Tuning Reactivities of tert-Butyllithium by the Addition of Stoichiometric Amounts of Tetrahydrofuran.

In alkyllithium chemistry the highest reactivity has historically been linked to the smallest degree of aggregation possible. Since tert-butyllithium is known to form a monomer in tetrahydrofuran solution, using just stoichiometric amounts of the lewis base to selectively form a dimeric species seemed irrational. In this study, we showed a considerable increase of the reactivity of t-BuLi when using stoichiometric amounts of THF in the non-polar solvent n-pentane in order to enable the deprotonation of simple methyl silanes and other low C-H-acidic substrates. In this context, we were able to obtain the corresponding aggregates of t-BuLi with the ligand THF in suspension and as crystalline solids and investigate them by single crystal X-ray structural analysis, in situ FTIR spectroscopy and quantum chemical calculations. Furthermore, we were able to explain the enhanced reactivity of t-BuLi with stoichiometric amounts of THF on the basis of structural features of the bridged dimer obtained under these conditions. With these findings, we present a new target in the aggregation of alkyllithium reagents: the selectively formed "frustrated" aggregates!

Collective Synthesis of Sarpagine and Macroline Alkaloid-Inspired Compounds.

Design strategies that can access natural-product-like chemical space in an efficient manner may facilitate the discovery of biologically relevant compounds. We have employed a divergent intermediate strategy to construct an indole alkaloid-inspired compound collection derived from two different molecular design principles, i.e. biology-oriented synthesis and pseudo-natural products. The divergent intermediate was subjected to acid-catalyzed or newly discovered Sn-mediated conditions to selectively promote intramolecular C- or N-acylation, respectively. After further derivatization, a collection totalling 84 compounds representing four classes was obtained. Morphological profiling via the cell painting assay coupled with a subprofile analysis showed that compounds derived from different design principles have different bioactivity profiles. The subprofile analysis suggested that a pseudo-natural product class is enriched in modulators of tubulin, and subsequent assays led to the identification of compounds that suppress in vitro tubulin polymerization and mitotic progression.

Morphological Profiling Identifies the Motor Protein Eg5 as Cellular Target of Spirooxindoles.

Oxindoles and iso-oxindoles are natural product-derived scaffolds that provide inspiration for the design and synthesis of novel biologically relevant compound classes. Notably, the spirocyclic connection of oxindoles with iso-oxindoles has not been explored by nature but promises to provide structurally related compounds endowed with novel bioactivity. Therefore, methods for their efficient synthesis and the conclusive discovery of their cellular targets are highly desirable. We describe a selective RhIII -catalyzed scaffold-divergent synthesis of spirooxindole-isooxindoles and spirooxindole-oxindoles from differently protected diazooxindoles and N-pivaloyloxy aryl amides which includes a functional group-controlled Lossen rearrangement as key step. Unbiased morphological profiling of a corresponding compound collection in the Cell Painting assay efficiently identified the mitotic kinesin Eg5 as the cellular target of the spirooxindoles, defining a unique Eg5 inhibitor chemotype.

Towards Substrate-Reagent Interaction of Lochmann-Schlosser Bases in THF: Bridging THF Hides Potential Reaction Site of a Chiral Superbase.

The metalation of N,N-dimethylaminomethylferrocene in THF by the superbasic mixture of n BuLi/KOt Bu proceeds readily at low temperatures to afford a bimetallic Li2 K2 aggregate containing ferrocenyl anions and tert-butoxide. Starting from an enantiomerically enriched ortho-lithiated aminomethylferrocene, an enantiomerically pure superbase can be prepared. The molecular compound exhibits superbasic behavior deprotonating N,N-dimethylbenzylamine in the α-position and is also capable of deprotonating toluene. Quantum chemical calculations provide insight into the role of the bridging THF molecule to the possible substrate-reagent interaction. In addition, a benzylpotassium alkoxide adduct gives a closer look into the corresponding reaction site of the Lochmann-Schlosser base that is reported herein.

Chain Length Effect on the Structural and Emission Properties of the CuI/Bis((4-methoxyphenyl)thio)alkane Coordination Polymers.

A systematic chain length variation of the ligand para-MeOC6H4S(CH2)mSC6H4OMe (1 ≤ m ≤ 8) was performed to study its effect on the structures and photophysical properties of the coordination polymers (CP) when reacted with CuI. Indeed, direct correlations are noted between these features and m. When m is an odd number, the secondary building unit is systematically the common closed-cubane Cu4I4 cluster, rendering the material strongly luminescent (i.e., emission quantum yield, Φe > 20%), and the CP is one-dimensional (1D). However, when m is 2, 4, and 6, the SBUs exhibit rare polymeric motifs of (Cu2I2)n: staircase ribbon, fused poly(rhombic pseudo-dodecahedron), and accordion ribbon, respectively, and the emission intensities are either very weak (Φe < 0.001%) or of medium intensity (Φe ∼ 10% when m = 6). When m = 8 (i.e. the most flexible chain), the SBU is a closed-cubane Cu4I4 and the emission intensity is medium (Φe ∼ 10%). A special case was observed for m = 3, where a co-crystallization of the molecular cluster Cu4I4(NCCH3)4 is observed in the lattice, which turns out to be quite important for the stability of the network.

Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype.

Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole- and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research.

A Fused Poly(truncated rhombic dodecahedron)-Containing 3D Coordination Polymer: A Multifunctional Material with Exceptional Properties.

The design of new and inexpensive metal-containing functional materials is of great interest. Herein is reported a unique thermochromic near-IR emitting coordination polymer, 3D-[Cu8I8(L1)2]n, CP2, which is formed when ArS(CH2)4SAr (L1, Ar = 4-C6H4OMe) reacts with 2 equiv of CuI in EtCN. In MeCN, CP1 ([Cu4I4(L1)(MeCN)2]n, consisting of an alternating [-Cu4I4-L1-Cu4I4-L1-]n chain where the Cu4I4 cubane units bear two metal-bound MeCN molecules, is formed. Heat-driven elimination of these MeCN's in solid CP1 also leads to CP2 through a predisposed organization of the Cu4I4 units prone to fusion after MeCN eliminations (i.e., a rare case of template effect). The CP2 structure exhibits parallel 1D-(Cu8I8)n chains, (z-axis; designated 1D-[CuI]n) as secondary building units (SBU) held together by parallel thioether ligands (x,y-axes), forming a nonporous 3D network. The structure of this 1D-[CuI]n SBU is unprecedented and consists of a series of fused and twisted open Cu4I4 cubanes forming a fused poly(truncated rhombic dodecahedron). Unexpectedly, the compact 3D CP2 exhibits a solid-to-solid phase transition at 100 °C and a hysteresis of ∼20 °C. CP1 emits intensively (298 K: λemi = 564 nm; Φe = 0.35), whereas CP2 presents a strongly red-shifted weaker emission (298 K: λemi ∼ 740 nm, Φe < 0.0001). Moreover, CP2, which is stable over long periods of time, exhibits thermochromism where the emission intensity of the near-IR band decreases significantly at the benefit of a ligand-centered phosphorescence at 415 nm. Altogether, these properties listed above make CP2 exceptional. The low-energy singlet and triplet excited states have been assigned to ligand/metal-to-ligand charge transfer based on DFT and TD-DFT computations.

Abnormalities of Aspiration and Swallowing Function in Survivors of Acute Respiratory Failure.

The mechanisms responsible for aspiration are relatively unknown in patients recovering from acute respiratory failure (ARF) who required mechanical ventilation. Though many conditions may contribute to swallowing dysfunction, alterations in laryngeal structure and swallowing function likely play a role in the development of aspiration. At four university-based tertiary medical centers, we conducted a prospective cohort study of ARF patients who required intensive care and mechanical ventilation for at least 48 h. Within 72 h after extubation, a Fiberoptic Flexible Endoscopic Evaluation of Swallowing (FEES) examination was performed. Univariate and multivariable analyses examined the relationship between laryngeal structure and swallowing function abnormalities. Aspiration was the primary outcome, defined as a Penetration- Aspiration Scale (PAS) score of 6 or greater. Two other salient signs of dysphagia-spillage and residue-were secondary outcomes. A total of 213 patients were included in the final analysis. Aspiration was detected in 70 patients (33%) on at least one bolus. The most commonly aspirated consistency was thin liquids (27%). In univariate analyses, several abnormalities in laryngeal anatomy and structural movement were significantly associated with aspiration, spillage, and residue. In a multivariable analysis, the only variables that remained significant with aspiration were pharyngeal weakness (Odds ratio = 2.57, 95%CI = 1.16-5.84, p = 0.019) and upper airway edema (Odds ratio = 3.24, 95%CI = 1.44-7.66, p = 0.004). These results demonstrated that dysphagia in ARF survivors is multifactorial and characterized by both anatomic and physiologic abnormalities. These findings may have important implications for the development of novel interventions to treat dysphagia in ARF survivors.Clinical Trials Registration ClinicalTrials.gov Identifier: NCT02363686, Aspiration in Acute Respiratory Failure Survivors.

The Association Between Endotracheal Tube Size and Aspiration (During Flexible Endoscopic Evaluation of Swallowing) in Acute Respiratory Failure Survivors.

OBJECTIVES: To determine whether a modifiable risk factor, endotracheal tube size, is associated with the diagnosis of postextubation aspiration in survivors of acute respiratory failure. DESIGN: Prospective cohort study. SETTING: ICUs at four academic tertiary care medical centers. PATIENTS: Two hundred ten patients who were at least 18 years old, admitted to an ICU, and mechanically ventilated with an endotracheal tube for longer than 48 hours were enrolled. INTERVENTIONS: Within 72 hours of extubation, all patients received a flexible endoscopic evaluation of swallowing examination that entailed administration of ice, thin liquid, thick liquid, puree, and cracker boluses. Patient demographics, treatment variables, and hospital outcomes were abstracted from the patient's medical records. Endotracheal tube size was independently selected by the patient's treating physicians. MEASUREMENTS AND MAIN RESULTS: For each flexible endoscopic evaluation of swallowing examination, laryngeal pathology was evaluated, and for each bolus, a Penetration Aspiration Scale score was assigned. Aspiration (Penetration Aspiration Scale score ≥ 6) was further categorized into nonsilent aspiration (Penetration Aspiration Scale score = 6 or 7) and silent aspiration (Penetration Aspiration Scale score = 8). One third of patients (n = 68) aspirated (Penetration Aspiration Scale score ≥ 6) on at least one bolus, 13.6% (n = 29) exhibited silent aspiration, and 23.8% (n = 50) exhibited nonsilent aspiration. In a multivariable analysis, endotracheal tube size (≤ 7.5 vs ≥ 8.0) was significantly associated with patients exhibiting any aspiration (Penetration Aspiration Scale score ≥ 6) (p = 0.016; odds ratio = 2.17; 95% CI 1.14-4.13) and with risk of developing laryngeal granulation tissue (p = 0.02). CONCLUSIONS: Larger endotracheal tube size was associated with increased risk of aspiration and laryngeal granulation tissue. Using smaller endotracheal tubes may reduce the risk of postextubation aspiration.

Relationship Between Laryngeal Sensation, Length of Intubation, and Aspiration in Patients with Acute Respiratory Failure.

Dysphagia is common in hospitalized patients post-extubation and associated with poor outcomes. Laryngeal sensation is critical for airway protection and safe swallowing. However, current understanding of the relationship between laryngeal sensation and aspiration in post-extubation populations is limited. Acute respiratory failure patients requiring intensive care unit admission and mechanical ventilation received a Flexible Endoscopic Evaluation of Swallowing (FEES) within 72 h of extubation. Univariate and multivariable analyses were performed to examine the relationship between laryngeal sensation, length of intubation, and aspiration. Secondary outcomes included pharyngolaryngeal secretions, pneumonia, and diet recommendations. One-hundred and three patients met inclusion criteria. Fifty-one patients demonstrated an absent laryngeal adductor reflex (LAR). Altered laryngeal sensation correlated with the presence of secretions (p = 0.004). There was a significant interaction between the LAR, aspiration, and duration of mechanical ventilation. Altered laryngeal sensation was significantly associated with aspiration on FEES only in patients with a shorter length of intubation (p = 0.008). Patients with altered laryngeal sensation were prescribed significantly more restricted liquid (p = 0.03) and solid (p = 0.001) diets. No relationship was found between laryngeal sensation and pneumonia. There is a high prevalence of laryngeal sensory deficits in mechanically ventilated patients post-extubation. Altered laryngeal sensation was associated with secretions, aspiration, and modified diet recommendations especially in those patients with a shorter length of mechanical ventilation. These results demonstrate that laryngeal sensory abnormalities impact the development of post-extubation dysphagia.

Endoscopic Assessment of Swallowing After Prolonged Intubation in the ICU Setting.

OBJECTIVES: The purpose of this study was to identify the frequency of swallowing dysfunction after extubation in a sample of patients with no preexisting dysphagia. METHODS: Mechanically ventilated patients in the ICU with no prior history of dysphagia received a flexible endoscopic evaluation of swallowing (FEES) exam within 72 hours after extubation. The FEES was then analyzed for variables related to swallowing patterns and laryngeal pathology. Univariate analyses were performed to identify relationships between variables. RESULTS: Fifty-nine patients were included in this study. After extubation, 21 (35.6%) penetrated and 13 (22.0%) aspirated. The mean days intubated was 9.4 ± 6.1. Various forms of laryngeal injury were associated with worse swallowing scores, and delayed onset of the swallow was a common finding in all patients post extubation. Of the 44 participants evaluated ≤ 24 hours post extubation, 56.8% penetrated/aspirated. Of the 15 patients evaluated >24 hours post extubation, 60.0% penetrated/aspirated. CONCLUSIONS: This study found a high frequency of dysphagia after prolonged intubation in patients with no preexisting dysphagia. Important variables leading to dysphagia are often overlooked, such as swallowing delay and laryngeal pathology. The timing of swallowing assessments did not reveal any difference in dysphagia frequency, suggesting that it might not be necessary to wait to perform dysphagia screens or evaluations.

Effect of Lidocaine on Swallowing During FEES in Patients With Dysphagia.

PURPOSE: The aims of this study were to assess the effects of 0.2 mL of 4% atomized lidocaine on swallowing and tolerability during Fiberoptic Endoscopic Evaluation of Swallowing (FEES). METHODS: A single blinded study was conducted with 17 dysphagic patients, who received 4 standardized boluses in 2 sequential FEES exams under 2 conditions: non-anesthetized (decongestant only) and anesthetized (lidocaine 4%+decongestant). After each procedure, patients rated their pain on the Wong Baker FACES Pain Rating Scale. Clinicians scored each swallow with the Penetration Aspiration Scale (PAS) and an author-developed Residue Rating Scale. Because the assessments were ordinal, a series of Wilcoxon signed-rank tests were conducted to detect differences between the 2 conditions. RESULTS: No significant differences were detected between groups on PAS or residue in the 4 boluses. Pain scores, however, were significantly lower in the anesthetized condition than the decongested-only condition (P=.035). CONCLUSION: The findings of this study indicated that 0.2 mL of 4% lidocaine enhanced exam tolerability and did not impair the swallow in dysphagic patients.

Implementing Dysphagia Outcome Assessments into Clinical Settings: Leveraging Principles of Implementation, Dissemination, and Psychometrics.

PURPOSE: Myriad dysphagia assessment tools have been designed, but their application is variable. This is partly due to a lack of implementation and dissemination strategy as well as to limited guidance regarding which instruments are optimally designed and best used for clinical and research applications. METHOD: This tutorial provides a high-level overview of implementation and dissemination, their interaction with psychometrics and knowledge coproduction, and how these concepts relate to proper development and widespread application of contextually relevant, psychometrically optimized, evidence-based dysphagia assessment instruments. RESULTS: A review of the literature identified two dysphagia assessment instruments that purposefully integrated implementation and dissemination processes after measurement development. Application of knowledge coproduction was not identified in any papers reporting development and testing of dysphagia assessment instruments. A better understanding of coproduction and psychometrics when developing measures, while simultaneously applying implementation science and dissemination strategies, can result in the development of optimal dysphagia assessment tools that are more consistently adopted into clinical practice. CONCLUSIONS: Clinicians and researchers should promote the development of psychometrically sound measures, and employ principles of implementation science and effective dissemination strategies to advocate for, and promote the use of, well-designed instruments within their appropriate clinical contexts. Support from governing bodies and funding agencies could enhance future efforts to develop, and encourage widespread uptake of, optimally developed dysphagia assessment tools.

Discovery of a Novel Pseudo-Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling.

The pseudo-natural product (pseudo-NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three-dimensional pseudo-NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B.

The Boston Residue and Clearance Scale: preliminary reliability and validity testing.

BACKGROUND: There is no appropriately validated scale with which to rate the problem of residue after swallowing. The Boston Residue and Clearance Scale (BRACS) was developed to meet this need. Initial reliability and validity were assessed. METHODS: BRACS is an 11-point ordinal residue rating scale scoring three aspects of residue during a fiberoptic endoscopic evaluation of swallowing (FEES): (1) the amount and location of residue, (2) the presence of spontaneous clearing swallows, and (3) the effectiveness of clearing swallows. To determine inter-rater and test-retest reliability, 63 swallows from previously recorded FEES procedures were scored twice by 4 raters using (1) clinical judgment (none, mild, mild-moderate, moderate, moderate-severe, severe) and (2) BRACS. Concurrent validity was tested by correlating clinical judgment scores with BRACS scores. Internal consistency of the items in BRACS was examined. A factor analysis was performed to identify important factors that suggest grouping within the 12 location items in BRACS. RESULTS: BRACS showed excellent inter-rater reliability (intraclass correlation coefficient, ICC = 0.81), test-retest reliability (ICC: 0.82-0.92), high concurrent validity (Pearson's r = 0.76), and high internal consistency (Cronbach's α = 0.86). Factor analysis revealed 3 main latent factors for the 12 location items. CONCLUSION: BRACS is a valid and reliable tool that can rate the severity of residue.

Tutorial on Clinical Practice for Use of the Fiberoptic Endoscopic Evaluation of Swallowing Procedure With Adult Populations: Part 1.

PURPOSE: Representatives of the American Board of Swallowing and Swallowing Disorders (AB-SSD) and American Speech-Language-Hearing Association (ASHA) Special Interest Group (SIG) 13: Swallowing and Swallowing Disorders (Dysphagia) developed this tutorial to identify and recommend best practice guidelines for speech-language pathologists who conduct and interpret fiberoptic endoscopic evaluation of swallowing (FEES) procedures in adults. This document also includes proposed training needs and methods for achieving competency. Expert opinion is provided regarding indications for performing the FEES exam, potential contraindications, adverse effects and safety, equipment and personal protection, the exam protocol, interpretation and documentation of findings, and training requirements to perform and interpret the exam. CONCLUSIONS: This tutorial by the AB-SSD and SIG 13 represents the first update about the FEES procedure since ASHA's position paper and technical report published in 2004. Creation of this document by members of the AB-SSD and SIG 13 is intended to guide professionals who are training for or practicing FEES in the adult population toward established best practices and the highest standards of care.

The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation.

Identification and analysis of small molecule bioactivity in target-agnostic cellular assays and monitoring changes in phenotype followed by identification of the biological target are a powerful approach for the identification of novel bioactive chemical matter in particular when the monitored phenotype is disease-related and physiologically relevant. Profiling methods that enable the unbiased analysis of compound-perturbed states can suggest mechanisms of action or even targets for bioactive small molecules and may yield novel insights into biology. Here we report the enantioselective synthesis of natural-product-inspired 8-oxotetrahydroprotoberberines and the identification of Picoberin, a low picomolar inhibitor of Hedgehog (Hh)-induced osteoblast differentiation. Global transcriptome and proteome profiling revealed the aryl hydrocarbon receptor (AhR) as the molecular target of this compound and identified a cross talk between Hh and AhR signaling during osteoblast differentiation.

Natural product fragment combination to performance-diverse pseudo-natural products.

Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.

Synthesis and crystal structure of [Zn6Br4(C9H18NO)4(OH)4]·2C3H6O2.

The complete mol-ecule of the hexa-metallic title complex, namely, tetra-bromido-tetra-µ-hydroxido-hexa-kis-[µ-2-methyl-3-(pyrrolidin-1-yl)propan-2-olato]hexa-zinc(II) acetone disolvate, [Zn6Br4(C9H18NO)4(OH)4]·2C3H6O2, is generated by a crystallographic centre of symmetry. Two of the unique zinc atoms adopt distorted ZnO2NBr tetra-hedral coordination geometries and the other adopts a ZnO3N tetra-hedral arrangement. Both unique alkoxide ligands are N,O-chelating and both hydroxide ions are µ2 bridging. The crystal structure displays an O-H⋯O hydrogen bond between a µ2-OH group and an acetone solvent mol-ecule. The Hirshfeld surface has been calculated and is described.