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Nuclear Quantum Effects in Gas-Phase Ethylene Glycol
No full textPath integral molecular simulations are used to explore the nuclear quantum effects (NQEs) on the structure, dihedral landscape and infrared spectrum of ethylene glycol. The simulations are carried out on a new reaction surface Hamiltonian-based model potential energy surface, with especial focus on the role of the OCCO and HOCC dihedrals. By contrast with classical simulations, we analyse how the intramolecular interaction between the OH groups changes due to zero-point effects as well as temperature. These are found to be weak. The NQEs on the free energy profile along the OCCO dihedral are analysed, where notable effects are seen at low temperatures and found to be correlated with the radii of gyration of the atoms. Finally, the power spectrum of the molecule from path integral simulations is compared with the experimental infrared spectrum, yielding good agreement of band positions
Ultrafast Halogen Dance Reactions Enabled by Catalytic Potassium Hexamethyldisilazide
No full textLochmann–Schlosser base, a stoichiometric combination of nBuLi and KOtBu, is commonly used as a superbase for deprotonating a wide range of organic compounds. In the present study, we report that catalytic potassium hexamethyldisilazide (KHMDS) exhibits higher catalytic activity than KOtBu for successive bromine–metal exchanges. Accordingly, 1–10 mol% of KHMDS dramatically enhances halogen dance reactions to introduce various electrophiles to bromopyridine, bromoimidazole, bromothiophene, bromofuran, and bromobenzene derivatives with the bromo group translocated from the original position. A dual catalytic cycle is proposed to explain the ultrafast bromine transfer
Some features of photoelectrophysical properties of new photosensitive composites based on naphthalimide-containing copolymer sensitized by organic dyes
No full textNovel polymeric film composites based on naphthalimide-containing methacrylic copolymer doped with symmetrical cationic polymethine dyes with different polymethine chain length have been prepared. It was found that the obtained film composites exhibit photovoltaic properties in the absorption spectral region of the dyes. If the length of the polymethine chain is reduced the value of the photovoltaic response is increased as a result of decrease in the energy of the highest occupied orbital of the dye molecule. In the samples of the composite films with a free film surface the photovoltaic effect is determined by diffusion of the more mobile photogenerated positive charge carriers and by their recombination time
Systematic investigation of selected bio-molecules, potentially effective in inhibiting SARS-CoV-2/COVID-19 via in-silico analysis
No full textThere have been millions of cases of Corona virus (SARS-CoV-2) with high infectious properties around the globe during the year 2019. The situation has fostered urgency among scientists to develop a novel treatment. As the mortality rate was higher due to the high spreading properties, few medications were prescribed by health experts viz. Remdesivir, dexamethasone, azithromycin and hydroxychloroquine. Although now a drug has been approved and a vaccines have been administered to alleviate the symptoms and counter the situation; another avenue that can help is an alternative Ayurvedic treatment that is safe and has no adverse effects. Hence, this study is conducted on chosen promising plants that are blessed with potent chemical constituents. The literature survey reveals that these chmical constituents helps to strengthen the body’s immune system, reduce inflammation, provide antioxidants, and improve body’s resistance. Therefore, in the present study, In-silico analysis of selected markers against 6LU7, the protein crystallographic structure of SARS-CoV-2 Mpro was performed. The obtained mean binding energy of all compounds viz. Nobiletin, Tangeretin, sideroxylonal C, Coriandron, Epicatechin, epigallactocatechin gallate, luteolin, Ombuin, Tamarixetin, 6-deacetylnimbin, nimbolide, Tricin were noted as -5.66, -6.00, -6.46, -6.40, -6.91, -6.51, -6.34, -6.46, -6.99, -6.82, -6.51, -7.85, -6.35 kcal/mol respectively. In addition, 9 of the bioactive markers, such as Nobiletin, Tangeretin, Epicatechin, epigallocatechin gallate (EGCG), Ombuin, Tamarixetin, and nimbolide, show similar binding active sites with synthetic compound Remdesivir. viz. PHE140, CYS145, GLU166, GLN189. The investigation also focuses on ADMET modeling, binding energy scores, and binding affinity. However, prerequisite of vaccination is an important key to break the spreading of infection
Saccharide concentration prediction from proxy sea surface microlayer samples analyzed via infrared spectroscopy and quantitative machine learning
No full textSolvated organics in the ocean are present in relatively small concentrations but contribute largely to ocean chemical diversity and complexity. Existing in the ocean as dissolved organic carbon (DOC) and enriched within the sea surface microlayer (SSML), these compounds have large impacts on atmospheric chemistry through their contributions to cloud nucleation, ice formation and other climatological processes. The ability to quantify the concentrations of organics in ocean samples is critical for understanding these marine processes. The work presented herein details an investigation to develop machine learning (ML) methodology utilizing infrared spectroscopy data to accurately estimate saccharide concentrations in complex solutions. We evaluated multivariate linear regression (MLR), K-Nearest-Neighbors (KNN), Decision Trees (DT), Gradient Boosted Regressors (GBR), Multilayer Perceptrons (MLP), and Support Vector Regressors (SVR) toward this goal. SVR models are shown to predict the accurate generalized saccharide concentrations best. Our work presents an application combining fast spectroscopic techniques with ML to analyze organic composition proxy ocean samples to target a generalized method for analyzing field marine samples more efficiently, without sacrificing accuracy or precision
In vivo polymer mechanochemistry with polynucleotides
No full textPolymer mechanochemistry utilizes mechanical force to activate latent functionalities in macromolecules and widely relies on ultrasonication techniques. Although ultrasound is a clinically established modality, fundamental constraints of frequency and power intensity have prohibited the application of the polymer mechanochemistry principles in a biomedical context up to now. Here, a universal polynucleotide framework is presented that allows the binding and release of therapeutic oligonucleotides, both DNA- and RNA-based, as cargo by biocompatible imaging ultrasound. It is shown that the high molar mass, colloidal assembly, and a distinct mechanochemical mechanism enable the force-induced release of cargo and subsequent activation of biological function in vitro and in vivo. Thereby, an avenue for the exploration of biological questions and therapeutics development steered by mechanical force is uncovered
Combining IC50 or Ki Values From Different Sources is a Source of Significant Noise
No full textAs part of the ongoing quest to find or construct large data sets for use in validating new machine learning (ML) approaches for bioactivity prediction, it has become distressingly common for researchers to combine literature IC50 data generated using different assays into a single data set. It is well known that there are many situations where this is scientifically risky thing to do even when the assays are against exactly the same target, but the risks of assays being incompatible is even higher when pulling data from large collections of literature data like ChEMBL. Here, we estimate the amount of noise present in combined data sets by comparing results where results for the same compound are reported in multiple assays against the same target. This approach shows that IC50 assays selected using minimal curation settings have poor agreement with each other: almost 65% of the points differ by more than 0.3 log units, 27% differ by more than one log unit, and the correlation between the assays, as measured by Kendall’s τ is only 0.51. Requiring that most of the assay metadata in ChEMBL matches (“maximal curation”) in order to combine two assays, improves the situation (48% of the points differ by more than 0.3 log units, 13% by more than one log unit, and Kendall’s τ is 0.71) at the expense of having smaller data sets. Surprisingly, our analysis shows similar amounts of noise when combining data from different literature Ki assays. We suggest that good scientific practice requires careful curation when combining data sets from different assays and hope that our maximal curation strategy will help to improve the quality of the data that is being used to build and validate ML models for bioactivity prediction. To help achieve this, the code and ChEMBL queries that we used for the maximal curation approach are available as open-source software in our GitHub repository, https://github.com/rinikerlab/overlapping_assays
Homogenous Palladium-Catalyzed Dehalogenative Deuteration and Tritiation of Aryl Halides with D2/T2 Gas
No full textCatalytic dehalogenative deuteration and tritiation with D2/T2 gas is a widely employed method for precisely introducing hydrogen isotopes into specific positions within organic molecules. While palladium(0) based heterogeneous catalysts, such as Pd/C, are commonly used for this purpose, challenges related to functional group tolerance and incomplete iso-tope incorporation are often encountered, particularly with respect to aryl bromides and chlorides. These long-standing issues pose a hurdle to achieving optimal results in tracer synthesis. The limited incorporation of isotopes for aryl bro-mides and chlorides presents a significant obstacle to the application of this method in the preparation of high specific activity tritium tracers. Herein, we present a novel palladium catalytic system using Zn(OAc)2 as an additive, which ena-bles homogeneous dehalogenative deuteration and tritiation using D2/T2 gas. Under mild reaction conditions, a wide range of drug-like aryl halides and pseudohalides undergo selective deuteration with complete isotope incorporation. The reaction displays excellent compatibility with diverse functional groups, including multiple bonds, O/N-benzyl, and cy-ano groups, which are frequently problematic in Pd/C reactions. Furthermore, this method was successfully applied to the tritiation of four halogenated pharmaceutically relevant molecules, resulting in predictable high specific activity per halogen atom (26.5-27.7 Ci/mmol). Notably, the developed system allows gram-scale preparation of a deuterium-containing intermediate, a crucial step in synthesizing a deuterium-labeled drug molecule. A reaction pathway involving a key intermediate, Pd(Ar)OAc, was proposed to activate hydrogen gas during dehalogenative deuteration and tritiation. This innovative method has potential to change the practice of dehalogenative deuteration and tritiation in the realm of hydrogen isotope labeling
Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the Ataxia telangiectasia and RAD3-related (ATR) kinase
No full textThe Ataxia telangiectasia and RAD3-related (ATR) kinase is a key regulator of DNA replication stress responses and DNA-damage checkpoints. Several potent and selective ATR inhibitors are reported and four of them are currently in clinical trials in combination with radio- or chemotherapy. Based on the idea of degrading target proteins rather than inhibiting them, we designed, synthesized and biologically characterized a library of ATR-targeted proteolysis targeting chimera (PROTACs). Among the synthesized compounds, the lenalidomide-based PROTAC 42i was the most promising. In pancreatic and cervix cancer cells cancer cells (MIA PaCa-2), it reduced ATR to 40% of the levels in untreated cells. 42i selectively degraded ATR through the proteasome, dependent on the E3 ubiquitin ligase component cereblon, and without affecting the associated kinases ATM and DNA-PKcs. 42i may be a promising candidate for further optimization and biological characterization in various cancer cells
Diborane Reductions of CO2 and CS2 Mediated by Dicopper μ-Boryl Complexes of a Robust Bis(Phosphino)-1,8-Napthyridine Ligand
No full textA symmetrical dinucleating 1,8-naphthyridine ligand featuring phosphino side arms linked through fluorene-9,9-diyl moieties (PNNPFlu) was synthesized and used to obtain the cationic organodicopper complexes 2, [(PNNPFlu)Cu2(µ‐Ph)][NTf2]; [NTf2] = bis(trifluoromethane)sulfonimide, and 6, [(PNNPFlu)Cu2(µ‐CCPh)][NTf2], as well as the µ‐tert-butoxide 3, [(PNNPFlu)Cu2(µ‐OtBu)][NTf2]. Complex 3 reacted with diboranes to afford dicopper µ‐boryl species (4, with µ‐Bcat; cat = catecholate and 5, with µ‐Bpin; pin = pinacolate). Complexes 4 and 5 are more reactive in C–H bond activations of terminal alkynes and toward activations of CO2 and CS2, in comparison to dicopper µ‐boryl complexes supported by a 1,8-naphthyridine-based ligand with two di(pyridyl) side arms. The molecular structures (determined by X-ray crystallography) and DFT analysis indicate that the higher reactivity of 4 and 5 relate to changes in the coordination sphere of copper, rather than to perturbations on the Cu–B bonding interactions. Addition of xylyl isocyanide (CNXyl) to 4 gave 7, [(PNNPFlu)Cu2(µ‐Bcat)(CNXyl)][NTf2], demonstrating that the lower coordination number at copper is chemically significant. Reactions of 4 and 5 with CO2 yielded the corresponding dicopper borate complexes (8, [(PNNPFlu)Cu2(µ‐OBcat)][NTf2]; 9, [(PNNPFlu)Cu2(µ‐OBpin)][NTf2]), with 4 demonstrating catalytic CO2 reduction in the presence of excess diborane. Related reactions of 4 and 5 with CS2 provided the insertion products 10, {[(PNNPFlu)Cu2]2[µ‐S2C(Bcat)2]}[NTf2]2 and 11, [(PNNPFlu)Cu2(µ,κ2‐S2CBpin)][NTf2], respectively. These insertion products feature Cu–S–C–B linkages analogous to those of proposed, analogous CO2 insertion intermediates