DMSO promoted catalyst-free oxidative C-N/C-O couplings towards synthesis of imidazoles and oxazoles.

Dimethyl sulfoxide (DMSO)-promoted catalyst-free oxidative C-N coupling and C-O coupling under oxidant-free conditions are outlined. This protocol is operationally simple and leads to various functionalized substituted imidazoles or oxazoles in good yields. To date, a very limited number of oxidation protocols have been established, where DMSO acts solely as a catalyst or an oxidant or both. In this report, DMSO is not only used as a C-N/C-O coupling agent but is also used as the oxidant required for these oxidative transformations. Hence, our demonstrated DMSO-promoted catalyst-free coupling transformation has the ability to lead to a new dimension in the field of oxidative coupling.

A machine-learning tool to identify bistable states from calcium imaging data.

Mapping neuronal activation using calcium imaging in vivo during behavioural tasks has advanced our understanding of nervous system function. In almost all of these studies, calcium imaging is used to infer spike probabilities because action potentials activate voltage-gated calcium channels and increase intracellular calcium levels. However, neurons not only fire action potentials, but also convey information via intrinsic dynamics such as by generating bistable membrane potential states. Although a number of tools for spike inference have been developed and are currently being used, no tool exists for converting calcium imaging signals to maps of cellular state in bistable neurons. Purkinje neurons in the larval zebrafish cerebellum exhibit membrane potential bistability, firing either tonically or in bursts. Several studies have implicated the role of a population code in cerebellar function, with bistability adding an extra layer of complexity to this code. In the present study, we develop a tool, CaMLSort, which uses convolutional recurrent neural networks to classify calcium imaging traces as arising from either tonic or bursting cells. We validate this classifier using a number of different methods and find that it performs well on simulated event rasters as well as real biological data that it had not previously seen. Moreover, we find that CaMLsort generalizes to other bistable neurons, such as dopaminergic neurons in the ventral tegmental area of mice. Thus, this tool offers a new way of analysing calcium imaging data from bistable neurons to understand how they participate in network computation and natural behaviours. KEY POINTS: Calcium imaging, compriising the gold standard of inferring neuronal activity, does not report cellular state in neurons that are bistable, such as Purkinje neurons in the cerebellum of larval zebrafish. We model the relationship between Purkinje neuron electrical activity and its corresponding calcium signal to compile a dataset of state-labelled simulated calcium signals. We apply machine-learning methods to this dataset to develop a tool that can classify the state of a Purkinje neuron using only its calcium signal, which works well on real data even though it was trained only on simulated data. CaMLsort (Calcium imaging and Machine Learning based tool to sort intracellular state) also generalizes well to bistable neurons in a different brain region (ventral tegmental area) in a different model organism (mouse). This tool can facilitate our understanding of how these neurons carry out their functions in a circuit.

Metal-Free Activation of Molecular Oxygen by Quaternary Ammonium-Based Ionic Liquid: A Detail Mechanistic Study.

Most oxidation processes in common organic synthesis and chemical biology require transition metal catalysts or metalloenzymes. Herein, we report a detailed mechanistic study of a metal-free oxygen (O2) activation protocol on benzylamine/alcohols using simple quaternary alkylammonium-based ionic liquids to produce products such as amide, aldehyde, imine, and in some cases, even aromatized products. NMR and various control experiments established the product formation and reaction mechanism, which involved the conversion of molecular oxygen into a hydroperoxyl radical via a proton-coupled electron transfer process. Detection of hydrogen peroxide in the reaction medium using colorimetric analysis supported the proposed mechanism of oxygen activation. Furthermore, first-principles calculations using density functional theory (DFT) revealed that reaction coordinates and transition state spin densities have a unique spin conversion of triplet oxygen leading to formation of singlet products via a minimum energy crossing point. In addition to DFT, domain-based local pair natural orbital coupled cluster, (DLPNO-CCSD(T)), and complete active space self-consistent field, CASSCF(20,14) methods complemented the above findings. Partial density of states analysis showed stabilization of π* orbital of oxygen in the presence of ionic liquid, making it susceptible to hydrogen abstraction in a mild, metal-free condition. Inductively coupled plasma atomic emission spectroscopic (ICP-AES) analysis of reactant and ionic liquids clearly showed the absence of any significant transition metal contamination. The current results described the origin of O2 activation within the context of molecular orbital (MO) theory and opened up a new avenue for the use of ionic liquids as inexpensive, multifunctional and high-performance alternative to metal-based catalysts for O2 activation.

Coligands Controlled Reactivities of Ruthenium(II) Precursors: Antiferromagnetically Coupled Ruthenium(III)-Phenoxyl versus Ruthenium(II)-Phenoxyl Forms.

The study disclosed that the reactivities of [RuII (PPh3)3Cl2] and [RuII(PPh3)3(CO)(H)Cl] precursors toward a trimethoxyarylimino-phenol derivative are sensibly different. The former promotes methoxy demethylation reaction affording a [Phenolato-RuIII-Phenolato] unit, while the latter containing π-acidic CO and hydride as coligands leads to C-H activation reaction, generating a [Phenolato-RuII-Aryl] unit. Notably, the oxidized analogues of these two forms produce antiferromagnetically coupled [RuIII-phenoxyl] and paramagnetic [RuII-phenoxyl] forms, which exhibit diverse reactivities. Surprisingly, the magnetically coupled [RuIII-phenoxyl] form obtained from [Phenolato-RuIII-Phenolato] motif leads to coligand, PPh3 oxidation and undergoes dimerization, making a Ru-Ru bond (2.599(2) Å), while the [RuII-phenoxyl] form obtained from [Phenolato-RuII-Aryl] motif leads to C-C coupling and H abstraction reactions. The coupling reaction affords a 4,4'-dibenzosemiquinonate anion radical complex, but the H-abstraction of the phenoxyl form gives a [RuII-Phenol] complex. For comparison, [RuII(IQR 0)] and [RuII(ISQR·-)] complexes were also isolated, where IQR 0 and ISQR·- are p-R-o-iminobenzoquinone and p-R-o-iminobenzosemiquinonate anion radicals. However, they fail to promote any bond-formation reaction. The molecular and electronic structures of the ruthenium (II/III) complexes were confirmed by single-crystal X-ray crystallography, EPR spectroscopy, and DFT calculations.

O2 Activation by a Coordinated -NH- Function: Hydrogen Atom Transfer and Aromatic Ring Oxidation.

Herein, we disclose a unique method of oxidation of a 1,4-naphthoquinone ring in air. We report that (1,4-naphthoquinone)-NH-N=C(OH)Ph (H3L) coordinated to octahedral ruthenium(II) and osmium(II) ions activates an 3O2 molecule spontaneously. Hydrogen atom transfer (HAT) from the -NH- function of H3L to 3O2 and subsequent (2e + 2H+) oxidation forming (1,3,4-trioxonaphthalen)=N-N=C(OH)Ph (HLOX) have been established. The H3L → HLOX transformation occurs via (3-hydroperoxy-1,4-naphthoquinone)=N-N=C(O-)Ph (HLOOH-) as an intermediate. The primary step is HAT generating H2L•- and hydroperoxide (OOH•) radicals. H2L•- is delocalized over the aromatic ring and incites coupling reactions via ortho carbon and produces coordinated HLOOH-. In solution, the homolytic cleavage of the peroxo bond leads to aromatic ring oxidation, affording LOX-. Ruthenium(II) and osmium(II) complexes of the types [MII(H2L-)(PPh3)2X], [MII(HLOOH-)(PPh3)2X], and trans-[MII(LOX-)(PPh3)2X] were successfully isolated in good yields. Notably, the cyclic voltammograms of all of the complexes exhibit reversible anodic waves due to MIII/MII redox couples. The rate constants of the [MII(H2L-)(PPh3)2X] → [MII(HLOOH-)(PPh3)2X] conversions determined by time-driven UV-vis spectroscopy in dry CH2Cl2, wet CH2Cl2, and D2O wet CH2Cl2 in air at 298 K follow the order kCH2Cl2-H2O> kCH2Cl2-D2O> kCH2Cl2. It is established that the rate constants are dependent on the 3O2 content of the solution but not on the concentration of the complex.

Comment on "Disclosing Cyclic(Alkyl)(Amino)Carbenes as a One-Electron Reductant: Synthesis of Acyclic(Amino)(Aryl)Carbene-Based Kekulé Diradicaloids".

This correspondence addresses a misassignment of an EPR spectrum of 2 in a recent publication (Chem. Eur. J. 2022, 28, e202104567) by Dr. Jana and co-workers. The original authors have prepared this correspondence together with Dr. Korth.

A Methoxylation-Promoted CPET Reaction.

The manuscript discloses a methoxylation reaction to an aromatic carbonyl function that carries out a CPET reaction oxidizing a transition metal ion. Spontaneous methoxylation of a redox non-innocent fragment coordinated to a high spin cobalt(II) ion, promoted concerted proton electron transfer (CPET) reaction oxidizing cobalt(II) to cobalt(III) in air and subsequent demethoxylation induced reduction of cobalt(III) to cobalt(II) producing H2 O2 are authenticated. The cobalt(III)/cobalt(II) electron transfer (ET) potential of the designed complex in CH2 Cl2 is -0.27 V vs Fc+ /Fc redox couple. However, in presence of MeOH the reduction potential decreases to -1.02 V due to CPET involving MeOH proton. In CH2 Cl2 /CHCl3 spontaneous demethoxylation occurs giving back the original complex and reactive methoxyl radical that reacts with O2 producing H2 O2 . Overall one molecule of MeOH produces one molecule of H2 O2 . To analyze the involvement of the proton, the rate constants of the CPET reactions in CH2 Cl2 -MeOH (2 : 1) and CH2 Cl2 -CD3 OD (2 : 1) and the demethoxylation reaction in CHCl3 at 330 K were determined by time drive UV-Vis spectroscopy.

Substrate Switchable Pathway for Selective Construction of Bridged Dibenzo[b,f][1,5]diazocines and Bridged Spiromethanodibenzo[b,e]azepines.

An operationally simple method for the synthesis of bridged dibenzo[b,f][1,5]diazocines and bridged spiromethanodibenzo[b,e]azepines exhibiting bridged eight-membered and seven-membered molecular architecture is reported. This unique approach is based on substrate selective mechanistic pathway, including an unprecendented aerial oxidation-driven mechanism for the synthesis of bridged spiromethanodibenzo[b,e]azepines. The reaction is highly atom economic, and in addition, it allows the construction of two rings and four bonds in a single operation under metal-free condition. The easy availability of ß enaminone and ortho phathalaldehyde as starting materials and the simple operation make this approach suitable for the preparation of important dibenzo[b,f][1,5]diazocine and spiromethanodibenzo[b,e]azepine cores.

Aqueous mediated iodine catalyzed C-N coupling followed by C-C coupling towards 5H-pyrazino[2,3-b]indoles.

Our study describes a new development featuring iodine-catalyzed two consecutive oxidative cross-coupling reactions involving Cα(sp3)-H of benzyl amines followed by intramolecular cyclization in water under air. Here, C-N coupling followed by C-C coupling occurs in a green environment to provide a variety of 5H-pyrazino[2,3-b]indoles within a short time period.

Cetuximab-conjugated PLGA nanoparticles as a prospective targeting therapeutics for non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most prevalent cancers diagnosed worldwide, yet managing it is still challenging. The epidermal growth factor receptor (EGFR) exhibits aberrant signalling in a wide range of human cancers, and it is reported to overexpress in most NSCLC cases. The monoclonal antibody [Cetuximab (Cet)] was conjugated onto the surface of the poly (lactide-co-glycolide) (PLGA) nanoparticles which were loaded with docetaxel (DTX) for the development of targeted therapy against lung cancer. This site-specific delivery system exhibited an enhanced cellular uptake in lung cancer cells which overexpress EGFR (A549 and NCI-H23). The nanoparticles also showed better therapeutic effectiveness against NSCLC cells, as evidenced by reduced IC50 values, cell cycle arrest at the G2/M phase, and increased apoptosis. The improved efficacy and in vivo tolerance of Cet-DTX NPs were demonstrated in benzo(a)pyrene (BaP)-induced lung cancer mice model. Histopathological analysis showed that intravenous injection of Cet-DTX NP to mice carrying lung cancer greatly reduced tumour development and proliferation. Comparing Cet-DTX NP to free drug and unconjugated nanoparticles, it also had negligible side effects and improved survival rates. Therefore, Cet-DTX NPs present a promising active targeting carrier for lung tumour-NSCLC-selective treatment.

Multi-Modal Point-of-Care Diagnostics for COVID-19 Based on Acoustics and Symptoms.

BACKGROUND: The COVID-19 pandemic has highlighted the need to invent alternative respiratory health diagnosis methodologies which provide improvement with respect to time, cost, physical distancing and detection performance. In this context, identifying acoustic bio-markers of respiratory diseases has received renewed interest. OBJECTIVE: In this paper, we aim to design COVID-19 diagnostics based on analyzing the acoustics and symptoms data. Towards this, the data is composed of cough, breathing, and speech signals, and health symptoms record, collected using a web-application over a period of twenty months. METHODS: We investigate the use of time-frequency features for acoustic signals and binary features for encoding different health symptoms. We experiment with use of classifiers like logistic regression, support vector machines and long-short term memory (LSTM) network models on the acoustic data, while decision tree models are proposed for the symptoms data. RESULTS: We show that a multi-modal integration of inference from different acoustic signal categories and symptoms achieves an area-under-curve (AUC) of 96.3%, a statistically significant improvement when compared against any individual modality ([Formula: see text]). Experimentation with different feature representations suggests that the mel-spectrogram acoustic features performs relatively better across the three kinds of acoustic signals. Further, a score analysis with data recorded from newer SARS-CoV-2 variants highlights the generalization ability of the proposed diagnostic approach for COVID-19 detection. CONCLUSION: The proposed method shows a promising direction for COVID-19 detection using a multi-modal dataset, while generalizing to new COVID variants.

Assessment of superiority of HSP70-targeting aptamer-functionalized drug-nanocarrier over non-targeted commercially available counterpart in HCC therapy: in vitro and in vivo investigations and molecular modeling.

AIMS: This research aims to compare the therapeutic potential of target-specific phosphorothioate backbone-modified aptamer L5 (TLS9a)-functionalized paclitaxel (PTX)-loaded nanocarrier (PTX-NPL5) that we formulated with that of non-targeted commercial formulation, protein albumin-bound nanoparticles of PTX, Abraxane® (CF) against hepatocellular carcinoma (HCC) through a myriad of preclinical investigations. MAIN METHODS: A variety of in vitro and in vivo assays have been executed to compare the therapeutic effects of the formulations under investigation, including the investigation of the degree of apoptosis induction and its mechanism, cell cycle analysis, the level of ROS production, and redox status, the morphological and histological characteristics of malignant livers, and in vivo imaging. The formulations were also compared concerning pharmacokinetic behaviors. Finally, in silico molecular docking has been performed to predict the possible interactions between aptamer and target(s). KEY FINDINGS: PTX-NPL5 exhibited therapeutic superiority over CF in terms of inducing apoptosis, cell cycle arrest, endorsing oxidative stress to neoplastic cells, and reducing hepatic cancerous lesions. Unlike CF, PTX-NPL5 did not exhibit any significant toxicity in healthy hepatocytes, proving enough impetus regarding the distinctive superiority of PTX-NPL5 over CF. The pharmacokinetic analysis further supported superior penetration and retention of PTX-NPL5 in neoplastic hepatocytes compared to CF. A molecular modeling study proposed possible interaction between aptamer L5 and heat shock protein 70 (HSP70). SIGNIFICANCE: The target-specificity of PTX-NPL5 towards neoplastic hepatocytes, probably achieved through HSP70 recognition, enhanced its therapeutic efficacy over CF, which may facilitate its real clinical deployment against HCC in the near future.

Steric-Hindrance-Induced Diastereoselective Radical Nitration of 3-Alkylidene-2-oxindoles Followed by Tosylhydrazine-Mediated Sulfonation.

Metal-free radical nitration of the ß C-H bond of 3-alkylidene-2-oxindoles with tert-butyl nitrite (TBN) has been explored. Interestingly, (E)-3-(2-(aryl)-2-oxoethylidene)oxindole and (E)-3-ylidene oxindole give different diastereomers on nitration. The mechanistic investigation revealed that the diastereoselectivity was controlled by the size of the functional group. Another transformation of 3-(nitroalkylidene) oxindole into 3-(tosylalkylidene) oxindole was performed through metal and oxidant-free tosylhydrazine-mediated sulfonation. Both methods have the advantages of readily available starting materials and operational simplicity.

Metal-free, I2-promoted direct synthesis of 2-cyano-substituted maleimides via a unique 3,3-dicyano-2-arylacrylic acid intermediate.

A robust, I2-mediated cyclization reaction was developed for the synthesis of 2-cyano-substituted maleimides from arylethylidene malononitriles and amines via unique a 3,3-dicyano-2-arylacrylic acid intermediate. The reaction duration was short and devoid of an expensive transition-metal catalyst, ligands or toxic carbon monoxide. We executed an I2/DMSO-mediated desirable oxidation of the C(sp3)-H bond of the carbonyl precursor followed by the formation of a 3,3-dicyano-2-arylacrylic acid intermediate. Use of readily available starting materials under mild and operationally simple reaction conditions are the major advantages of this strategy.

Two pillared-layer metal-organic frameworks based on the pinwheel trinuclear carboxylate-clusters of Zn(II) and Co(II): synthesis, crystal structures, magnetic study, and Lewis acid catalysis.

Using a dicarboxylic acid, [1,1'-biphenyl]-4,4'-dicarboxylic acid (H2L1) and an exobidentate ligand, (1E,1'E)-N,N'-(1,4-phenylene)bis(1-(pyridin-4-yl)methanimine) (L2), two 3D interpenetrated networks, {[Zn3(L1)3(L2)]·9H2O}n (Zn-MOF) and {[Co3(L1)3(L2)(DMF)]·0.5DMF}n (Co-MOF), have been prepared in good yields. The crystal structure analysis of Zn-MOF and Co-MOF revealed that both have a 3D pillared-layer structure based on pinwheel trinuclear metal-carboxylate clusters as secondary building units (SBUs). Furthermore, the structures also exhibited three-fold interpenetration. Although the overall networks in Zn-MOF and Co-MOF showed significant resemblances, there are marked differences in their crystal structures, which are associated with the coordination environment of the metal centre and the binding modes of the carboxylates. Gas adsorption studies (N2 at 77 K and 1 bar) indicated that Co-MOF is more porous than Zn-MOF. Magnetic measurements on Co-MOF indicate a significant antiferromagnetic interaction (45 K to 303 K) between trimeric Co(II) S = 3/2 spins through syn-syn carboxylato bridges. Both MOFs were studied for the Lewis acid catalyzed Knoevenagel condensation reactions between benzaldehydes and malononitrile with an active methylene group, where Zn-MOF was found to be a better catalyst than Co-MOF. This was supported by the Monte Carlo simulations indicating the better substrate binding ability of Zn-MOF than Co-MOF.

Automatic Classification of Healthy Subjects and Patients With Essential Vocal Tremor Using Probabilistic Source-Filter Model Based Noise Robust Pitch Estimation.

Essential voice tremor (EVT) is a voice disorder resulting from dyscoordination within the laryngeal musculature. A low-frequency fluctuations of fundamental voice frequency or the strength of excitation amplitude is the main consequence of the disorder. The automatic classification of healthy control and EVT is useful tool for the clinicians. A typical automatic EVT classification involves three steps. The first step is to compute the pitch contour from the speech. The second step is to compute the features from the pitch contour, and the final step is to use a classifier to classify the features into healthy or EVT. It is shown that a high-resolution pitch contour estimated from the glottal closure instants (GCIs) is useful for EVT classification. The HPRC estimation can be very poor in the presence of noise. Hence, a probabilistic source filter model based noise robust GCI detection is used for HPRC estimation. The Empirical mode decomposition based feature extraction is used followed by a support vector machine classifier. The EVT classification performance is evaluated using recordings from 45 subjects. The proposed method is found to perform better than the baseline techniques in eight different additive noise conditions with six SNR levels.

Diastereo- and regioselective petasis aryl and allyl boration of ninhydrins towards synthesis of functionalized indene-diones and dihydrobenzoindeno-oxazin-ones.

Petasis aryl and allyl borations were accomplished using substituted ninhydrins, boronic acids or 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 1,2-aminophenols in Hexafluoroisopropanol (HFIP) without any catalysts to synthesize different aryl and allyl derivatives of ninhydrins. The nature of substitution in the boronic acids and 1,2-amino phenols was the key factor in determining the diastereo-regioselectivity and the type of product distributions. The products were isolated and characterized by HMBC, HSQC, 1H, 13C NMR experiments and X-ray single crystallographic analysis. A probable reaction pathway involves in situ formation of acyclic and cyclic ninhydrin-amino alcohol adducts, with the positioned hydroxyl group determining the stereo-regioselective outcome via tetracoordinated boron intermediates. A metal free diastereo- and regioselective Petasis aryl and allyl boration of ninhydrins.

FeCl3-Catalyzed Synthesis of 6-Thioxo-hexahydroindeno[1',2':4,5]imidazo[1,5-a]pyridin-12(6H)-ones via an Interesting [1,2] Oxygen Shift Pathway.

An iron-catalyst mediated one-pot multicomponent route for the synthesis of novel 6-thioxo-hexahydroindeno[1',2':4,5]imidazo[1,5-a]pyridin-12(6H)-one scaffolds has been developed using ninhydrin, l-proline, and aryl isothiocyanates in ethanol medium. This methodology offers an interesting [1,2] oxygen shift mechanism pathway via a number of ring-opening and ring-closing cascade steps to provide diverse substituted hexahydroindeno-imidazo[1,5-a]pyridinones in excellent to good yields. The stereochemistry of the proline ring is lost during the course of the reaction. This protocol is well acceptable toward both electron-accepting and electron-donating functionalities at the ortho-, meta-, and para-positions of the isothiocyanate moiety. Nonhazardous conditions, step economic, and easy operational process are the advantages of this methodology.

Disclosing Cyclic(Alkyl)(Amino)Carbenes as One-Electron Reductants: Synthesis of Acyclic(Amino)(Aryl)Carbene-Based Kekulé Diradicaloids.

Herein, we disclose cyclic(alkyl)(amino)carbenes (CAACs) to be one-electron reductants under the formation of a transient radical cation as indicated by EPR spectroscopy. The disclosed CAAC reducing reactivity was used to synthesize acyclic(amino)(aryl)carbene-based Thiele and Chichibabin hydrocarbons, a new class of Kekulé diradicaloids. The results demonstrate CAACs to be potent organic reductants. Notably, the acyclic(amino)(aryl)carbene-based Chichibabin's hydrocarbon shows an appreciable population of the triplet state at room temperature, as evidenced by both variable-temperature NMR and EPR spectroscopy.

Activation of O2 across a C(sp3)-C(sp3) bond.

The activation of atmospheric molecular dioxygen (O2) is reported, which occurred across a C(sp3)-C(sp3) bond of a piperazine derivative without any catalyst at ambient conditions under the formation of 1,2,4,7-dioxadiazoctane, an 8-membered (larger-ring) cyclic organic peroxide.