiagnóstico/métodos , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4/genética , Linfo-Histiocitose Hemofagocítica/diagnóstico , Pequeno RNA não Traduzido/genética , RNA Viral/genética , Linfócitos T CD8-Positivos/virologia , Pré-Escolar , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/virologia , Masculino , Prognóstico , Coloração e Rotulagem , Carga ViralRESUMO
Z or E enolate geometry is the primary determinant of diastereoselectivity in the aldol reaction. Although amide and thioamide enolates are anticipated to have predominantly the E geometry because of the intrinsic steric demand, spectroscopic confirmation of the geometry in solution has remained elusive, particularly in the realm of highly stereoselective catalytic asymmetric aldol reactions. Herein we demonstrate that the 7-azaindoline auxiliary enables direct observation of the exclusive formation of the Z-enolate of the thioamide en route to a highly syn-selective aldol reaction.
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An efficient cooperative chiral Lewis acid/photoredox catalytic system for engaging highly reactive radicals in highly enantioselective conjugate addition to α,ß-unsaturated carbonyls is highly desirable. Direct photoexcitation of unbound substrates typically induces undesired background pathways for racemic products and remains a formidable challenge to be addressed in the area of enantioselective photocatalysis. Herein, we report a cooperative catalytic system comprising a chiral Cu(i) complex and an Ir(iii) photocatalyst fueled by visible-light irradiation that allows for seamless integration of the catalytic formation of α-amino alkyl radicals and subsequent enantioselective addition to α,ß-unsaturated amides. A 7-aza-6-MeO-indoline attachment on the amide substrates plays a pivotal role in suppressing the undesired pathways, resulting in excellent enantioselectivity and enabling expedited access to valuable γ-aminobutyramides. The indoline amide was readily diversified with full recovery of the azaindoline attachment, highlighting the synthetic utility of this cooperative catalytic system.
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An anti-selective catalytic asymmetric Michael-type vinylogous addition of ß,γ-butenolides to chromones was developed. The catalyst system developed herein is characterized by tuning of the steric and electronic effects using a proper Biphep-type chiral ligand to invert the diastereoselection, and improvement of the catalyst turnover by a coordinative phenolic additive. The catalytic protocol renders potentially biologically active natural product analogs accessible in good yield with moderate diastereoselectivity and high enantiomeric purity, mostly greater than 99% ee.
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The bottom-up synthesis of structurally well-defined motifs of graphitic materials is crucial to understanding their physicochemical properties and to elicit new functions. Herein, we report the design and synthesis of TriQuinoline (TQ) as a molecular model for pyridinic-nitrogen defects in graphene sheets. TQ is a trimer of quinoline units concatenated at the 2- and 8-positions in a head-to-tail fashion, whose structure leads to unusual aromatisation behaviour at the final stage of the synthesis. The central atomic-sized void endows TQ with high proton affinity, which was confirmed empirically and computationally. TQâ¢H+ is a two-dimensional cationic molecule that displays both π-π and CH-π contact modes, culminating in the formation of the ternary complex ([12]cycloparaphenylene(CPP) â (TQâ¢H+/coronene)) that consists of TQâ¢H+, coronene (flat), and [12]cycloparaphenylene ([12]CPP) (ring). The water-miscibility of TQâ¢H+ allows it to serve as an efficient DNA intercalator for e.g. the inhibition of topoisomerase I activity.
Assuntos
Técnicas de Química Sintética , Grafite/química , Polímeros/síntese química , Quinolinas/síntese química , Modelos MolecularesRESUMO
Despite significant advances in catalytic asymmetric reactions with decent stereocontrol, those using acetonitrile as a pronucleophile are often disregarded due to their low reactivity and insufficient enantioselectivity. Herein we report the resurgence of this reaction in the chemical toolbox with high enantioselectivity (avg. > 95% ee). The combined use of a Ni(II) complex ligated with a chiral biscarbene and tBuOK engages acetonitrile in the catalytic generation of an α-cyanocarbanion and subsequent highly enantioselective addition to aldimines.