CYP3A Mediates an Unusual C(sp2)-C(sp3) Bond Cleavage via Ipso-Addition of Oxygen in Drug Metabolism.

Mammalian cytochrome P450 drug-metabolizing enzymes rarely cleave carbon-carbon (C-C) bonds and the mechanisms of such cleavages are largely unknown. We identified two unusual cleavages of non-polar, unstrained C(sp2)-C(sp3) bonds in the FDA-approved tyrosine kinase inhibitor pexidartinib that are mediated by CYP3A4/5, the major human phase I drug metabolizing enzymes. Using a synthetic ketone, we rule out the Baeyer-Villiger oxidation mechanism that is commonly invoked to address P450-mediated C-C bond cleavages. Our studies in 18O2 and H2 18O enriched systems reveal two unusual distinct mechanisms of C-C bond cleavage: one bond is cleaved by CYP3A-mediated ipso-addition of oxygen to a C(sp2) site of N-protected pyridin-2-amines, and the other occurs by a pseudo-retro-aldol reaction after hydroxylation of a C(sp3) site. This is the first report of CYP3A-mediated C-C bond cleavage in drug metabolism via ipso-addition of oxygen mediated mechanism. CYP3A-mediated ipso-addition is also implicated in the regioselective C-C cleavages of several pexidartinib analogs. The regiospecificity of CYP3A-catalyzed oxygen ipso-addition under environmentally friendly conditions may be attractive and inspire biomimetic or P450-engineering methods to address the challenging task of C-C bond cleavages.

Accessing Pyridines via a Nitrene Internalization Process.

Pyridines are valuable pharmacophores, and their access via direct and selective transmutation of carbon atom with desired nitrogen could become crucial in drug discovery processes. However, only scarce examples can be found when it comes C-to-N-transmutation reactions of aromatics that could lead to the facile synthesis of pyridines or other azaarenes. In this context, Levin and co-workers recently disclosed a process leading to pyridines from the corresponding aryl azides via the regioselective nitrene internalization process. Notably, the transformation did not lead to any further modification of the rest of the aromatic skeleton. This innovative work enabled selectively accessing various pyridine derivatives through direct nitrogen scan operations on benzene derivatives, which were otherwise not feasible.

Visible-Light-Induced Diradical-Mediated ipso-Cyclization towards Double Dearomative [2+2]-Cycloaddition or Smiles-Type Rearrangement.

When mono-radical ipso-cyclization of aryl sulfonamides tend to undergo Smiles-type rearrangement through aromatization-driven C-S bond cleavage, diradical-mediated cyclization must perform in a distinct reaction pathway. It is interesting meanwhile challenging to tune the rate of C-S bond cleavage to achieve a chemically divergent reaction of (hetero) aryl sulfonamides in a visible-light induced energy transfer (EnT) reaction pathway involving diradical species. Herein a chemically divergent reaction based on the designed indole-tethered (hetero)arylsulfonamides is reported which involves a diradical-mediated ipso-cyclization and a controllable cleavage of an inherent C-S bond. The combined experimental and computational results have revealed that the cleavage of the C-S bond in these substrates can be controlled by tuning the heteroaryl moieties: a) If the (hetero)aryl is thienyl, furyl, phenanthryl, etc., the radical coupling of double dearomative diradicals (DDDR) precedes over C-S bond cleavage to afford cyclobutene fused indolines by double dearomative [2+2]-cycloaddition; b) if the (hetero)aryl is phenyl, naphthyl, pyridyl, indolyl etc., the cleavage of C-S bond in DDDR is favored over radical coupling to afford biaryl products.

Synthesis and biological evaluation of benzofuran piperazine derivatives as potential anticancer agents.

This work describes about the synthesis and evaluation of substituted benzofuran piperazines as potential anticancer agents. The synthesized candidates have been evaluated for their cell proliferation inhibition properties in six murine and human cancer cell lines. In vitro evaluation of apoptosis and cell cycle analysis with the lead candidate 1.19 reveals that necrosis might be an important pathway for the candidate compounds to cause cell death. Further, in vivo evaluation of the lead compound shows that this candidate is well tolerated in healthy mice. Additionally, an in vivo anticancer efficacy study in mice using a MDA-MB-231 xenograft model with the lead compound provides good anti-cancer efficacy.

Regioselective SmI2-Mediated Radical ipso-Substitution Cyclization for the Construction of Pyrrolophenanthridinone Skeletons: The Synthesis of Amaryllidaceae Alkaloids.

Here, we report a regioselective, samarium(II) diiodide mediated intramolecular radical ipso-substitution cyclization. Through the use of a methoxy group as a leaving group, it was possible to regulate the regioselectivity of the reaction by changing the temperature and additives. We applied the developed reaction to the synthesis of four Amaryllidaceae alkaloids and have shown that the present reaction successfully overcomes regioselectivity issues encountered with other cyclization methods.

An IPSO-FW-WSVM Method for Stock Trading Signal Forecasting.

Trading signal detection is a very popular yet challenging research topic in the financial investment area. This paper develops a novel method integrating piecewise linear representation (PLR), improved particle swarm optimization (IPSO) and a feature-weighted support vector machine (FW-WSVM) to analyze the nonlinear relationships between trading signals and the stock data hidden in historical data. First, PLR is applied to generate numerous trading points (valleys or peaks) based on the historical data. These turning points' prediction is formulated as a three-class classification problem. Then, IPSO is utilized to find the optimal parameters of FW-WSVM. Lastly, we conduct a series of comparative experiments between IPSO-FW-WSVM and PLR-ANN on 25 stocks with 2 different investment strategies. The experiment results show that our proposed method achieves higher prediction accuracy and profitability, which indicates the IPSO-FW-WSVM method is effective in the prediction of trading signals.

Catalytic ipso-Nitration of Organosilanes Enabled by Electrophilic N-Nitrosaccharin Reagent.

Nitroaromatic compounds represent one of the essential classes of molecules that are widely used as feedstock for the synthesis of intermediates, the preparation of nitro-derived pharmaceuticals, agrochemicals, and materials on both laboratory and industrial scales. We herein disclose the efficient, mild, and catalytic ipso-nitration of organotrimethylsilanes, enabled by an electrophilic N-nitrosaccharin reagent and allows chemoselective nitration under mild reaction conditions, while exhibiting remarkable substrate generality and functional group compatibility. Additionally, the reaction conditions proved to be orthogonal to other common functionalities, allowing programming of molecular complexity via successive transformations or late-stage nitration. Detailed mechanistic investigation by experimental and computational approaches strongly supported a classical electrophilic aromatic substitution (SE Ar) mechanism, which was found to proceed through a highly ordered transition state.

Quantitative 1H-NMR analysis reveals steric and electronic effects on the substrate specificity of benzoate dioxygenase in Ralstonia eutropha B9.

The cis-dihydroxylation of arenes by Rieske dearomatizing dioxygenases (RDDs) represents a powerful tool for the production of chiral precursors in organic synthesis. Here, the substrate specificity of the RDD benzoate dioxygenase (BZDO) in Ralstonia eutropha B9 whole cells was explored using quantitative 1H nuclear magnetic resonance spectroscopy (q1H-NMR). The specific activity, specific carbon uptake, and regioselectivity of the dihydroxylation reaction were evaluated in resting cell cultures for a panel of 17 monosubstituted benzoates. Two new substrates of this dioxygenase system were identified (2-methyl- and 3-methoxybenzoic acid) and the corresponding cis-diol metabolites were characterized. Higher activities were observed for benzoates with smaller substituents, predominantly at the 3-position. Elevated activities were also observed in substrates bearing greater partial charge at the C-2 position of the benzoate ring. The regioselectivity of the reaction was directly measured using q1H-NMR and found to have positive correlation with increasing substituent size. These results widen the pool of cis-diol metabolites available for synthetic applications and offer a window into the substrate traits that govern specificity for BZDO.

Multi-Sensor Fusion by CWT-PARAFAC-IPSO-SVM for Intelligent Mechanical Fault Diagnosis.

A new method of multi-sensor signal analysis for fault diagnosis of centrifugal pump based on parallel factor analysis (PARAFAC) and support vector machine (SVM) is proposed. The single-channel vibration signal is analyzed by Continuous Wavelet Transform (CWT) to construct the time-frequency representation. The multiple time-frequency data are used to construct the three-dimension data matrix. The 3-level PARAFAC method is proposed to decompose the data matrix to obtain the six features, which are the time domain signal (mode 3) and frequency domain signal (mode 2) of each level within the three-level PARAFAC. The eighteen features from three direction vibration signals are used to test the data processing capability of the algorithm models by the comparison among the CWT-PARAFAC-IPSO-SVM, WPA-PSO-SVM, WPA-IPSO-SVM, and CWT-PARAFAC-PSO-SVM. The results show that the multi-channel three-level data decomposition with PARAFAC has better performance than WPT. The improved particle swarm optimization (IPSO) has a great improvement in the complexity of the optimization structure and running time compared to the conventional particle swarm optimization (PSO.) It verifies that the proposed CWT-PARAFAC-IPSO-SVM is the most optimal hybrid algorithm. Further, it is characteristic of its robust and reliable superiority to process the multiple sources of big data in continuous condition monitoring in the large-scale mechanical system.

Performance Degradation Prediction Using LSTM with Optimized Parameters.

Predicting the degradation of mechanical components, such as rolling bearings is critical to the proper monitoring of the condition of mechanical equipment. A new method, based on a long short-term memory network (LSTM) algorithm, has been developed to improve the accuracy of degradation prediction. The model parameters are optimized via improved particle swarm optimization (IPSO). Regarding how this applies to the rolling bearings, firstly, multi-dimension feature parameters are extracted from the bearing's vibration signals and fused into responsive features by using the kernel joint approximate diagonalization of eigen-matrices (KJADE) method. Then, the between-class and within-class scatter (SS) are calculated to develop performance degradation indicators. Since network model parameters influence the predictive accuracy of the LSTM model, an IPSO algorithm is used to obtain the optimal prediction model via the LSTM model parameters' optimization. Finally, the LSTM model, with said optimal parameters, was used to predict the degradation trend of the bearing's performance. The experiment's results show that the proposed method can effectively identify the trends of degradation and performance. Moreover, the predictive accuracy of this proposed method is greater than that of the extreme learning machine (ELM) and support vector regression (SVR), which are the algorithms conventionally used in degradation modeling.

Alkylation-Terminated Catellani Reactions Using Alkyl Carbagermatranes.

The Catellani reaction has received substantial attention because it enables rapid multiple derivatization on aromatics. While using alkyl electrophiles to achieve ortho-alkylation was one of the earliest applications of the Catellani reaction, ipso-alkylation-terminated reactions with ß-H-containing reactants has not been realized to date. Herein, we report alkylation-terminated Catellani reaction using alkyl carbagermatranes (abbreviated as alkyl-Ge) as nucleophiles. The reactivity of alkyl-Ge and alkyl-B(OH)2 in this reaction is discussed. This approach enables efficient dialkylation with ß-H-containing reactants, which was previously inaccessible by Catellani reactions.

Total Synthesis of Zephycarinatines via Photocatalytic Reductive Radical ipso-Cyclization.

We report herein a nonbiomimetic strategy for the total synthesis of the plicamine-type alkaloids zephycarinatines C and D. The key feature of the synthesis is a stereoselective reductive radical ipso-cyclization using visible-light-mediated photoredox catalysis. This cyclization enabled the construction of a 6,6-spirocyclic core structure through the addition of a carbon-centered radical onto the aromatic ring. Biological evaluation of zephycarinatines and their derivatives revealed that the synthetic derivative with a keto group displays moderate inhibitory activity against LPS-induced NO production. This approach could offer future opportunities to expand the chemical diversity of plicamine-type alkaloids as well as providing useful intermediates for their syntheses.

Abnormal Nucleophilic Substitution on Methoxytropone Derivatives: Steric Strategy to Synthesize 5-Substituted Azulenes.

Azulene is a non-alternant non-benzenoid aromatic system, and in turn, it possesses unusual photophysical properties. Azulene-based conjugated systems have received increasing interest in recent years as optoelectronic materials. Despite the routes available for the preparation of substituted azulene derivatives, there remain few methods that allow regioselective substitution on the seven-membered ring of azulenes due to the subtle reactivity difference among the various positions. This report explores the reactivity of substituted tropolones as the azulene precursors and also provides a new method to create 5-substituted azulenes. The reaction of cyanoacetate enolate with unsubstituted 2-methoxytropone affords azulene through the attack of the nucleophile on the C-2 center (normal pathway). We have observed that 3-substituted 2-methoxytropones undergo steric-guided nucleophilic addition at the C-7 center (abnormal pathway) to afford 5-substituted azulene derivatives. Based on this observation and DFT calculation, a new synthetic strategy is devised for the regioselective synthesis of 5-substituted multifunctional azulenes, which cannot be accessed by any other method.

Synthesis of Functionalized Monoaryl-λ3 -iodanes through Chemo- and Site-Selective ipso-Substitution Reactions.

Monoaryl-λ3 -iodanes are potentially attractive arylating agents. They are generally synthesized from aryl iodides via oxidation, which can cause functional group incompatibility, especially when polyfunctionalized derivatives are desired. This work describes the direct synthesis of monoaryl-λ3 -iodanes through a chemoselective ipso-substitution reaction of arylgermanes and arylstannanes with iodine tris(trifluoroacetate). The generated iodanes were converted to iodonium ylides or used for further transformations in one pot. The presented method enables the preparation of polyfunctionalized monoaryl-λ3 -iodanes.

ipso-Arylative Ring-Opening Polymerization as a Route to Electron-Deficient Conjugated Polymers.

ipso-Arylative ring-opening polymerization of 2-bromo-8-aryl-8H-indeno[2,1-b]thiophen-8-ol monomers proceeds to Mn up to 9 kg mol-1 with conversion of the monomer diarylcarbinol groups to pendent conjugated aroylphenyl side chains (2-benzoylphenyl or 2-(4-hexylbenzoyl)phenyl), which influence the optical and electronic properties of the resulting polythiophenes. Poly(3-(2-(4-hexylbenzoyl)phenyl)thiophene) was found to have lower frontier orbital energy levels (HOMO/LUMO=-5.9/-4.0 eV) than poly(3-hexylthiophene) owing to the electron-withdrawing ability of the aryl ketone side chains. The electron mobility (ca. 2×10-3  cm2 V-1 s-1 ) for poly(3-(2-(4-hexylbenzoyl)phenyl)thiophene) was found to be significantly higher than the hole mobility (ca. 8×10-6  cm2 V-1 s-1 ), which suggests such polymers are candidates for n-type organic semiconductors. Density functional theory calculations suggest that backbone distortion resulting from side-chain steric interactions could be a key factor influencing charge mobilities.

Biodegradation of sulfamethoxazole by a bacterial consortium of Achromobacter denitrificans PR1 and Leucobacter sp. GP.

In the last decade, biological degradation and mineralization of antibiotics have been increasingly reported feats of environmental bacteria. The most extensively described example is that of sulfonamides that can be degraded by several members of Actinobacteria and Proteobacteria. Previously, we reported sulfamethoxazole (SMX) degradation and partial mineralization by Achromobacter denitrificans strain PR1, isolated from activated sludge. However, further studies revealed an apparent instability of this metabolic trait in this strain. Here, we investigated this instability and describe the finding of a low-abundance and slow-growing actinobacterium, thriving only in co-culture with strain PR1. This organism, named GP, shared highest 16S rRNA gene sequence similarity (94.6-96.9%) with the type strains of validly described species of the genus Leucobacter. This microbial consortium was found to harbor a homolog to the sulfonamide monooxygenase gene (sadA) also found in other sulfonamide-degrading bacteria. This gene is overexpressed in the presence of the antibiotic, and evidence suggests that it codes for a group D flavin monooxygenase responsible for the ipso-hydroxylation of SMX. Additional side reactions were also detected comprising an NIH shift and a Baeyer-Villiger rearrangement, which indicate an inefficient biological transformation of these antibiotics in the environment. This work contributes to further our knowledge in the degradation of this ubiquitous micropollutant by environmental bacteria.

Strategy for Fault Diagnosis on Train Plug Doors Using Audio Sensors.

As the only entry/exit for passengers getting on and off a train, the train plug door is of great importance to keep train operation safe and reliable. As signal processing technologies develop rapidly, taking the easy acquisition advantages of sound signals, a novel fault diagnosis method for train plug doors using multi-scale normalized permutation entropy (MNPE) and an improved particle swarm optimization based multi-class support vector machine (IPSO-MSVM) is proposed. Firstly, sound samples are collected using high-precision audio sensor. In the features extraction process, a hybrid method blending empirical mode decomposition (EMD), multi-scale permutation entropy (MNPE) with Fisher discrimination criterion is utilized. First, EMD is used to decompose each sound signal into several intrinsic mode functions (IMFs) and a residue for stationary processing. Then, MNPE features are extracted from the IMFs. To obtain the most significant features, the Fisher discrimination criterion is further applied. To address the time-consuming defects of traditional grid based method for selecting the optimal parameters of multi-class SVM, an improved PSO (IPSO) is proposed. The superiority of the IPSO-MSVM model and the hybrid feature extraction method was tested on the collected sound samples by comparing to commonly applied methods. Results indicate the identification accuracy of the proposed method is highest, which reaches 90.54%, demonstrating its feasibility.

Light-Weight Integration and Interoperation of Localization Systems in IoT.

As the ideas and technologies behind the Internet of Things (IoT) take root, a vast array of new possibilities and applications is emerging with the significantly increased number of devices connected to the Internet. Moreover, we are also witnessing the fast emergence of location-based services with an abundant number of localization technologies and solutions with varying capabilities and limitations. We believe that, at this moment in time, the successful integration of these two diverse technologies is mutually beneficial and even essential for both fields. IoT is one of the major fields that can benefit from localization services, and so, the integration of localization systems in the IoT ecosystem would enable numerous new IoT applications. Further, the use of standardized IoT architectures, interaction and information models will permit multiple localization systems to communicate and interoperate with each other in order to obtain better context information and resolve positioning errors or conflicts. Therefore, in this work, we investigate the semantic interoperation and integration of positioning systems in order to obtain the full potential of the localization ecosystem in the context of IoT. Additionally, we also validate the proposed design by means of an industrial case study, which targets fully-automated warehouses utilizing location-aware and interconnected IoT products and systems.

Biodegradation of 7-Hydroxycoumarin in Pseudomonas mandelii 7HK4 via ipso-Hydroxylation of 3-(2,4-Dihydroxyphenyl)-propionic Acid.

A gene cluster, denoted as hcdABC, required for the degradation of 3-(2,4-dihydroxyphenyl)-propionic acid has been cloned from 7-hydroxycoumarin-degrading Pseudomonas mandelii 7HK4 (DSM 107615), and sequenced. Bioinformatic analysis shows that the operon hcdABC encodes a flavin-binding hydroxylase (HcdA), an extradiol dioxygenase (HcdB), and a putative hydroxymuconic semialdehyde hydrolase (HcdC). The analysis of the recombinant HcdA activity in vitro confirms that this enzyme belongs to the group of ipso-hydroxylases. The activity of the proteins HcdB and HcdC has been analyzed by using recombinant Escherichia coli cells. Identification of intermediate metabolites allowed us to confirm the predicted enzyme functions and to reconstruct the catabolic pathway of 3-(2,4-dihydroxyphenyl)-propionic acid. HcdA catalyzes the conversion of 3-(2,4-dihydroxyphenyl)-propionic acid to 3-(2,3,5-trihydroxyphenyl)-propionic acid through an ipso-hydroxylation followed by an internal (1,2-C,C)-shift of the alkyl moiety. Then, in the presence of HcdB, a subsequent oxidative meta-cleavage of the aromatic ring occurs, resulting in the corresponding linear product (2E,4E)-2,4-dihydroxy-6-oxonona-2,4-dienedioic acid. Here, we describe a Pseudomonas mandelii strain 7HK4 capable of degrading 7-hydroxycoumarin via 3-(2,4-dihydroxyphenyl)-propionic acid pathway.

Modern Aspects of the Smiles Rearrangement.

The Smiles rearrangement is an intramolecular SN Ar reaction, breaking a C-X single bond and forming a new C-X or C-C bond though ipso substitution. Its vast scope, in terms of nucleophile, leaving group, and ring-size of the transition state, make it a powerful tool for arene functionalization, as it can be employed strategically to switch easily-forged bonds with more difficult connections that would be challenging to realize in the intermolecular mode. The reaction has received significantly renewed attention in recent years, as advances in areas such as arene C-X bond formation and radical generation have been harnessed for new arene syntheses through Smiles chemistry. In addition, new reaction modes have been discovered, such as the Clayden rearrangement of lithiated ureas, creating innovative applications for Smiles rearrangements in asymmetric arylation. This Minireview will discuss advances in these areas in the recent literature, covering both two-electron, polar Smiles rearrangements along with single-electron radical transformations.