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.

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

Improved Method for Preparation of 3-(1H-Indol-3-yl)benzofuran-2(3H)-ones.

3-(1H-Indol-3-yl)benzofuran-2(3H)-ones were efficiently accessed via polyphosphoric acid-mediated condensation of 3-(2-nitrovinyl)-1H-indoles with phenols.

Electrophilically Activated Nitroalkanes in Double Annulation of [1,2,4]Triazolo[4,3-a]quinolines and 1,3,4-Oxadiazole Rings.

Nitroalkanes activated with polyphosphoric acid could serve as efficient electrophiles in reactions with amines and hydrazines, enabling various cascade transformations toward heterocyclic systems. This strategy was developed for an innovative synthetic protocol employing simultaneous or sequential annulation of two different heterocyclic cores, affording [1,2,4]triazolo[4,3-a]quinolines with 1,3,4-oxadiazole substituents.

[3 + 2]-Annulation of pyridinium ylides with 1-chloro-2-nitrostyrenes unveils a tubulin polymerization inhibitor.

Indolizines and pyrazolo[1,5-a]pyridines were prepared via [3 + 2]-cycloaddition of pyridinium ylides to 1-chloro-2-nitrostyrenes. The synthesized molecules were evaluated for antiproliferative activities against a BE(2)-C neuroblastoma cell line with several compounds decreasing the viability of cancer cells. Indolizine 9db showed higher potency than that of all-trans-retinoic acid, an approved cancer drug. Mechanistically, it was found to inhibit tubulin polymerization and it is thus proposed that the discovered chemistry can be exploited for the development of novel microtubule-targeting anticancer agents.

Electrophilically Activated Nitroalkanes in Synthesis of 3,4-Dihydroquinozalines.

Nitroalkanes activated with polyphosphoric acid serve as efficient electrophiles in reactions with various nucleophilic amines. Strategically placed second functionality allows for the design of annulation reactions enabling preparation of various heterocycles. This strategy was employed to develop an innovative synthetic approach towards 3,4-dihydroquinazolines from readily available 2-(aminomethyl)anilines.

Extraosseous Ewing's Sarcoma: Pictorial Review of Imaging Findings, Differential Diagnosis, and Pathologic Correlation.

Extraosseous Ewing's sarcoma (EES), first described in 1969, is a malignant mesenchymal tumor just like its intraosseous counterpart. Although Ewing's sarcomas are common bone tumors in young children, EESs are rarer and more commonly found in older children/adults, often carrying a poorer prognosis. We discuss the multimodality imaging features of EES and the differential diagnosis of an aggressive appearing mass in proximity to skeletal structures, with pathologic correlates. This review highlights the need to recognize the variability of radiologic findings in EES such as the presence of hemorrhage, rich vascularity, and cystic or necrotic regions and its imaging similarity to other neoplasms that are closely related pathologically.

Does electrophilic activation of nitroalkanes in polyphosphoric acid involve formation of nitrile oxides?

The mechanistic rationale involving activation of nitroalkanes towards interaction with nucleophilic reagents in the presence of polyphosphoric acid (PPA) was re-evaluated. Could nitrile oxide moieties be formed during this process? This experiment demonstrates that at least in some cases this could happen, as generated nitrile oxides were successfully intercepted as adducts of [3 + 2] cycloadditions.

Synthesis of imidazo[1,5-a]pyridines via cyclocondensation of 2-(aminomethyl)pyridines with electrophilically activated nitroalkanes.

Imidazo[1,5-a]pyridines were efficiently prepared via the cyclization of 2-picolylamines with nitroalkanes electrophilically activated in the presence of phosphorous acid in polyphosphoric acid (PPA) medium.

Nitroalkanes as electrophiles: synthesis of triazole-fused heterocycles with neuroblastoma differentiation activity.

We discovered a reaction of nitroalkanes with 2-hydrazinylquinolines, 2-hydrazinylpyridines and bis-2,4-dihydrazinylpyrimidines in polyphosphoric acid (PPA) affording 1,2,4-triazolo[4,3-a]quinolines, 1,2,4-triazolo[4,3-a]pyridines and bis[1,2,4]triazolo[4,3-a:4',3'-c]pyrimidines, respectively. The reaction expands the scope of heterocyclic annulations involving phosphorylated nitronates, believed to be the electrophilic intermediates formed from nitroalkanes in PPA. Several of the synthesized triazoles showed promising anticancer activity by inducing differentiation in neuroblastoma cancer cells. Due to the urgent need for novel differentiation agents for neuroblastoma therapy, this finding warrants further evaluation of this class of compounds against neuroblastoma.

Palliative Care in the Neuro-ICU: Perceptions, Practice Patterns, and Preferences of Neurointensivists.

INTRODUCTION: The proportion of hospitals with specialist palliative care services in the USA has increased substantially over the past decade. Severe acute brain injury presents with unique challenges, especially regarding quality of life. The growth and increased recognition of neurocritical care as a subspecialty has not been paralleled by studies regarding how best to integrate palliative care for this unique patient population. Thus, we surveyed members of the Neurocritical Care Society (NCS) to explore current practice patterns, perceptions, and preferences regarding integration of palliative care in the neurological intensive care unit (Neuro-ICU). METHODS: We created a 19-item survey using SurveyMonkey to assess practice patterns, perceptions, and preferences of neurointensivists regarding integration of palliative care in the Neuro-ICU. The survey, approved by the NCS research committee, was distributed to all active members of the NCS. RESULTS: A total of 424 NCS members representing 19% of the 2200 list serve members completed the survey. The majority (58%) of respondents were attending physicians, who worked primarily in a dedicated Neuro-ICU (67%), at university affiliated academic medical centers (65%). Palliative care consultations are utilized infrequently (< 11%) by the majority of the respondents (59%). The most common indication for a palliative consultation was to discuss goals of care and make treatment decisions (73%). A large majority (77%) either agreed or strongly agreed that palliative care services were utilized in the management of difficult cases apart from discussions regarding withdrawal of life sustaining therapy. Palliative care needs of Neuro-ICU patients were considered different from patients in other ICUs by the majority of respondents (66%). CONCLUSION: Our study provides insights into the current perceptions, practice patterns, and preferences of neurointensivists as it relates to palliative care consultation in the Neuro-ICU.

Avoiding unnecessary bronchoscopy in children with suspected foreign body aspiration using computed tomography.

BACKGROUND: Bronchoscopy is the standard of care for diagnosis and treatment of foreign body aspiration (FBA). Drawbacks of this approach include its invasiveness, the potential for exacerbation of reactive airway disease, and the need for general anesthesia. Computed tomography (CT) can potentially identify patients with FBA, thereby avoiding unnecessary bronchoscopies in patients with at-risk reactive airways. METHODS: A retrospective review was performed to identify patients who underwent CT and/or bronchoscopy for suspected foreign body aspiration (FBA) from June 2012 to September 2018. Variables included clinical history, exam findings, radiographic findings, and operative findings. A telephone survey was performed for patients who had a CT without bronchoscopy. Three radiologists performed rereads of all CTs. RESULTS: A total of 133 patients were evaluated for FBA, and 84 were treated with bronchoscopy. For those with a CT demonstrating a foreign body, findings were confirmed on bronchoscopy in 17/18 (94.4%). For those with bronchoscopy alone, 39/64 (60.9%) were found to have a foreign body (p < 0.01). CT excluded FBA in 49 patients. Sensitivity was 100%, specificity was 98%, and interobserver reliability was excellent (κ = 0.88). CONCLUSION: CT is an accurate and reliable diagnostic tool in the evaluation of FBA that can increase the rate of positive bronchoscopy. TYPE OF STUDY: Retrospective comparative study. LEVEL OF EVIDENCE: Level III.

Synthesis of Spiro[indole-3,5'-isoxazoles] with Anticancer Activity via a Formal [4 + 1]-Spirocyclization of Nitroalkenes to Indoles.

An acid-assisted [4 + 1]-cycloaddition of indoles with nitrostyrenes affords 4' H-spiro[indole-3,5'-isoxazoles] in a diastereomerically pure form. Several of these spirocyclic molecules exhibit promising anticancer activity by reducing viability and inducing differentiation of neuroblastoma cells.

Electrophilic activation of nitroalkanes in efficient synthesis of 1,3,4-oxadiazoles.

A novel methodology for general and chemoselective preparation of non-symmetric 1,3,4-oxadiazoles is developed. This unusual reaction proceeds via polyphosphoric acid-assisted activation of nitroalkanes towards nucleophilic attack with acylhydrazides.

Ethical Considerations in End-of-life Care in the Face of Clinical Futility.

Management of patients with terminal brain disorders can be medically, socially, and ethically complex. Although a growing number of feasible treatment options may exist, there are times when further treatment can no longer meaningfully improve either quality or length of life. Clinicians and patients should discuss goals of care while patients are capable of making their own decisions. However, because such discussions can be challenging, they are often postponed. These discussions are then conducted with patients' health care proxies after patients lose the capacity to make their own decisions. Disagreements may arise when a patient's surrogate desires continued aggressive interventions that are either biologically futile (incapable of producing the intended physiologic result) or potentially inappropriate (potentially capable of producing the patient's intended effect but in conflict with the medical team's ethical principles). This article explores best practices in addressing these types of conflicts in the critical care unit, but these concepts also broadly apply to other sites of care.

Metal-Templated Assembly of Cyclopropane-Fused Diazepanones and Diazecanones via exo- trig Nucleophilic Cyclization of Cyclopropenes with Tethered Carbamates.

A strain-release-driven, cation-templated nucleophilic 7- and 8- exo-trig-cyclization of tethered Boc-protected amines to cyclopropenes is described. The featured reaction proceeds in diastereo- and regioselective fashion and allows for preparation of the corresponding 2,5-diazabicyclo[5.1.0]octan-6-ones and 2,6-diazabicyclo[6.1.0]nonan-7-ones as sole products in high yields. Preliminary studies on anticancer activities of these novel cyclopropane-fused medium heterocycles were performed.

Unexpected cyclization of 2-(2-aminophenyl)indoles with nitroalkenes to furnish indolo[3,2-c]quinolines.

The polyphosphoric acid-mediated reaction of 2-(2-aminophenyl)indenes with nitroalkenes was tested in the frame of synthetic studies towards CDK inhibitors with the paullone core. Unexpectedly, this reaction proceeded via a different mechanistic pathway affording derivatives of the natural alkaloid isocryptolepine. The scope of this unusual transformation was investigated and a mechanistic rationale explaining this outcome is offered.

Desymmetrization of Cyclopropenes via the Potassium-Templated Diastereoselective 7- exo- trig Cycloaddition of Tethered Amino Alcohols toward Enantiopure Cyclopropane-Fused Oxazepanones with Antimycobacterial Activity.

A strain-release-driven, cation-templated intramolecular nucleophilic addition of tethered alkoxides to prochiral cyclopropenes is described. Employment of chiral ß- and γ-amino alkoxides allowed for highly diastereoselective assembly of a small series of enantiopure cyclopropane-fused oxazepanones. It was shown that the chiral center at C-4 plays a crucial role in controlling desymmetrization of the cyclopropenyl moiety, instigated by a profound potassium-templated effect. The preliminary biological activities of the new cyclopropane-fused medium heterocycles against Gram-positive bacteria, Gram-negative bacteria, mycobacteria, cancer cells, and fungus were evaluated.

A nitroalkane-based approach to one-pot three-component synthesis of isocryptolepine and its analogs with potent anti-cancer activities.

A second generation polyphosphoric acid-mediated one-pot three-component synthesis of indoloquinoline scaffold is developed. This improved version of the process involves electrophilically activated nitroalkanes for the installation of strategic C-C and C-N bonds and ring C assembly. This modification allows the elimination of unnecessary solvent change operations and all steps are carried out in a true, uninterrupted one-pot manner. A further improvement involves the possibility to install an ortho-amino group in situ. A synthetic application of this method is showcased by the concise synthesis of an isocryptolepine alkaloid and its synthetic analogs with potent anticancer activities.

One-Pot, Three-Component Assembly of Indoloquinolines: Total Synthesis of Isocryptolepine.

Indolo[3,2-c]quinolones have been efficiently synthesized via an acid-mediated, one-pot, three-component condensation of arylhydrazines, o-aminoacetophenones, and triazines or nitriles. The synthetic application of this method is showcased by the concise synthesis of isocryptolepine alkaloid and a series of its synthetic analogues with demonstrated cancer cell antiproliferative activities.