One-Pot Synthesis of -Fused Quinolone-4 Tetracyclic Scaffolds from 2,2-Disubstituted Indolin-3-ones.

A cascade transformation of C2-quaternary indoxyls leading to an efficient assembly of complex (dihydro)indolo[1,2-]quinolin-5-one ring systems is reported. The method involves the gram-scale preparation of 2-(2-aryl-3-oxoindolin-2-yl)-2-phenylacetonitriles which are then converted with methyl ketones to the corresponding 2-(2-oxo-2-aryl(alkyl)ethyl)-2-phenylindolin-3-ones. The latter can either be isolated with good yields (75-96%) or, in the case of -nitroacetophenone, used for further base-assisted intramolecular SAr cyclization resulting in indoxyl-fused quinolone-4 hybrids (up to 95%).

Brain Tissue Oxygen Dynamics Under Localised Hypoxia in the Awake State and the Physical Neuroprotective Effects of General Anaesthesia.

Brain health directly depends on maintaining a level of tissue oxygen that is high enough to avoid global hypoxia and local brain ischaemia. It is well documented that general anaesthesia has an anti-hypoxic neuroprotective effect. Previous studies of this effect primarily assessed the biochemical actions of anaesthetics.

Syntheses of 3-(2-Nitrovinyl)-indoles, Benzo[]carbazoles, Naphtho[2,1-]carbazoles, and 1-Hydroxy-β-carbolines Lead to Identification of Antiproliferative Compounds Active under Hypoxia.

Herein, we describe a novel reaction between C-2-substituted indoles and 2-nitroacetophenones leading to a variety of indole-containing heterocyclic scaffolds. At 60 °C in AcOH with HSO as catalyst, C-2 aryl indoles give 3-(2-nitrovinyl)-indoles with high or geometric selectivity depending on the type of substrate utilized. These compounds undergo an electrocyclization process in a sealed vial in a microwave apparatus in DMF at 250 °C to give benzo[]carbazoles and naphtho[2,1-]carbazoles depending on whether the C-2 aromatic moiety is phenyl or naphthyl.

Metal-Free, PPA-Mediated Fisher Indole Synthesis via Tandem Hydroamination-Cyclization Reaction between Simple Alkynes and Arylhydrazines.

A new variant of Fisher indole synthesis involving Bronsted acid-catalyzed hydrohydrazination of unactivated terminal and internal acetylenes with arylhydrazines is reported. The use of polyphosphoric acid alone either as the reaction medium or in the presence of a co-solvent appears to provide the required balance for activating the C-C triple bond towards the nucleophilic attack of the hydrazine moiety without unrepairable reactivity loss of the latter due to competing amino group protonation. Additionally, the formal hydration of acetylenes to the corresponding ketones occurs under the same conditions, making it an alternative approach for generating carbonyl groups from alkynes.

Abnormal local cortical functional connectivity due to interneuron dysmaturation after neonatal intermittent hypoxia.

Background: Premature infants often experience frequent hypoxic episodes due to immaturity of respiratory control that may result in disturbances of gray and white matter development and long-term cognitive and behavioral abnormalities. We hypothesize that neonatal intermittent hypoxia alters cortical maturation of excitatory and inhibitory circuits that can be detected early with functional MRI.

Methods: C57BL/6 mouse pups were exposed to an intermittent hypoxia (IH) regimen consisting of 12 to 20 daily hypoxic episodes of 5% oxygen exposure for 2 min at 37C from P3 to P7, followed by MRI at P12 and electrophysiological recordings in cortical slices and in vivo at several time points between P7 and P13.

2-(3-Indolyl)acetamides and their oxazoline analogues: Anticancer SAR study.

We previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group.

Brain Tissue Oxygen and BOLD fMRI Under Different Levels of Neuronal Activity.

Localized increases in neuronal activity are supported by the hemodynamic response, which delivers oxygen to the brain tissue to support synaptic functions, action potentials and other neuronal processes. However, it remains unknown if changes in baseline neuronal activity, which are expected to reflect neuronal metabolic demand, alter the relationship between the local hemodynamic and oxygen behaviour. In order to better characterize this system, we examine here the relationship between brain tissue oxygen (PO) and hemodynamic responses (BOLD functional MRI) under different levels of neuronal activity.

Electric Field Effects on Brain Activity: Implications for Epilepsy and Burst Suppression.

Electric fields are now considered a major mechanism of epileptiform activity. However, it is not clear if another electrophysiological phenomenon, burst suppression, utilizes the same mechanism for its bursting phase. Thus, the purpose of this study was to compare the role of ephaptic coupling-the recruitment of neighboring cells via electric fields-in generating bursts in epilepsy and burst suppression.

Synthesis of β-Carbolines with Electrocyclic Cyclization of 3-Nitrovinylindoles.

The β-carboline motif is common in drug discovery and among numerous biologically active natural products. However, its synthetic preparation relies on multistep sequences and heavily depends on the type of substitution required in the core of the desired β-carboline target. Herein, we demonstrate that this structural motif can be accessed with the microwave-assisted electrocyclic cyclization of heterotrienic aci (alkylideneazinic acid) forms of 3-nitrovinylindoles.

A New, Convenient Way to Fully Substituted α,β-Unsaturated γ-Hydroxy Butyrolactams.

The synthesis of novel, highly functionalized 5-hydroxy 3-pyrrolin-2-ones via a two-step procedure involving an addition reaction between KCN and corresponding chalcones, followed by ring condensation of the obtained β-cyano ketones with het(aryl)aldehydes under basic conditions is described. This protocol enables the preparation of various 3,5-di-aryl/heteroaryl-4-benzyl substituted α,β-unsaturated γ-hydroxy butyrolactams, which are subjects of significant interest to synthetic organic and medicinal chemistry.

A Two-Step Synthesis of Unprotected 3-Aminoindoles via Post Functionalization with Nitrostyrene.

A novel, low-cost method for the preparation of not easily accessible free 3-aminoindoles has been developed. This approach is based on a well-established reaction between indoles and nitrostyrene in the presence of phosphorous acid, which results in the formation of 4'-phenyl-4'H-spiro[indole-3,5'-isoxazoles]. The latter could be transformed to corresponding aminated indoles by reaction with hydrazine hydrate in good or excellent yields upon microwave-assisted heating.

A Diastereoselective Assembly of Tetralone Derivatives via a Tandem Michael Reaction and -Substitution of the Nitro Group.

A highly diastereoselective tandem reaction of 2'-nitrochalcones is reported, involving Michael addition and a subsequent -substitution of the nitro group to produce 1-tetralones with two contiguous chiral centers. A related annulation reaction of 2'-nitrochalcones with potassium cyanide affording 1-indanones with a C3-quaternary chiral center is also demonstrated.

One-Pot Synthesis of Polynuclear Indole Derivatives by Friedel-Crafts Alkylation of γ-Hydroxybutyrolactams.

The Friedel-Crafts reaction of novel 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones was used for low cost, one-pot preparation of polycyclic indole derivatives structurally similar to Ergot alkaloids.

Synthesis of 2-carboxyaniline-substituted maleimides from 2'-nitrochalcones.

A practical, one-pot approach to 3-anilino-4-(het)arylmaleimides by simple heating of aqueous DMSO solution of 2'-nitrochalcones with potassium cyanide in the presence of formic acid has been developed. This new reaction provides effective access to a variety of β-substituted α-aminomaleimides which have recently become a subject of growing interest as small, easily modified and environmentally responsive fluorescent probes.

An Effective Synthesis of Previously Unknown 7-Aryl Substituted Paullones.

A straightforward three-step procedure affording a wide range of novel 7-aryl substituted paullone derivatives was developed. This scaffold is structurally similar to 2-(1-indol-3-yl)acetamides-promising antitumor agents-hence, could be useful for the development of a new class of anticancer drugs.

Functional Deficiency of Interneurons and Negative BOLD fMRI Response.

The functional deficiency of the inhibitory system typically appears during development and can progress to psychiatric disorders or epilepsy, depending on its severity, in later years. It is known that interneurons, the major source of GABAergic inhibition in the cerebral cortex, can make direct connections with arterioles and participate in the regulation of vasomotion. The goal of this study was to mimic the functional deficiency of interneurons through the use of localized microinjections of the GABA antagonist, picrotoxin, in such a concentration that it did not elicit epileptiform neuronal activity.

Temporal trajectories of normal myelination and axonal development assessed by quantitative macromolecular and diffusion MRI: Ultrastructural and immunochemical validation in a rabbit model.

Introduction: Quantitative and non-invasive measures of brain myelination and maturation during development are of great importance to both clinical and translational research communities. While the metrics derived from diffusion tensor imaging, are sensitive to developmental changes and some pathologies, they remain difficult to relate to the actual microstructure of the brain tissue. The advent of advanced model-based microstructural metrics requires histological validation.

Function and development of interneurons involved in brain tissue oxygen regulation.

The regulation of oxygen in brain tissue is one of the most important fundamental questions in neuroscience and medicine. The brain is a metabolically demanding organ, and its health directly depends on maintaining oxygen concentrations within a relatively narrow range that is both sufficiently high to prevent hypoxia, and low enough to restrict the overproduction of oxygen species. Neurovascular interactions, which are responsible for oxygen delivery, consist of neuronal and glial components.

Brain tissue oxygen dynamics while mimicking the functional deficiency of interneurons.

The dynamic interaction between excitatory and inhibitory activity in the brain is known as excitatory-inhibitory balance (EIB). A significant shift in EIB toward excitation has been observed in numerous pathological states and diseases, such as autism or epilepsy, where interneurons may be dysfunctional. The consequences of this on neurovascular interactions remains to be elucidated.

Effects of Severe Plastic Deformation and Ultrasonic Treatment on the Structure, Strength, and Corrosion Resistance of Mg-Al-Zn Alloy.

Nowadays, there is a great demand for increasing the strength and corrosion resistance of magnesium alloys for their wider use in machine engineering, oil industry, and medicine. This paper is devoted to a study on the effects of the combined process of reduction and equal channel angular pressing, as well as the subsequent ultrasonic irradiation on the structure, strength, and corrosion properties of the Mg-Al-Zn alloy. Deformation processing results in an increase of the strength up to 280 ± 10 MPa.

Reductive Cleavage of 4'-Spiro[indole-3,5'-isoxazoles] En Route to 2-(1-Indol-3-yl)acetamides with Anticancer Activities.

Unusual cascade transformation involving ring opening and 1,2-alkyl shift was observed upon the reduction of 4'-spiro[indole-3,5'-isoxazoles] or 2-(3-oxoindolin-2-yl)acetonitriles with sodium borohydride. This reaction allowed for expeditious and highly efficient preparation of 2-(1-Indol-3-yl)acetamides with antiproliferative properties.

A Convenient Way to Quinoxaline Derivatives through the Reaction of 2-(3-Oxoindolin-2-yl)-2-phenylacetonitriles with Benzene-1,2-diamines.

Microwave-assisted reaction between 2-(3-oxoindolin-2-yl)-2-phenylacetonitriles andbenzene-1,2-diamines leads to the high-yielding formation of the corresponding quinoxalines as sole, easily isolaable products. The featured transformation involves unusual extrusion of phenylacetonitrile molecule and could be performed in a short sequence starting from commonly available indoles and nitroolefins.

Nitrovinylindoles as Heterotrienes: Electrocyclic Cyclization En Route to β-Carbolines: Total Synthesis of Alkaloids Norharmane, Harmane, and Eudistomin N.

Unusual cascade transformation was developed involving microwave assisted electrocyclic cyclization of aci (alkylideneazinic acid) forms of nitrovinylindoles acting as heterotrienes. Subsequent one-pot reduction allowed for efficient access to β-carbolines, including several natural products, alkaloids norharmane, harmane and eudistomin N.