bluuebunny/crossref_metadata_2025 huggingface dataset:
Impacts of FERC Order No. 2222 on Dairy Manure Processing in Wisconsin
Authors: Erickson Evan , Tominac Philip , Zavala Victor
Published: February 2022

The agricultural practice of spreading dairy manure to fertilize crop fields leads to widespread air and water pollution, due to uncontrolled release of greenhouse gases, nutrients, and pathogens. The associated environmental and health impacts can be mitigated by deploying manure processing (MP) systems that can capture methane to produce electricity and that facilitate nutrient management. Unfortunately, electricity rates available to MP systems in the United States (US) provide limited economic incentives to promote their deployment. Recent policy enacted by the Federal Energy Regulatory Commission (Order 2222) enables distributed energy resource (DER) systems (such as MP systems) to participate in wholesale electricity markets. We present supply chain and market analyses in Wisconsin showing that this order can help activate an electricity bioeconomy that can help mitigating environmental and health impacts resulting from manure spreading. We estimate that this bioeconomy could generate up to $131 million in revenue for dairy farms annually while averting $39 million in greenhouse gas emissions and $182 million in nutrient emissions.
Low cost and open source purification apparatus for GMP [13N]ammonia production
Authors: Kamar Farah , Kovacs Michael S. , Hicks Justin W.
Published: February 2022

Nitrogen-13 labeled ammonia ([13N]NH3) has been used for myocardial perfusion imaging with Positron Emission Tomography for decades. Recent increases to regulatory oversight have led to stricter adherence Good Manufacturing Practice (GMP) to produce this short half-life (9.97 min) radiopharmaceutical. This has increased production costs. Our cyclotron facility initially developed a manual GMP production method, but it was prone to human error. With increased costs in mind, we developed and validation an Arduino-based device to purifying [13N]NH3 for clinical use. Construction, programming, and GMP validation results are discussed. The automated method was found to produce equivalent quality radiopharmaceutical but was more reproducible and robust.
Pseudo-Natural Products Occur Frequently in Biologically Relevant Compounds
Authors: Waldmann Herbert , Gally José-Manuel , Pahl Axel , Czodrowski Paul
Published: February 2022

A new methodology for classifying fragment combinations and characterizing pseudo-natural products (PNPs) is described. The source code is based on open-source tools and is organized as a Python package. Tasks can be executed individually or within the context of scalable, robust workflows. First, structures are standardized and duplicate entries are filtered out. Then, molecules are probed for the presence of predefined fragments. For molecules with more than one match, fragment combinations are classified. The algorithm considers the pair-wise relative position of fragments within the molecule (fused atoms, linkers, intermediary rings), resulting in 18 different possible fragment combination categories. Finally, all combinations for a given molecule are assembled into a fragment combination graph, with fragments as nodes and combination types as edges. This workflow was applied to characterize PNPs in the ChEMBL database via comparison of fragment combination graphs with Natural Product (NP) references, represented by the Dictionary of Natural Products. The Murcko fragments extracted from 2,000 structures previously described were used to define NP-fragments. The results indicate that ca. 23% of the biologically relevant compounds listed in ChEMBL comply to the PNP definition, and that, therefore, PNPs occur frequently among known biologically relevant small molecules. The majority (>95%) of PNPs contains two to four fragments, mainly (>95%) distributed in five different combination types. These findings may provide guidance for the design of new PNPs.
Global, High-Resolution, Reduced-Complexity Air Quality Modeling Using InMAP (Intervention Model for Air Pollution)
Authors: Thakrar Sumil , Tessum Christopher , Apte Joshua , Balasubramanian Srinidhi , Millet Dylan B , Pandis Spyros , Marshall Julian D. , Hill Jason
Published: February 2022

Each year, millions of premature deaths worldwide are caused by exposure to outdoor air pollution, especially fine particulate matter (PM2.5). Designing policies to reduce these deaths relies on air quality modeling for estimating changes in PM2.5 concentrations from many policy scenarios at high spatial resolution. However, air quality modeling typically has high requirements for computation and expertise, which limits policy design, especially in countries where most PM2.5-related deaths occur. Lower requirement reduced-complexity models exist but are generally unavailable worldwide. Here, we adapt InMAP, a reduced-complexity model originally developed for the United States, to simulate annual-average primary and secondary PM2.5 concentrations across a global-through urban spatial domain: “Global InMAP”. Global InMAP uses a variable resolution grid, with 4 km horizontal grid cell widths in cities. We evaluate Global InMAP performance both against measurements and a state-of-the-science chemical transport model, GEOS-Chem. For the emission scenarios considered, Global InMAP reproduced GEOS-Chem pollutant concentrations with a normalized mean bias of 59%–121%, which is sufficient for initial policy assessment and scoping. Global InMAP can be run on a desktop computer; simulations here took 2.6–4.4 hours. This work presents a global, open-source, reduced-complexity air quality model to facilitate air pollution policy assessment worldwide, providing a screening tool for reducing the deaths where they occur most.
Multistimuli Responsive Dynamic Effects in a One-Dimensional Coordination Polymer
Authors: Rath Bibhuti Bhusan , Gupta Mayank , Vittal Jagadese J.
Published: February 2022

The development of multistimuli receptive actuators demands rational combination of suitable functionalities. Achieving such actuating properties in a single crystalline material is a challenge. In spite of several investigation on photo-, thermo- and mechano- responsive crystals, single crystalline material displaying all these effects is unknown. By a judicious combination of photoreactive 2-fluoro-4’-styrylpyridine units and flexible Pb(SCN)2 units, multistimuli responsive 1D CP showing all these dynamic effects has been fabricated. Single crystals of the CP display rapid ballistic events upon UV irradiation triggered by [2+2] cycloaddition of the photoreactive ligands. In addition, macroscopic jumping, bending, splitting of the crystals were observed during both heating and cooling cycles, because of the reversible phase transition. In addition, slander crystals of the CP exhibt elastic deformation upon the application of mechanical force. With handful examples CPs showing macroscopic dynamic effects, this CP paves the way for designing multistimuli responsive multi-salient actuating materials.
Encapsulation of Paramagnetic Chelates in Perfluorcarbon-loaded Fractal Nanoparticles Enables Modulation of Fluorine-19 and Proton Magnetic Resonance Imaging Signal
Authors: Verbeelen Margot , White Paul , Staal Alexander H.J. , Swider-Cios Edyta , Cortenbach Kimberly R.G. , van Riessen N. Koen , Cadiou Cyril , Chuburu Françoise , Srinivas Mangala , Koshkina Olga
Published: February 2022

19F magnetic resonance imaging (19F MRI) is an emerging technique for quantitative imaging of novel therapies, such as cellular therapies and theranostic nanoparticles. A modification of perfluorocarbon (PFC)-loaded, nanocarrier-based 19F MRI probes with paramagnetic chelates can enhance probe’s functionality. Liquid PFC-loaded nanocarriers typically have a core-shell structure with PFC in the core due to the poor miscibility of PFC. However, paramagnetic relaxation enhancement acts only at a distance of a few angstroms. Thus, efficient modulation of 19F signal is possible only with fluorophilic PFC-soluble chelates. Such chelates, however, cannot interact with the surroundings of nanoparticles. Conversely, chelates on the surface typically affect only the aqueous environment but not the 19F signal. We show that the confinement of PFC in biodegradable polymeric nanoparticles with fractal structure enables modulation of longitudinal and transverse 19F relaxation, as well as proton signal, using non-fluorophilic paramagnetic chelates. We compared nanoparticles with fractal multicore versus conventional core-shell structure, where the PFC is encapsulated in the core(s) and the chelate in the surrounding polymeric matrix. Importantly, paramagnetic chelates affected both longitudinal and transverse 19F relaxation in fractal multicore nanoparticles, but not in core-shell nanocapsules. Both relaxation rates of 19F nucleus increased with an increasing concentration of the paramagnetic chelate. Moreover, as the polymeric matrix remained water-permeable, proton enhancement additionally was observed in MRI. In the future, the effects of fractal confinement could be combined with more effective paramagnetic chelates to develop multifunctional imaging probes, for example, for high-sensitivity 19F MRI combined with sensing.
Catalytic Deracemization of α-Branched Aldehydes via Visible Light Promoted E/Z Isomerization of Enamine Intermediate
Authors: Huang Mouxin , Zhang Long , Pan Tianrun , Luo Sanzhong
Published: February 2022

Catalytic deracemization of α-branched aldehydes represents an unmet challenge with fundamental importance in carbonyl chemistry. In this work, we report a photochemical E/Z isomerization strategy for the deracemization of α-branched aldehydes by using simple aminocatalysts and readily available photosensitizers. Various racemic α-branched aldehydes could be directly transformed into their corresponding single enantiomers in high enantioselectivity. Rapid photodynamic E/Z isomerization and highly stereospecific iminium/enamine tautomerization are two key factors that underlie the highly effective enantio-enrichment. This study presents a distinctive photochemical E/Z isomerizing strategy for externally tuning enamine catalysis.
Accurate Simulations of Lipid Monolayers Require a Water Model With Correct Surface Tension
Authors: Tempra Carmelo , Ollila O.H. Samuli , Javanainen Matti
Published: February 2022

Lipid monolayers provide our lungs and eyes their functionality, and serve as proxy systems in biomembrane research. Therefore, lipid monolayers have been studied intensively also using molecular dynamics simulations, which are able to probe their lateral structure and interactions with, e.g., pharmaceuticals or nanoparticles. However, such simulations have struggled in describing the forces at the air–water interface. Particularly the surface tension of water and long-range van der Waals interactions have been considered critical, but their importance in monolayer simulations has been evaluated only separately. Here we combine the recent C36/LJ-PME lipid force field that in- cludes long-range van der Waals forces with water models that reproduce experimental surface tensions to elucidate the importance of these contributions in monolayer simulations. Our results suggest that a water model with correct surface tension is necessary to reproduce experimental surface pressure–area isotherms and monolayer phase behavior, while standard cutoff-based CHARMM36 lipid model with the 4-point OPC water model still provides the best agreement with experiments. Our results emphasize the importance of using high quality water models in applications and parameter development in molecular dynamics simulations of biomolecules.
Red-Light Triggered Photouncaging from Dicyanomethylene-4H-pyran Phototrigger in Aqueous Solution: Applied as a Single Component Nano-Drug Delivery System for Cancer Therapy
Authors: Roy Biswajit , Mengji Rakesh , Kundu Moumita , Ghosh Sujit , Mondal Mahitosh , Jana Avijit , Singh N. D. Pradeep
Published: February 2022

The development of Photoremovable protecting groups (PRPGs), which can be activated in the ʽphototherapeutic windowʼ for biological applications, is highly challenging. Only PRPGs based on BODIPY dye have been developed so far, which can be excited ≥600 nm. Herein, we developed for the first time NIR dye hydroxystyryl dicyanomethylene-4H-pyran (DCM) as a PRPG that can be operated in the phototherapeutic window. Ours easily synthesized DCM photocages efficiently released aromatic and aliphatic carboxylic acids in an aqueous solution on irradiation using the light of wavelength ≥600 nm and 650 nm, separately. As an application, we used our DCM-PRPG as a single component nanocarrier drug delivery system (DDS) to uncage valproic acid (a known histone deacetylase inhibitor) for cancer treatment. In vitro studies revealed that our DDS, hydroxystyryl dicyanomethylene-4H-pyran valproic acid conjugate nanoparticles (DCM-VPA-NPs) exhibited good cellular internalization, biocompatibility, and enhanced cytotoxicity upon irradiation.
An evaluation of palladium-based catalysts for the base-free borylation of alkenyl carboxylates
Authors: Gaube Gregory , Pipaon Fernandez Nahiane , Leitch David
Published: February 2022

Synthesis of organoboron derivatives is a key application of catalytic cross-coupling, with the Pd-catalyzed Miyaura borylation among the most versatile methods available. We have evaluated several Pd-based systems for borylation of alkenyl acetates and pivalates, with the optimal system heavily dependant on the substrate structure.
Alkali Cation Effect on CO2 Electroreduction to CO: A Local Colligative Property
Authors: Shin Seung-Jae , Choi Hansol , Ringe Stefan , Won Da Hye , Choi Chang Hyuck , Kim Hyungjun
Published: February 2022

Converting carbon dioxide (CO2) into valuable products is one of the most important processes for a sustainable society. Especially, the electrochemical CO2 reduction reaction (CO2RR) offers an effective means, but its reaction mechanism is not yet fully understood. Here, we demonstrate that cation-coupled electron transfer (CCET) is a rate-determining step in the CO2RR to carbon monoxide. The first-principles-based multiscale simulation identifies a single cation that coordinates a CO2− intermediate adsorbed on Ag electrode. The CCET is experimentally verified by a collapse of the CO2RR polarization curves upon correcting Nernstianly for a bulk cation concentration. As further confirmation, a kinetic study shows that the CO2RR obeys first-order kinetics on a local cation concentration. Finally, this work unveils that the cation effect on CO2RR originates from the local colligative property, and further highlights the importance of ion-pairing tendency for electrochemical interface design to achieve high-performance CO2 electrolysis.
Heterologous Biosynthesis and Genomics-Driven Derivatization of Fungal Bioactive Sesterterpenoid Variecolin
Authors: Yan Dexiu , Arakelyan Jemma , Wan Teng , Chan Tsz Ki , Ahn Dohyun , Cheung Tsz Kiu , Chan Ho Ching , Choi Inseo , Ho Pui Yi , Hu Feijun , Kim Yujeong , Lau Hill Lam , Law Ying Lo , Leung Chi Seng , Raina Ritvik , Tong Chun Yin , Wong Kai Kap , Yim Wing Lam , Babak Maria V. , Kong Richard Y. C. , Matsuda Yudai
Published: February 2022

The biosynthetic gene cluster of fungal bioactive sesterterpenoids, variecolin (1) and variecolactone (2), was identified in Aspergillus aculeatus ATCC 16872. Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB. Intriguingly, the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues, one of which exhibited potent anticancer activity comparable to that of 1.
Single-Macromolecular Level Imaging of a Hydrogel Structure
Authors: Kiyama Ryuji , Nonoyama Takayuki , Tomas Sedlacik , Jinnai Hiroshi , Gong Jian Ping
Published: February 2022

Hydrogels are promising materials for several applications, including cell scaffolds and artificial load-bearing substitutes (cartilages, ligaments, tendons, etc.). Direct observation of the nanoscale polymer network of hydrogels is essential in understanding its properties. However, imaging of individual network strands at the molecular level is not achieved yet due to the lack of suitable methods. Herein, for the first time, we developed a novel mineral-staining method and network fixation method for transmission electron microscopy observation to visualize the hydrogel network in its unperturbed conformation with nanometer resolution. Surface network observation indicates that the length of surface dangling chains, which play a major role in friction and wetting, can be estimated from the gel mesh size. Moreover, bulk observations reveals a hierarchical formation mechanism of gel heterogeneity. These observations have the great potential to advance gel science by providing comprehensive perspective that link bulk gel properties with nanoscale.
Maximizing TADF via Conformational Optimization
Authors: Kim Changhae Andrew , Van Voorhis Troy
Published: February 2022

e investigate a new strategy to enhance thermally activated delayed fluorescence (TADF) in organic light-emitting diodes (OLEDs). Given that the TADF rate of a molecule depends on its conformation, we hypothesize that there exists a conformation that maximizes the TADF rate. In order to test this idea, we use time-dependent density functional theory (TDDFT) to simulate the TADF rates of several TADF emitters, while shifting their geometries towards higher TADF rates in a select subspace of internal coordinates. We find that geometric changes in this subspace can increase the TADF rate up to three orders of magnitude with respect to the minimum energy conformation, and the simulated TADF rate can even be brought into the submicrosecond timescales under the right conditions. Furthermore, the TADF rate enhancement can be maintained with a conformational energy that might be within the reach of modern synthetic chemistry. Analyzing the maximum TADF conformation, we extract a number of structural motifs that might provide a useful handle on the TADF rate of a donor-acceptor (DA) system. The incorporation of conformational engineering into the TADF technology could usher in a new paradigm of OLEDs.
The presence and role of the intermediary CO reservoir in heterogeneous electroreduction of CO2
Authors: Louisia Sheena , Kim Dohyung , Li Yifan , Gao Mengyu , Yu Sunmoon , Yang Peidong
Published: February 2022

Despite the importance of the microenvironment in heterogeneous electrocatalysis, its role remains unclear due to a lack of suitable characterization techniques. Multi-step reactions like the electroconversion of CO2 to multicarbons (C2+) are especially relevant considering the potential creation of a unique microenvironment as part of the reaction pathway. To elucidate the significance of the microenvironment during CO2 reduction, we develop on-stream substitution of reactant isotope (OSRI), a new method which relies on the subsequent introduction of CO2 isotopes. Combining electrolytic experiments with a numerical model, this method reveals the presence of a reservoir of CO molecules concentrated near the catalyst surface that influences C2+ formation. Application of OSRI on a Cu nanoparticle (NP) ensemble and an electropolished Cu foil demonstrates that a CO monolayer covering the surface does not provide the amount of CO intermediates necessary to facilitate C-C coupling. Specifically, the C2+ turnover increases only after reaching a density of ~100 CO molecules per surface Cu atom. The Cu NP ensemble satisfies this criterion at an overpotential 100 mV lower than the foil, making it a better candidate for efficient C2+ formation. Furthermore, given the same reservoir size, the ensemble’s intrinsically higher C-C coupling ability is highlighted by the 4-fold higher C2+ turnover it achieves at a more positive potential. The OSRI method provides an improved understanding of how the presence of CO intermediates in the microenvironment impacts C2+ formation during the electroreduction of CO2 on Cu surfaces.
Seeding the Multi-dimensional Nonequilibrium Pulling for Hamiltonian Variation: Indirect Nonequilibrium Free Energy Simulations at QM levels
Authors: Sun Zhaoxi , He Qiaole
Published: February 2022

The combination of free energy simulations in the alchemical and configurational spaces provides a feasible route to access the thermodynamic profiles under a computationally demanding target Hamiltonian. Normally, due to the significant differences between the computational cost of ab initio quantum mechanics (QM) calculations and those of semi-empirical quantum mechanics (SQM) and molecular mechanics (MM), this indirect method could be used to obtain the QM thermodynamics by combining the SQM or MM results and the SQM-to-QM or MM-to-QM corrections. In our previous works, a multi-dimensional nonequilibrium pulling framework for Hamiltonian variations has been introduced based on bidirectional pulling and bidirectional reweighting. The method performs nonequilibrium free energy simulations in the configurational space to obtain the thermodynamic profile along the conformational change pathway under a selected computationally efficient Hamiltonian, and uses the nonequilibrium alchemical method to correct or perturb the thermodynamic profile to that under the target Hamiltonian. The BAR-based method is designed to achieve the best generality and transferability and thus leads to modest (~20 folds) speedup. In this work, we explore the possibility of further accelerating the nonequilibrium free energy simulation by employing unidirectional pulling and using the selection criterion to obtain the initial configurations used to initiate nonequilibrium trajectories following the idea of adaptive steered molecular dynamics (ASMD). A single initial condition is used to seed the whole multi-dimensional nonequilibrium free energy simulation and the sampling is performed fully in the nonequilibrium ensemble. Introducing very short ps-length equilibrium sampling to grab more initial seeds could also be helpful. The ASMD scheme estimates the free energy difference with the unidirectional exponential average (EXP), but it does not follow exactly the requirements of the EXP estimator. Another deficiency of the seeding simulation is the inherently sequential or serial pulling due to the inter-segment dependency, which triggers some problems in the parallelizability of the simulation. Numerical tests are performed to grasp some insights and guidelines for using this selection-criterion-based ASMD scheme. The presented selection-criterion-based multi-dimensional ASMD scheme follows the same perturbation network of the BAR-based method, and thus could be used in various Hamiltonian-variation cases.
Base dependent 1,3-dithioacetals rearrangement over sulfoxidation under visible-light photocatalysis to access disulfide-linked-dithioesters
Authors: Bhat Dr. Ramakrishna G. , Dharpure Pankaj D. , Behera Mousumi , Thube Archana S.
Published: February 2022

Base dependent oxidative rearrangement of dithiolanes and dithianes to access disulfide-linked-dithioesters under visible-light photoredox catalytic conditions has been disclosed. The protocol demonstrated the ability to synthesize either rearranged product or sulfoxide by simply switching the base with inherent ability to make hydrogen bonding with sulfur atom. Unlike, the usual deprotection of thioacetals to corresponding aldehydes under the oxidative conditions, we observed the unique regioselective oxidative reactivity of thioacetals to form disulfide-linked-dithioester or sulfoxides. The generality of the protocol has been demonstrated by exploring a wide range of substrates. As an application the in-situ generated thyil radical has been trapped with disulfides to prepare hetro-disulfides of potential utility. The protocol proved to be practical on gram scale quantity and relied on clean energy source for the transformation. Based on the series of control experiments, cyclic volametry and Stern-Volmer studies the plausible mechanism has been proposed.
Star-shaped molecules cross-bind to SARS-CoV2 spike α-helices in silico
Authors: coll julio
Published: February 2022

Despite docking to the isolated α-helix residues 960-1010 (“spring-loaded switch-folding”, SLSF) of wild-type S spike trimers of Severe Acute Respiratory Syndrome coronavirus (SARS)-CoV2, the star-shaped hydrophobic Tinosorb failed to dock to SLSF inside the S (S-SLSF) and to inhibit viral-host cell membrane fusion1. This work discovered computational star-shaped-similar molecules exhibiting lower binding-scores (higher-affinities) to S-SLSF with probable cross-binding properties of their targeted α-helices but with lower hydrophobicities and smaller molecular sizes. Most star-shaped-similar leads contained Trihydroxyl-Triphenyls arms branching from each of the three carbons of a central Triazine core (TTT). Deconstruction of TTTs by core-replacement (X), fragment extension (F), and 2D deep-screening among millions of molecular possibilities, found additional leads that by combining structural features (F+TTX) reduced their binding-scores to S-SLSF. Such leads maximize their possibilities to stabilize wild-type S-SLSF α-helices, with the aim to reduce host-coronavirus membrane fusion using drug-like ligands rather than mutations.
Star-shaped Triazine-derivatives: would they crossbind SARS-CoV-2 spike helices?
Authors: coll julio
Published: February 2022

This work describes synthesizable water-soluble Triazine-derivatives computationally crossbinding the S spike helices of Severe Acute Respiratory Syndrome coronavirus (SARS)-CoV-2. The "spring-loaded switch-folding” (S-SLSF) α-helices included in the S homotrimer top-to-bottom cavity and implicated in viral-host membrane fusion were targeted by star-shaped Trihydroxyl-Triphenyl-Triazines (TTT) leads at subnanomolar binding-scores. Exploration of in silico leads among millions of molecular candidates, included several similar searches, core-replacement, fragment extensions, or convolutional neural network deep-screening combined with hundreds of water-soluble lead-derivatives identified by manual iterations and commercially available building-blocks for chemical synthesis. The lead-derivatives are briefly discussed for in vitro validation and possibilities of fusion inhibition substituting mutations.
Direct Observations of Anthracene Clusters at Ice Surfaces
Authors: Chakraborty Subha , Stubbs Annastacia , Kahan Tara
Published: February 2022

Heterogeneous processes can control atmospheric composition. Snow and ice present important, but poorly understood, reaction media that can greatly alter the composition of air in the cryosphere in polar and temperate regions. Atmospheric scientists struggle to reconcile model predictions with field observations in snow-covered regions due to experimental challenges associated with monitoring reactions at air-ice interfaces, and debate regarding reaction kinetics and mechanisms has persisted for over a decade. In this work, we use wavelength-resolved fluorescence microscopy to determine the distribution and chemical speciation of the pollutant anthracene at the surfaces of environmentally relevant frozen surfaces. We show that anthracene adsorbs to frozen surfaces in monomeric form, but that following lateral diffusion, molecules ultimately reside within brine channels at saltwater ice surfaces, and in micron-sized clusters at freshwater ice surfaces; emission profiles indicate extensive self-association. We also measure anthracene photodegradation kinetics in aqueous solution and artificial snow prepared from frozen freshwater and saltwater solutions and use the micro-spectroscopic observations to explain the rate constants measured in different environments. These results resolve long-standing debates and will improve predictions of pollutant fate in the cryosphere. The techniques used can be applied to numerous surfaces within and beyond the atmospheric sciences.
Improved syntheses of halogenated benzene-1,2,3,4-tetracarboxylic diimides
Authors: Zou Brian , Stellmach Kellie A. , Luo Stella M. , Gebresilassie Feven L. , Zhang Cathy K. , Bass Adam D. , Janzen Daron E. , Cao Dennis D.
Published: February 2022

The preparation of halogenated benzene-1,2,3,4-tetracarboxylic diimide derivatives is challenging because of the possibility of competitive incorrect cyclizations and SNAr reactivity. Here, we demonstrate that the direct reaction of benzene-1,2,3,4-tetracarboxylic acids with primary amines in acetic acid solvent successfully provides a range of desirable ortho-diimide products in good yields. Furthermore, we demonstrate that sterically challenging N-derivatizations can be readily achieved under microwave reactor conditions, and that SNAr reactivity is only observed when excess amine is used. The halogenated diimides described here are attractive building blocks for organic materials chemistry.
Catalytic Static Mixer-Enabled Hydrogenation of a Key Fenebrutinib Intermediate: Real-time Analysis for a Stable and Scalable Process
Authors: Lebl René , Bachmann Stephan , Tosatti Paolo , Sedelmeier Joerg , Püntener Kurt , Williams Jason D. , Kappe C. Oliver
Published: February 2022

Catalytic static mixer (CSM) technology is presented as an industrially-viable solution for an aromatic nitro group reduction in the synthesis of fenebrutinib. Factors effecting catalyst inhibition could be rapidly understood and mitigated by the use of real-time analytics (FT-IR, UHPLC). This facilitated the development of stable and optimal conditions in a system with 4 CSMs positioned inside a thermostated shell-and-tube reactor. Additional care was taken to ensure the control of three key impurities to low levels (< 0.10 area% by offline UHPLC analysis). The optimal conditions (0.4 M concentration, 20 bar, 120 °C, 3.3 equiv H2) were then scaled up to a reactor with 8 CSMs, whereby an improvement in space-time yield was observed. Over 16 h of processing, a stable impurity profile was observed, without metal leaching. Finally, the reaction was performed in a system with 16 CSMs, which also provided an increase in space-time yield (to 26.2 mol/L/h or 6.5 kg/L/h), resulting in 174 g/h throughput, whilst maintaining an excellent impurity profile.
Splitting chemical structure data sets for federated privacy-preserving machine learning
Authors: Simm Jaak , Humbeck Lina , Zalewski Adam , Sturm Noe , Heyndrickx Wouter , Moreau Yves , Beck Bernd , Schuffenhauer Ansgar
Published: February 2022

With the increase in applications of machine learning methods in drug design and related fields, the challenge of designing sound test sets becomes more and more prominent. The goal of this challenge is to have a realistic split of chemical structures (compounds) between training, validation and test set such that the performance on the test set is meaningful to infer the performance in a prospective application. This challenge is by its own very interesting and relevant,but is even more complex in a federated machine learning approach where multiple partners jointly train a model under privacy-preserving conditions where chemical structures must not be shared between the different participating parties in the federated learning. In this work we discuss three methods which provide a splitting of the data set and are applicable in a federated privacy-preserving setting, namely: a. locality-sensitive hashing (LSH), b. sphere exclusion clustering, c. scaffold-based binning (scaffold network). For evaluation of these splitting methods we consider the following quality criteria: bias in prediction performance, label and data imbalance, distance of the test set compounds to the training set and compare them to a random splitting. The main findings of the paper are a. both sphere exclusion clustering and scaffold-based binning result in high quality splitting of the data sets, b. in terms of compute costs sphere exclusion clustering is very expensive in the case of federated privacy-preserving setting.
Structural Basis for the Friedel-Crafts Alkylation in Cylindrocyclophane Biosynthesis
Authors: Wang Hua-Qi , Mou Shu-Bin , Xiao Wen , Hou Xu-Dong , Zhou Huan , Wang Su-Jing , Wang Qian , Gao Jiali , Wei Zhiyi , Liu Lijun , Xiang Zheng
Published: February 2022

The Lewis acid-catalyzed Friedel-Crafts alkylation of an aromatic ring with an alkyl halide is extensively used in organic synthesis. However, its biological counterpart was not reported until the elucidation of the cylindrocyclophane biosynthetic pathway in Cylindrospermum licheniforme ATCC 29412 by Balskus and co-workers. CylK is the key enzyme to catalyze the formation of the cylindrocyclophane scaffold through the Friedel-Crafts alkylation reactions with regioselectivity and stereospecificity. Further research demonstrates that CylK can accept other resorcinol rings and secondary alkyl halides as substrates. To date, the crystal structure of CylK has not been disclosed and the catalytic mechanism remains obscure. Herein we report the crystal structures of CylK in its apo form and its complexes with the analogues of its substrate and reaction intermediate. Combining the crystal structures, free energy simulations and the mutagenesis experiments, we proposed a concerted double-activation mechanism, which could explain the regioselectivity and stereospecificity. This work provides a foundation for engineering CylK as a biocatalyst to expand its substrate scope and applications in organic synthesis.
Disparities in Air Pollution Exposure in the United States by Race-Ethnicity and Income, 1990 – 2010
Authors: Liu Jiawen , Clark Lara P. , Bechle Matthew , Hajat Anjum , Kim Sun-Young , Robinson Allen , Sheppard Lianne , Szpiro Adam A. , Marshall Julian D.
Published: February 2022

All data used are publicly available. Demographic data are available via IPUMS National Historic Geographic Information Systems [www.nhgis.org]; air pollution estimates are available via the EPA CACES project [www.caces.us]).
Direct metal-carbon bonding in symmetric bis(C-H) agostic Nickel(I) complexes
Authors: He Weiying , Beattie D. Dawson , Zhou Hao , Bowes Eric G. , Schafer Laurel L , Love Jennifer A , Kennepohl Pierre
Published: February 2022

Agostic interactions are examples of σ-type interactions, typically resulting from interactions between C-H σ-bonds with empty transition metal d orbitals. Such interactions often reflect the first step in transition metal-catalysed C-H activation processes and thus are of criticial importance in understanding and controlling σ bond activation chemistries. Herein, we report on the unusual electronic structure of linear electron-rich d9 Ni(I) complexes with symmetric bis(C-H) agostic interactions. A combination of Ni K edge and L edge XAS with supporting TD-DFT/DFT calculations reveals an unconventional covalent agostic interaction with limited contributions from the valence Ni 3d orbitals. The agostic interaction is driven via the empty Ni 4p orbitals. The surprisingly strong Ni 4p-derived agostic interaction is dominated by σ contributions with minor π contributions. The resulting ligand-metal donation occurs directly along the C-Ni bond axis, reflecting a novel mode of bis- agostic bonding.
Local perturbations of periodic systems. Chemisorption and point defects by GoGreenGo.
Authors: Tchougreeff Andrei L. , Kuhsnir Timofey , Popov Ilya
Published: February 2022

We present a software package GoGreenGo -- aimed to model local perturbations of periodic systems due to either chemisorption or point defects. The electronic structure of an ideal crystal is obtained by worldwide distributed standard quantum physics/chemistry codes, then processed by various tools performing projection to atomic orbital basis sets. Starting from this, the perturbation is addressed by GoGreenGo with use of the Green's functions formalism, which allows to evaluate its effect on the electronic structure, density matrix and energy of the system. In the present contribution the main accent is made on processes of chemical nature such as chemisorption or doping. We address a general theory and its computational implementation supported by a series of test calculations for benchmark model solids: simple, face-centered and body-centered cubium systems. In addition, more realistic problems of local perturbations in graphene lattice such as lattice substitution, vacancy and "on-top" chemisorption are considered.
Selective Covalent Targeting of SARS-CoV-2 Main Protease by Enantiopure Chlorofluoroacetamide
Authors: Yamane Daiki , Onitsuka Satsuki , Re Suyong , Isogai Hikaru , Hamada Rui , Hiramoto Tadanari , Kawanishi Eiji , Mizuguchi Kenji , Shindo Naoya , Ojida Akio
Published: February 2022

The pandemic of COVID-2019 has urged the development of antiviral agents against its causative pathogen SARS-CoV-2. The main protease (Mpro), a cysteine protease essential for viral replication, is a promising protein target. Here we report an irreversible SARS-CoV-2 Mpro inhibitor possessing chlorofluoroacetamide (CFA) as the warhead for covalent modification of Mpro. Ugi multi-component reaction employing chlorofluoroacetic acid allowed rapid generation of CFA derivatives, of which diastereomers displayed significantly different inhibitory activity against Mpro. We established a practical protocol for the optical resolution of chlorofluoroacetic acid, which enable the isolation of the stereoisomers of the best CFA compound. Kinetic analysis revealed that (R)-CFA is crucial for both binding affinity and the rate of irreversible inactivation of Mpro. Our findings highlight the prominent influence of the CFA chirality on the covalent modification of cysteine, and provide the basis for improving the potency and selectivity in the development of novel CFA-based covalent inhibitors.
Ultrafast Photochemistry of a Molybdenum Carbonyl-Nitrosyl Complex with a Triazacyclononane Coligand
Authors: Gessner Niklas , Bäck Anna K. , Knorr Johannes , Nagel Christoph , Marquetand Philipp , Schatzschneider Ulrich , González Leticia , Nuernberger Patrick
Published: February 2022

Transition metal complexes capable of releasing small-molecule messengers such as carbon monoxide and nitric oxide upon photoactivation are versatile tools in various fields of chemistry and biology. In this work, we report on the ultrafast photochemistry of [Mo(CO)2(NO)(iPr3tacn)]PF6 (iPr3tacn = 1,4,7-triisopropyl-1,4,7-triazacyclononane), which was synthesized and subsequently characterized in continuous illumination studies and with femtosecond UV-pump/UV-probe and UV-pump/MIR-probe spectroscopy, as well as with stationary calculations. The experimental and theoretical results demonstrate that while the photodissociation of one of the two CO ligands upon UV excitation can be inferred both on an ultrafast timescale as well as under exposure times of several minutes, no evidence of NO release is observed under the same conditions. The binding mode of the diatomic ligands is impacted by the electronic excitation, and excited molecules are observed on a timescale of tens of picoseconds before CO is released from the coordination sphere. Furthermore, based on calculated potential energy scans, we suggest that photolysis of NO could be possible after a subsequent excitation of an electronically excited state with a second laser pulse, or by accessing low-lying excited states that otherwise cannot be directly excited by light.
Probing tricarbocyanine dyes for targeted delivery of anthracyclines
Authors: Veriutin Dmitriy , Doroshenko Irina , Martynova Ekaterina , Sapozhnikova Ksenya , Svirshchevskaya Elena , Shibaeva Anna , Markova Alina , Chistov Alexey , Borisova Natalya , Shuvalov Maxim , Korshun Vladimir , Alferova Vera , Podrugina Tatyana
Published: February 2022

Heptamethine carbocyanine dyes possess bright fluorescence in the near IR range and affinity to cancer cells. Thus, these dyes could be utilized as fluorescent labels and vectors for drug delivery in their covalent conjugates with cytotoxic compounds. In this work we synthesized four drug-dye conjugates of tricarbocyanine dyes with anthracycline drug daunorubicin using a CuAAC reaction. Conjugates with hydrophobic dyes possess submicromolar cytotoxicity. Fluorescent imaging revealed significant accumulation of the conjugates in mitochondria, suggesting an enhancement of an additional mechanism of anthracycline cytotoxicity – generation of ROS. The hypothesis was supported by significant reduction of activity of the conjugates in presence of an antioxidant compound.
Interaction Energy Analysis of Monovalent Inorganic Anions in Bulk Water Versus Air/Water Interface
Authors: Herbert John , Paul Suranjan
Published: February 2022

Soft anions exhibit surface activity at the air/water interface that can be probed using surface-sensitive vibrational spectroscopy, yet the statistical mechanics behind this surface activity remains a matter of debate. Here, we examine the nature of anion–water interactions at the air/water interface using a combination of molecular dynamics simulations and quantum-mechanical energy decomposition analysis based on symmetry-adapted perturbation theory. Results are presented for a set of monovalent anions including Cl–, Br–, I–, CN–, OCN–, SCN–, NO2–, NO3–, and ClOn– (n = 1, 2, 3, 4), several of which are archetypal examples of surface-active species. In all cases, we find that average anion–water interaction energies are systematically larger in bulk water although the difference (with respect to the interaction energy in the interfacial environment) is well within the magnitude of the instantaneous fluctuations. Specifically for the surface-active species Br–(aq), I–(aq), ClO4–(aq), and SCN–(aq), and also for ClO–(aq), the charge-transfer (CT) energy is found to be larger at the interface than it is in bulk water, by an amount that is greater than the standard deviation of the fluctuations. The Cl– ion also has a slightly larger CT energy at the interface but NO3–(aq) does not; these two species are borderline cases where consensus is lacking regarding their surface activity. However, CT stabilization amounts to < 20% of the total induction energy, for all of the ions considered here, and CT-free polarization energies are systematically larger in bulk water, again in all cases, so the role of these effects in soft anion surface activity remains unclear. This analysis complements our recent work suggesting that the short-range solvation structure around these ions is scarcely different at the air/water interface from what it is in bulk water. Together, these observations suggest that changes in first-shell hydration structure around soft anions cannot explain observed surface activities.
A Visible Light-triggered Ferroptosis Probe: Visualization, Endoplasmic Reticulum Localization and Photo-induced Lipid Peroxidation
Authors: Song Zhibin , Xing Zhiming , Yan Jiangyu , Miao Yongxiang , Ruan Yawen , Zhou Youkang , Tang Yingqun , Li Guorui , Huang Jing , Peng Yiyuan
Published: February 2022

Accumulation of lethal lipid peroxidation plays the central role in ferroptosis initiation and execution. However, it remains unclear whether the location of lipid peroxidation accumulation in subcellular organelles contributes to ferroptosis initiation due to the lack of specific small-molecule probe. Here we report a quinazolinone-pyridine difluoroboron complex (BODIQPys) with vinyltriphenylamine modification, BODIQPy-TPA, as a near-infrared (NIR) bioimaging and photo-induced ferroptosis bifunctional probe. BODIQPy-TPA with D-π-A structure exhibits a good endoplasmic reticulum (ER) localization and photo-activated lipid reactive oxygen species (ROS) generation. The photo-induced ferroptosis is confirmed by morphological changes of live cell fluorescence imaging, suppression of cell death by a ferroptosis inhibitor (Fer-1) and down-regulation of ferritin heavy polypeptide 1 (FTH1). This study is the first example of visual photo-induced ferroptosis by small organic molecular probe, which provides a promising tool for further investigation of the direct relationship between lipid peroxidation accumulation and ferroptosis. Moreover, ferroptosis induced by photodynamic therapy (PDT) process in ER will be a good strategy to improve the efficiency of PDT for apoptosis-resistant tumor cells.
Hydration dynamics gives the distinctive brown color in the "brown ring" nitrate test
Authors: Banerjee Ambar , Coates Michael R. , Odelius Michael
Published: February 2022

The brown ring test is one of the most popular and visually appealing reagent tests, commonly known to chemistry undergrads and familiar even to school students. The exact composition, mechanism and structure of the complex has been investigated for nearly a century. Recent studies have elucidated its UV-vis, EPR and Mossbauer spectra, mechanistic details and kinetics, followed by crystallization and structure determination in solid state. Nonetheless these studies were unable to address the aspects of solution structure and dynamics of the brown ring complex. We have conducted ab initio molecular dynamics simulations of the classic brown ring complex in aqueous solution. In the process from the simulation trajectory, we have identified that the classically established pseudo-octahedral [Fe(H2O)5(NO)]2+ complex is in chemical equilibrium with the square-pyramidal [Fe(H2O)4(NO)]2+ complex through the exchange of one of the coordinated H2O molecules. The dynamics in aqueous solution between the penta-aqua and tetra-aqua complexes in the brown ring system has to our knowledge never been suggested earlier. Interestingly we find, using ab initio multi-reference quantum chemical methods i.e. CASSCF/NEVPT2 and CASPT2 calculations, that the mixture of these two complexes is what gives the distinctive brown coloration to the brown ring test. We show that its UV-vis spectrum can be theoretically reproduced only by accounting these two species, and not solely the classically established [Fe(H2O)5(NO)]2+ complex. The energetics of the penta-aqua and tetra-aqua complexes is also investigated at the level of multi-reference quantum chemical methods.
Simultaneous Measurement of Photocurrent and Recombination Emission in Organic Solar Cell
Authors: Lee Ji-Hyun , Hiramoto Masahiro , Izawa Seiichiro
Published: February 2022

In this study, we measured the recombination emission from the CT state under different applied voltage in the OSC device and a photocurrent density flowing on the circuit simultaneously. By the experiment, we extracted only the information of CT state emission at the interface and proposed `PL-V plot` that is the voltage dependence of PL intensity of the CT state. The PL-V plot includes the information only from the radiative recombination at donor/acceptor interface, and is complementary to the `J-V plot` that is the most important information for evaluating OSCs. The result demonstrated that the fill factor of PL-V plot is definitely higher than that of J-V plot because the PL-V plot observes the CT state recombination only at the D/A interface, predicting the ideal FF of the device.
Leveraging molecular structure and bioactivity with chemical language models for drug design
Authors: Moret Michael , Grisoni Francesca , Brunner Cyrill , Schneider Gisbert
Published: February 2022

Generative chemical language models (CLMs) can be used for de novo molecular structure generation. These CLMs learn from the structural information of known molecules to generate new ones. In this paper, we show that “hybrid” CLMs can additionally leverage the bioactivity information available for the training compounds. To computationally design ligands of phosphoinositide 3-kinase gamma (PI3Kγ), we created a large collection of virtual molecules with a generative CLM. This primary virtual compound library was further refined using a CLM-based classifier for bioactivity prediction. This second hybrid CLM was pretrained with patented molecular structures and fine-tuned with known PI3Kγ binders and non-binders by transfer learning. Several of the computer-generated molecular designs were commercially available, which allowed for fast prescreening and preliminary experimental validation. A new PI3Kγ ligand with sub-micromolar activity was identified. The results positively advocate hybrid CLMs for virtual compound screening and activity-focused molecular design in low-data situations.