bluuebunny/crossref_metadata_2025 huggingface dataset:
Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity
Authors: Imaide Satomi , Riching Kristin M. , Makukhin Nikolai , Vetma Vesna , Whitworth Claire , Hughes Scott J. , Trainor Nicole , Mahan Sarah D. , Murphy Nancy , Cowan Angus , Chan Kwok-Ho , Craigon Conner , Testa Andrea , Maniaci Chiara , Urh Marjeta , Daniels Danette L. , Ciulli Alessio
Published: February 2022

Bivalent PROTACs work drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhanced degradation. Here, we designed trivalent PROTACs consisting of a bivalent BET inhibitor and an E3 ligand, tethered via a branched linker. We identified VHL-based SIM1 as a low picomolar BET degrader, with preference for BRD2. Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anti-cancer activity. Mechanistically, SIM1 simultaneously engages with high avidity both BET bromodomains in a cis intramolecular fashion and forms a 1:1:1 ternary complex with VHL exhibiting positive cooperativity and high cellular stability with prolonged residence time. Collectively, our data along with favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities can be an enabling strategy for advancing functional outcomes.
Response process validity evidence in chemistry education research
Authors: Deng Jacky M. , Streja Nicholas , Flynn Alison B.
Published: February 2022

Response process validity evidence can provide researchers with insight into how and why participants interpret items on instruments (e.g., tests, questionnaires). In the chemistry education research literature and in the social sciences more broadly, there has been variable use and reporting of response process aspects of studies. This manuscript’s objective is to support researchers in developing purposeful, theory-driven protocols to investigate response processes. We highlight key considerations for researchers who are interested in using cognitive interviews in their research, including: the theoretical basis for response process, collecting response process validity evidence through cognitive interviews, and using that evidence to inform instrument modifications.
Towards optimal photocatalytic hydrogen generation from water using pyrene-based metal-organic frameworks
Authors: Kinik F. Pelin , Guerrero Andres Ortega , Ebrahim Fatmah Mish , Ireland Christopher P. , Kadioglu Ozge , Mace Amber , Asgari Mehrdad , Smit Berend
Published: February 2022

Metal organic frameworks (MOFs) are promising materials for the photocatalytic H2 evolution reaction (HER) from water. To find the optimal MOF for a photocatalytic HER one has to consider many different factors. For example, studies have emphasized the importance of light absorption capability, optical band gap and band alignment. However, most of these studies have been carried on very different materials. In this work, we present a combined experimental and computation study of the photocatalytic HER performance, of a set of isostructural pyrene-based MOFs (M-TBAPy, where M = Sc, Al, Ti, and In). We systematically studied the effects of changing the metal in the node on the different factors that contribute to the HER rate (e.g., optical properties, the band structure, water adsorption). In addition, for Sc-TBAPy we also studied the effect of changes in crystal morphology on the photocatalytic HER rate. We used this understanding to improve photocatalytic HER efficiency of Sc-TBAPy, to exceed the one reported for Ti-TBAPy, in the presence of co-catalyst.
Efficient simulation of arbitrary multi-component first-order binding kinetics for improved assay design and molecular assembly
Authors: Briggs Kyle , Bouhamidi Mohamed Yassine , He Liqun , Tabard-Cossa Vincent
Published: February 2022

Traditional ELISA, long the workhorse for specific target protein detection using microplate wells, is nearing its fundamen-tal limit of sensitivity. New opportunities in healthcare call for in vitro diagnostic tests with ultra-high sensitivity. Magnetic bead-based ELISA formats have been developed that can reach unprecedented sensitivities order of magnitude better than are allowed for by the rate constants for a single ligand-receptor interaction. However, these ultra-high sensitivity assays are highly vulnerable to a host of confounding factors, including nonspecific binding from background molecules and loss of low-abundance target to tube walls and during wash steps. Moreover, optimization of workflow is often time-consuming and expensive. In this work, we present a simulation tool that allows users to graphically define arbitrary binding assays, includ-ing fully reversible first-order binding kinetics, timed addition of extra components, and timed wash steps. The tool is freely available as a user-friendly webapp. The framework is lightweight and fast, allowing for inexpensive simulation and visuali-zation of arbitrarily complex assay schemes, including but not limited to digital immunoassays, DNA hybridization, and enzyme kinetics, for validation and optimization of assay designs without requiring any programming knowledge from the user. We demonstrate some of these capabilities and provide practical guidance on assay simulation design.
Activation by oxidation and ligand exchange in a molecular manganese vanadium oxide water oxidation catalyst
Authors: Cardenas Gustavo , Trentin Ivan , Schwiedrzik Ludwig , Hernández-Castillo David , Lowe Grace A. , Kund Julian , Kranz Christine , Klingler Sarah , Stach Robert , Mizaikoff Boris , Marquetand Philipp , Nogueira Juan J. , Streb Carsten , González Leticia
Published: February 2022

Despite their technological importance, reaction mechanisms of most water oxidation catalysts (WOCs) are poorly understood. We combine theoretical and experimental methods to reveal mechanistic insights into the reactivity of the highly active molecular WOC [Mn4V4O17(OAc)3]3-. Using density functional theory, electrochemistry and IR-spectroscopy, we propose a three-step activation mechanism: one-electron oxidation [Mn3+2Mn4+2]→[Mn3+Mn4+3], acetate-to-water ligand exchange, and another one-electron oxidation [Mn3+Mn4+3]→[Mn4+4]. Analysis of ligand exchange pathways shows that nucleophilic attack of water molecules along the Jahn-Teller axis of Mn3+ centers leads to lower activation barriers than attack at Mn4+ centers. Deprotonation of one water ligand by the leaving acetate group leads to formation of the activated species [Mn4V4O17(OAc)2(H2O)(OH)]1-. Computed Redox potentials are in excellent agreement with electrochemical measurements. This interplay between redox chemistry and ligand exchange controls the formation of the catalytically active species. These results provide key reactivity information essential to further study bio-inspired molecular WOCs and solid-state manganese oxide catalysts.
Insights into the Importance of WPD-Loop Sequence for Activity and Structure in Protein Tyrosine Phosphatases
Authors: Shen Ruidan , Crean Rory M. , Olsen Keith J. , Richan Teisha , Brandão Tiago A. S. , Berry Ryan D. , Tolman Alex , Loria J. Patrick , Johnson Sean J. , Kamerlin Shina Caroline Lynn , Hengge Alvan C.
Published: February 2022

Protein tyrosine phosphatases (PTPs) possess a mobile, conserved catalytic loop, the WPD-loop, which brings an aspartic acid into the active site where it acts as an acid/base catalyst. Prior experimental and computational studies, focused on the human enzyme PTP1B and the PTP from Yersinia pestis, YopH, suggested that loop conformational dynamics are important in regulating both catalysis and evolvability. Also, work on Chimeras of YopH bearing parts of the WPD-loop sequence from PTP1B demonstrated unusual structural perturbations and reduced activity. In the present study, we have generated a chimeric protein in which the WPD-loop of YopH is transposed into PTP1B, and eight chimeras that systematically restored the loop sequence back to native PTP1B. Of these, four chimeras were soluble and were subjected to detailed biochemical and structural characterization, and a computational analysis of their WPD-loop dynamics in catalysis. These chimeras maintain backbone structural integrity, with somewhat slower rates than either wild-type parent, despite unaltered chemical mechanisms and transition states. The chimeric proteins’ WPD-loops differ significantly in their relative stability and rigidity. In particular, the open WPD-loops sample multiple metastable and interconverting conformations. The time required for interconversion, coupled with electrostatic effects revealed by simulations, likely accounts for the activity differences between chimeras, and relative to the native enzymes. These differences in loop dynamics affect both the pH dependency of catalysis and turnover rate. Our results further the understanding of connections between enzyme activity and the dynamics of catalytically important groups, particularly the effects of non-catalytic residues on key conformational equilibria.
Automated High Throughput pKa and Distribution Coefficient Measurements of Pharmaceutical Compounds for the SAMPL8 Blind Prediction Challenge
Authors: Bahr Matthew , Nandkeolyar Aakankschit , Kenna John , DaVia Luigi , Nevins Neysa , Isik Mehtap , Chodera John , Mobley David
Published: February 2022

The goal of the SAMPL (Statistical Assessment of the Modeling of Proteins and Ligands) challenge is to improve the accuracy of current computational models to estimate free energy of binding, deprotonation, distribution and other associated physical properties that are useful for the design of new pharmaceutical products. New experimental datasets of physicochemical properties provide opportunities for prospective evaluation of computational prediction methods. Here, aqueous pKa and a range of bi-phasic logD values for a variety of pharmaceutical compounds were determined through a streamlined automated process to be utilized in the SAMPL8 physical property challenge. The goal of this paper is to provide an in-depth review of the experimental methods utilized to create a comprehensive data set for the blind prediction challenge. The significance of this work involves the use of high throughput experimentation equipment and instrumentation to produce acid dissociation constants for twenty-three drug molecules, as well as distribution coefficients for eleven of those molecules.
Evaluating performance and cycle life improvements in the latest generations of prismatic lithium-ion batteries
Authors: Svens Pontus , Groot Jens , Smith Alexander , Lacey Matthew , Wreland Lindström Rakel , Lindbergh Göran
Published: February 2022

The last decade has seen an enormous improvement of energy density for lithium-ion battery cells, particularly for automotive grade cells intended for use in electrified vehicles. This has led to vastly improved range for battery electric vehicles as well as for plug-in hybrids. However, the challenge of uncertain battery lifetime remains. The ageing effect due to fast charging is especially difficult to predict due to its non-linear dependence on charge rate, state-of-charge and temperature. We here present results from fast charging (1C and 3C in a 20 % to 80 % SOC-level) of several energy-optimized, prismatic lithium-ion battery cell generations utilizing NMC/graphite chemistry through comparison of capacity retention, resistance and dQ/dV analysis. Considerable improvements are observed throughout cell generations and the results imply that acceptable cycle life can be expected, even under fast charging, when restricting the usage of the available battery capacity. Even though this approach reduces the useable energy density of a battery system, this trade-off could still be acceptable for vehicle applications where conventional overnight charging is not possible. The tested cell format (the VDA PHEV2-standard) has been used for a decade in different electrified vehicles. The ongoing development and improvement of this cell format by several battery cell manufacturers suggests it will continue to be a good choice for future vehicles.
N-donor Base Adducts of P2O5 as Diphosphorylation Reagents
Authors: Shepard Scott , Cummins Christopher
Published: February 2022

Donor-stabilized adducts of the P2O5 molecule are reported. The compounds are of the general formula P2O5D2, where D = DABCO, pyridine, and DBU. The DABCO adduct was initially prepared from trimetaphosphate but could be prepared more conveniently from phosphorus pentoxide. The reactions leading to P2O5D2 (D = DABCO) also generate P3O8D3 and both adducts were structurally characterized. The pyridine adduct P2O5D2 (D = pyridine) was most easily prepared in good purity and yield and thus its diphosphorylation chemistry was developed. Its reaction with protic nucleophiles MeOH and HNEt2 yield salts of [P2O7Me2]2-, a dimethyl ester of pyrophosphate, and [P2O5(NEt2)2]2-, a phosphoramidate derivative which was structurally characterized. Diphosphorylation of adenosine monophosphate yielded a cyclic intermediate which could be opened by nucleophiles including water to provide ATP, diethylamine to provide γ-diethylamino-ATP, and uridine monophosphate to provide adenosine uridine tetraphosphate. Adenosine diphosphate was diphosphorylated to provide, following hydrolytic ring opening, adenosine tetraphosphate.
Mechanism of the Photodegradation of A-D-A Acceptors for Organic Photovoltaics
Authors: Che Yuxuan , Niazi Rizwan , Izquierdo Ricardo , Perepichka Dmitrii
Published: February 2022

In this work, we elucidate the photodegradation pathway of IT-4F, a benchmark A-D-A type semiconductor for organic photovoltaics. The photoproducts were isolated and shown to be isomers of IT-4F formed via a 6-e electrocyclic reaction between the dicyanomethylene unit and the thiophene ring, followed by a 1,5-sigmatropic hydride shift. Importantly, this photoisomerization is accelerated under inert conditions which is explained by DFT calculations that predict the reaction to occur via the excited triplet state (quenchable by oxygen). Adding controlled amounts of the photocyclized product P1 to PM6:IT-4F bulk heterojunction cells shows a progressive decrease of photocurrent and fill factor attributed to its poorer absorption and charge transport properties. The power conversion efficiency drops from 12% for pure IT-4F to 3% for pure P1 acceptor. This cyclization is a general photodegradation pathway for a series of analogous A-D-A molecules with 1,1-dicyanomethylene-3-indanone termini. However, the rate of the reaction varies widely with the nature of the donor moiety.
Strain driven negative Poisson's ratio and extraordinary light-harvesting response of Penta-BCN monolayer
Authors: Bhandari Sharma Shambhu , Bhatta Ramchandra , Adhikari Rajendra , Paudyal Durga
Published: February 2022

We report here, structural, dynamic, and mechanical stability in pentagonal boron carbon nitride (p-BCN) monolayer, a new member of direct bandgap two-dimensional (2D) semiconductor. The identified visible range bandgap with excellent mechanical strength allows it to be a promising candidate material in optoelectronics and nanomechanics. By employing density functional theory (DFT), we reveal a unique geometrical reconstruction with rigidity in B$ - $N and C$ - $N bond lengths with applied strain. These quasi-sp$ ^3$ hybridized short and strong covalent bonding and unique geometry support the monolayer to possess extraordinary mechanical response. Remarkably, the very rare, negative Poisson's ratio (NPR), with softening and hardening, mechanical anisotropy to isotropy is achieved with the application of a small value of strain. Similarly, the desired bandgap is manipulated by loading the biaxial strain. Most importantly, our predictions on p-BCN show excellent optical response such as good static dielectric constant and refractive index, strong optical absorption (up to 1.08$\times$10$ ^5 $ $ {cm}^{-1}$ in VR and 7.01$\times$10$ ^5 $ $ {cm}^{-1}$ in UV) with small energy loss and reflectance both appearing in visible and ultraviolet regions (UV). The desired optical response along with the blue and red shift is demonstrated by tailoring with tensile and compressive strain. Additionally, the predicted strong optical anisotropy provides it's application in polarized photodetection.
Toward the Creation of Induced Pluripotent Small (iPS) Molecules: Establishment of a Modular Synthetic Strategy to the Heronamide C-type Polyene Macrolactams and Their Conformational and Reactivity Analysis
Authors: Kanoh Naoki , Terajima Yuta , Tanaka Suguru , Terashima Ryusei , Nishiyama Hiromichi , Nagasawa Shota , Sasano Yusuke , Iwabuchi Yoshiharu , Nishimura Shinichi , Kakeya Hideaki
Published: February 2022

A highly modular synthetic strategy to the heronamide C-type polyene macrolactams was established by synthesizing 8-deoxyheronamide C (2). The developed strategy enabled not only the total synthesis of 8-deoxyheronamide C (2) but also the unified synthesis of four heronamide-like molecules named “heronamidoids” (5–8). Conformational and reactivity analysis of the heronamidoids clarified that (1) the C19 stereochemistry mainly affected the conformation of the amide linkage, resulting in the change of alignment of two polyene units and reactivity towards photochemical [6π+6π] cycloaddition, and (2) the C8,C9-diol moiety is important for the conversion to the heronamide A-type skeleton from the heronamide C skeleton.
Investigation of CO2 Orientational Dynamics through Simulated NMR Line Shapes
Authors: Melix Patrick , Heine Thomas
Published: February 2022

The dynamics of CO2 in third generation Metal-Organic Frameworks can be experimentally observed by 13C NMR spectroscopy. The obtained line shapes directly correlate with the motion of the adsorbed CO2, which in turn are readily available from classical molecular dynamics simulations. In this article, we present our publicly available implementation of an algorithm to calculate NMR line shapes from MD trajectories in a matter of minutes on any current personal computer. We apply the methodology to study an effect observed experimentally when adsorbing CO2 in different samples of the pillared layer MOF DUT-8(Ni). In 13C NMR experiments of adsorbed CO2 in this MOF, small (rigid) crystals result in narrower NMR line shapes than larger (flexible) crystals. The reasons for the higher mobility of CO2 inside the smaller crystals is unknown. Our ligand field molecular mechanics simulations provide atomistic insight into the effects visible in NMR experiments with limited computational effort.
Making it rain: cloud-based molecular simulations for everyone
Authors: Arantes Pablo Ricardo , Depólo Polêto Marcelo , Pedebos Conrado , Ligabue-Braun Rodrigo
Published: February 2022

We present a user-friendly front-end for running molecular dynamics (MD) simulations using OpenMM toolkit on the Google Colab framework. Our goals are: 1) to highlight the usage of a cloud-computing scheme for educational purposes for a hands-on approach when learning MD simulations and 2) to exemplify how low-income research groups can perform MD simulations in the microsecond timescale. We hope this work facilitates teaching and learning of molecular simulation throughout the community.
Is Dissociation of HCl in DMSO Clusters Bistable?
Authors: Sadhukhan Debopriya , Hsu Po-Jen , Kuo Jer-Lai , Patwari G Naresh
Published: February 2022

The dissociation of HCl embedded in DMSO clusters was investigated by projecting the solvent electric field along the HCl bond using B3LYP-D3/6-31+G(d) and MP2/6-31+G(d,p) levels of theory. The B3LYP-D3 calculations reveal that the dissociation of HCl embedded in DMSO clusters requires a critical electric field of 138 MV cm–1 along the H–Cl bond. However, a large number of exceptions wherein the electric field values much higher than the critical electric field of 137 MV cm–1 did not result in dissociation of HCl. On the other hand, the MP2 level calculations reveal that the critical electric field for the HCl dissociation is about 181 MV cm–1 with almost no exceptions. The B3LYP-D3 calculations suggest that the dissociation of HCl embedded in DMSO clusters is bistable, which is an artefact. The answer to the question raised as the title of this paper is NO.
Preparation of Bioderived and Biodegradable Surfactants Based on an Intrinsically Disordered Protein Sequence
Authors: Klass Sarah , Gleason Jamie , Omole Anthony , Onoa Bibiana , Bustamante Carlos , Francis Matthew
Published: February 2022

Surfactants, block-copolymers, and other types of micellar systems are used in a wide variety of biomedical and industrial processes. However, most commonly used surfactants are synthetically derived and pose environmental and toxicological concerns throughout their product life cycle. Because of this, bio-derived and bio-degradable surfactants are promising alternatives. For bio-surfactants to be implemented industrially, they need to be produced on a large scale and also have tailorable properties that match those afforded by the polymerization of synthetic surfactants. In this paper, a scalable and versatile production method for bio-surfactants based on a hydrophilic intrinsically disordered protein (IDP) sequence with a genetically engineered hydrophobic domain is used to study variables that impact their physicochemical and self-assembling properties. These amphiphilic sequences were found to self-assemble into micelles over a broad range of temperatures, pH values, and ionic strengths. To investigate the role of the IDP hydrophilic domain on self-assembly, variants with increased overall charges and systematically decreased IDP domain lengths were produced and examined for their sizes, morphologies, and critical micelle concentrations (CMCs). The results of these studies indicate that decreasing the length of the IDP domain and, consequently, the molecular weight and hydrophilic fraction, leads to smaller micelles. Additionally, significantly increasing the amount of charged residues in the hydrophilic IDP domain results in micelles of similar sizes, but with higher CMC values. This represents an initial step in developing a quantitative model for the future engineering of bio-surfactants based on this IDP sequence.
Direct C-H-Sulfonylation of 6-Membered Nitrogen-Heteroaromatics
Authors: Friedrich Marius , Schulz Lisa , Hofman Kamil , Zangl Rene , Morgner Nina , Shaaban Saad , Manolikakes Georg
Published: February 2022

Heterocyclic sulfones and sulfonamides represent important structural motives in medicinal chemistry and drug development. Therefore, efficient and reliable methods for their construction from simple building blocks are in high demand. Herein we report a novel approach for the direct C-H-sulfonylation of N heteroaromatics via N-activation with triflic anhydride (Tf2O), base-mediated addition of a sulfinate salt and subsequent rearomatization through trifluoromethanesulfinate elimination. This operationally simple one-pot protocol enables direct access to various sulfonylated 6-ring N-heterocycles. It is applicable to the late-stage functionalization of complex, drug-like molecules. The direct incorporation of sulfur dioxide with organometallic reagents as well as the utilization of a rongalite-based sulfonylation reagent provide opportunities for a highly modular synthesis of N-heterocyclic sulfones and sulfonamides from three different building blocks.
Hot Exciplexes in U-Shaped TADF Molecules with Emission from Locally Excited States
Authors: Schleper A. Lennart , Goushi Kenichi , Bannwarth Christoph , Haehnle Bastian , Welscher Philipp , Adachi Chihaya , Kuehne Alexander
Published: February 2022

Rapid reverse intersystem crossing and high color purity are vital characteristics of emitters with thermally activated delayed fluorescence in opto-electronic devices. We present a new approach, called “hot exciplexes” that enables access to both attributes at the same time. Hot exciplexes are produced by coupling facing donor and acceptor moieties to an anthracene bridge, yielding an exciplex with large T1 to T2 spacing. The hot exciplex model is investigated using optical spec-troscopy and quantum chemical simulations. Reverse intersystem crossing is found to occur preferentially from the T3 to the S1 state within only a few nanoseconds. Application and practi-cality of the model are shown by fabrication of organic light-emitting diodes with up to 32 % hot exciplex contribution and low efficiency roll-off.
Metal-Responsive Regulation of Enzyme Catalysis using Genetically Encoded Chemical Switches
Authors: Zubi Yasmine S. , Seki Kosuke , Li Ying , Hunt Andrew , Liu Bingqing , Roux Benoît , Jewett Michael C. , Lewis Jared C.
Published: February 2022

The design of allosteric regulation in proteins to dynamically control function is a challenge in synthetic biology. To address this challenge, we developed an integrated computational and experimental workflow to incorporate a metal-responsive chemical switch into proteins. Pairs of bipyridinylalanine (BpyAla) residues were genetically encoded into two structurally distinct enzymes, a serine protease and firefly luciferase, so that metal coordination would bias the conformations of these enzymes, leading to reversible control of activity. MD-simulations guided rational BpyAla placement, significantly reducing experimental workload, and cell-free protein synthesis coupled with high-throughput experimentation enabled rapid prototyping of variants. Ultimately, this strategy yielded enzymes with a robust 20-fold dynamic range in response to divalent metals over 24 on/off switches, demonstrating the potential of this approach. We envision that this strategy of genetically encoding chemical switches into enzymes will complement other protein engineering and synthetic biology efforts, enabling new opportunities for applications where precise regulation of protein function is critical.
Extended characterization of petroleum aromatics using off-line LC-GC-MS
Authors: Huynh Khoa , Jensen Annette Eva , Sundberg Jonas
Published: February 2022

Crude oil remains a grand challenge for analytical chemists. With the advent of multi-dimensional chromatography and high-resolution mass spectrometry, an impressive number of compounds have been identified. However, the large diversity in structure and abundance makes it difficult to obtain full compound coverage in a single analysis. Sample preparation methods such as solid-phase extraction and SARA-type analysis reduces this complexity. However, the molecular diversity within each fraction is still highly complex. Thus, in the routine analysis, only a small part of the chemical space is typically characterized. Obtaining a more detailed composition of crude oil is important for production, processing and environmental aspects. We have developed a high-resolution fractionation method for isolation and preconcentration of trace aromatics, including oxygenated and nitrogen-containing species. By the isolation of the more abundant aromatics, i.e. monoaromatics and naphthalenes, trace species can be enriched for analysis. This enables the identification of features not detectable by routine methods. We demonstrate the applicability by fractionation and subsequent GC-MS analysis of 14 crude oils sourced from the North Sea. The number of tentatively identified compounds increased by approximately 60 to 150% compared to solid-phase extraction and GC×GC-MS. Furthermore, the method was used to successfully isolate and identify a new set of heteroatom-containing aromatics (amines, ketones). The method is not intended to replace traditional sample preparation techniques or multi-dimensional chromatography but acts as a complementary tool. An in-depth comparison to routine characterization techniques is presented concerning advantages and disadvantages.
Spinristor: A Swiss Army Knife of Molecular Electronics
Authors: Farajpour Bonab Esmaeil , Jaros Adam , Badri Zahra , Tučková Lucie , Straka Michal , Foroutan-Nejad Cina
Published: February 2022

Here, we propose and provide in silico proof of concept of a spinristor; a new molecular electronic component that combines a spin-filter, a rectifier, and a switch, in a single molecule for in-memory processing. It builds on the idea of an open-shell transition metal ion enclosed within an elliptical fullerene connected to the source, drain, and a pair of gate electrodes. The spin- and electronic polarization due to the enclosed metal leads to differential rectification of the electrons at low voltages applied between the source-drain electrodes, VSD. The position of the encapsulated ion can be switched by a combination of a high VSD and a voltage applied between gate electrodes, VG, to switch the direction of the rectification and spin-filtering ratio. The system can thus be used as a switching rectifier and spin-filter, a spinristor. To the best of our knowledge, such a system has no macroscopic counterpart in electronics.
Mechanisms of Electrochemical N2 Splitting by a Molybdenum Pincer Complex
Authors: Bruch Quinton , Malakar Santanu , Goldman Alan , Miller Alexander
Published: February 2022

Molybdenum complexes supported by tridentate pincer ligands are exceptional catalysts for dinitrogen fixation using chemical reductants, but little is known about their prospects for electrochemical reduction of dinitrogen. The viability of electrochemical N2 binding and splitting by a molybdenum(III) pincer complex, (pyPNP)MoBr3 (pyPNP = 2,6-bis(tBu2PCH2)-C5H3N)), is established in this work, providing a foundation for a detailed mechanistic study of electrode-driven formation of the nitride complex (pyPNP)Mo(N)Br. Electrochemical kinetic analysis, optical and vibrational spectroelectrochemical monitoring, and computational studies point to two reaction pathways: in the “reaction layer” pathway, the molybdenum(III) precursor is reduced by 2e– and generates a bimetallic molybdenum(I) Mo2(-N2) species capable of N–N bond scission. In the “bulk solution” pathway the precursor is reduced by 3e– at the electrode surface to generate molybdenum(0) species that undergo chemical redox reactions via comproportionation in the bulk solution away from the electrode surface to generate the same bimetallic molybdenum(I) species capable of N2 cleavage. The comproportionation reactions reveal the surprising intermediacy of dimolybdenum(0) complex trans,trans-[(pyPNP)Mo(N2)2](-N2) in N2 splitting pathways. The same “over-reduced” molybdenum(0) species was also found to cleave N2 upon addition of lutidinium, an acid frequently used in catalytic reduction of dinitrogen.
Efficient direct nitrosylation of a-diimine rhenium tricarbonyl complexes to structurally nearly identical higher charge congeners activable towards photo-CO release
Authors: Nasiri Sovari Sara , Kolly Isabelle , Schindler Kevin , Cortat Youri , Shing-Chi Liu , Crochet Aurelien , Pavic Aleksandar , Zobi Fabio
Published: February 2022

The reaction of rhenium a-diimine (N-N) tricarbonyl complexes with nitrosonium tetrafluoroborate yields the corresponding dicarbonyl-nitrosyl [Re(CO)2(NO)(N-N)X]+ species (where X = halide). The complexes, accessible in a single step in good yied, are structurally nearly identical higher charge congeners of the tricarbonyl molecules. Substitution chemistry aimed at the realization of equivalent dicationic species (intended for applications as potential antimicrobial agents), revealed that the reactivity of metal ion in [Re(CO)2(NO)(N-N)X]+ is closer to that of a harder Re(III) acid, probably due to the stronger p-acceptor properties of NO+ as compared to those of CO. The metal ion thus shows great affinity for p-basic ligands, which are consequently difficult to replace by e.g. s-donor or week p-acids like pyridine. Attempts of direct nitrosylation of a-diimine fac-[Re(CO)3]+ complexes bearing p-basic OR-type ligands gave the [Re(CO)2(NO)(N-N)(BF4)][BF4] salt, as the only product in good yield, featuring a stable Re-F-BF3 bond. The solid state crystal structure of nearly all molecules presented could be elucidated. A fundamental consequence of the chemistry of [Re(CO)2(NO)(N-N)X]+ complexes, it that the same can be photo-activated towards CO release and represent an entirely new class of photoCORMs.
Single-Component, Photocatalytic H2 Production Through Acceptorless Alcohol Dehydrogenation: Atypical Metal-Ligand Cooperativity in a Ruthenium(II)-PN/P Complex
Authors: Fanara Paul , Vigneswaran Vipulan , Gunasekera Parami , MacMillan Samantha , Lacy David
Published: February 2022

Metal-ligand cooperativity (MLC) involving reversible aromatization/dearomatization of pyridine-derived pincer ligands is considered important in acceptorless (de)hydrogenation for dihydrogen generation and storage. Dehydrohalogenation of pyridine-derived pincer ruthenium complexes often leads to dearomatized moieties. Thus, we were surprised to find an aromatized kappa-3-NCP binding mode in [{LutP`}Ru(CO)(H)(PPh3)] (2) upon dehydrohalogenation of the lutidine-derived PN/P complex [{LutP}Ru(CO)(Cl)(H)(PPh3)] (1) with KOtBu. The reaction of H2 with 2 results in formation of a cis-dihydride [{LutP}Ru(CO)(H)2(PPh3)] (3) and labeling studies confirm cooperative metal-ligand activation. 3 exhibits reversible photochemistry that we leveraged to demonstrate a unique strategy for unsensitized single-component photocatalytic H2 production via acceptorless alcohol dehydrogenation. Although labeling studies implicate MLC processes during the photocatalytic reaction, they may be off-path intermediates, emphasizing that aromatization/dearomatization may not be necessary for acceptorless transformations.
Antiplasmodial diterpenoid alkaloid from Aconitum heterophyllum: Isolation, characterization, and UHPLC-DAD based quantification
Authors: - Anmol , Kumari Surekha , Kumar Rakesh , Singh Raman , Aggarwal Gaurav , Agrawal Prakhar , Sahal Dinkar , Sharma Upendra
Published: February 2022

Aconitum heterophyllum is a traditionally important medicinal plant having numerous therapeutic actions as documented in Ayurveda. This plant has been used alone as well as in combination with other plants for the preparation of different anti-malarial formulations. However, there is no report on the assessment of its anti-plasmodial activity, and the compound responsible for this activity. The main aim of this study was to conduct phytochemical investigation of A. heterophyllum roots for the preparation of extract, fractions and isolation of pure molecules to identify active fractions/molecules responsible for the anti-plasmodial activity, and development of UHPLC-DAD based analytical method which can be used for the quantification of marker compounds in the extracts and fractions. Hydro-alcoholic extract (1:1 v/v) and fractions (n-hexane, chloroform, ethyl acetate, n-butanol and water) were prepared from the dried powdered roots of A. heterophyllum. Fractions were further subjected to silica gel-based column chromatography to isolate pure specialized secondary metabolites from this plant. All extracts, fractions and pure molecules were evaluated against the chloroquine resistant Pf INDO and chloroquine sensitive Pf3D7 strains in culture for calculating their IC50 values. UHPLC-DAD based analytical method was also developed for the first time for the quantification and quality assessment of this commercially important Himalayan medicinal plant. Phytochemical investigation of A. heterophyllum root led to the isolation of six specialized metabolites named as 2-O-cinnamoyl hetisine (1), atisinium (2), 4-oxabicyclo [3.2.2] nona-1(7),5,8-triene (3), atisinium cinnamate (4), aconitic acid (5), and atisinium formate (6). Compound 1 is a new hetisine type diterpenoid alkaloid, compounds 4 and 6 are new counter ionic forms observed with atisinium ion, and compound 3 is being reported for the first time from this genus. Chloroform fraction was found to be the most active with IC50 (µg/mL) 1.01 (Pf INDO) and 1.32 (Pf3D7). The isolated molecule 2-O-cinnamoyl hetisine (1), a new diterpenoid alkaloid isolated from chloroform fraction, showed promising antiplasmodial activities with IC50 (µM) 1.92 (Pf INDO) and 10.8 (Pf 3D7). Activity of chloroform fraction was further validated by the developed UHPLC-DAD based method as the quantity of 2-O-cinnamoyl hetisine (1) was higher in the chloroform fraction (≅200 µg/mL) than in all other fractions (< 7µg/mL). Atisinium (2) and 2-O-cinnamoyl hetisine (1) were found to be the main marker compounds of this plant based on quantity and antiplasmodial activity, respectively. This study provides the scientific rational for the traditional use of this plant in treating malaria. Further, this study revealed that anti-malarial potential of this plant might be due to the presence of diterpenoid alkaloids.
Identification of Atovaquone as and Mebendazole as Repurposed Drugs with Antiviral Activity against SARS-CoV-2 (Version 5)
Authors: Ahmed Mahmoud , Farag Ayman , Wang Ping , Boys Ian N. , L. Eitson Jennifer , Ohlson Maikke B. , Fan Wenchun , McDougal Matthew B. , W. Schoggins John , Sadek Hesham
Published: February 2022

Given the continuing heavy toll of the COVID-19 pandemic, therapeutic options for treatment are urgently needed. Here, we adopted a repositioning approach using in silico molecular modeling to screen FDA-approved drugs with established safety profiles for potential inhibitory effects against SARS-CoV-2. We used structure-based drug design to screen more than 2000 FDA approved drugs against SARS-CoV-2 main protease enzyme (Mpro) substrate-binding pocket. We additionally screened the top hits from both sites for potential covalent binding via nucleophilic thiol attack of Cys 145. High-scoring candidates were then screened for antiviral activity against infectious SARS-CoV-2 in a cell-based viral replication assay, and counter screened for toxicity. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. In addition, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 M), mebendazole (IC50 19 M) and entacapone (IC50 9 M). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential antiviral mechanisms. Although atovaquone is a known DHODH inhibitor, we did not observe inhibition of DHODH by atovaquone at concentrations relevant to the SARS-CoV-2 IC50. Interestingly, metabolomic profiling of atovaquone treated cells demonstrated marked dysregulation of metabolites in the purine metabolism pathway. In summary, a number of our top hits from the in-silico screen demonstrated Mpro inhibitory activity associated with antiviral effects. Atovaquone and mebendazole are the most promising candidates targeting SARS-CoV-2 from our screen, however atovaquone did not significantly inhibit Mpro at therapeutically meaningful concentrations but may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.
The synthesis of chiral branched allylamines through dual photoredox/nickel catalysis
Authors: Garbacz Mateusz , Stecko Sebastian
Published: February 2022

Allylamines are versatile building blocks in the synthesis of various naturally occurring products and pharmaceuticals. In contrast to terminal allylamines, the methods of synthesis of their branched congeners with internal, stereodefined double bond are less explored. This work describes a new approach for a preparation of allylamines via cross-coupling of alkyl bromides with simple 3-bromoallylamines by merging photoredox and Ni-catalysis. The reaction proceeds under mild conditions, under blue light irradiation and in the presence of an organic dye, 4CzIPN, as a photocatalyst. The scope of suitable reaction partners is broad, including alkyl bromides bearing reactive functionalities (e.g., esters, nitriles, aldehydes, ketones, epoxides), and N-protected allylamines, as well as N-allylated secondary and tertiary amines and heterocycles. The employment of non-racemic starting mater.ials allows for rapid and easy construction of complex multifunctional allylamine derivatives without erosion of enatiomeric purity
Biological evaluation and spectral characterization of novel tetracenomycin X congener
Authors: Alferova Vera A. , Maviza Tinashe P. , Biryukov Mikhail B. , Zakalyukina Yuliya B. , Lukianov Dmitrii A. , Skvortsov Dmitry A. , Vasilyeva Lilia A. , Tashlitsky Vadim N. , Polshakov Vladimir I. , Dontsova Olga A. , Sergiev Petr V. , Korshuna Vladimir A. , Osterman ILya A.
Published: February 2022

The aromatic polyketide tetracenomycin X (TcmX) was recently found to be a potent inhibitor of protein synthesis, whose binding site is located in a unique locus within the tunnel of the large ribosomal subunit. The distinct mode of action makes this relatively narrow class of macrolides promising for drug development, in our quest to prevent the spread of drug resistant pathogens. Here we report the isolation and structure elucidation of novel natural tetracenomycin X congener – 6-hydroxytetraceonomycin X (6-OH-TcmX). In contrast to TcmX, 6-OH-TcmX exhibited lower antimicrobial and cytotoxic activity, but comparable in vitro protein synthesis inhibition ability. A survey on spectral properties of tetracenomycins showed profound differences in both UV-absorption and fluorescence spectra of TcmX and 6-OH-TcmX, suggesting the significant influence of 6-hydroxylation on tetracenomycin chromophore. Nonetheless, characteristic spectral properties of tetracenomycins make them suitable candidates as a foundation for semi-synthetic drug development (e.g., for targeted delivery, theranostics or cell imaging).
Transition metal migration and O2 formation underpin voltage hysteresis in oxygen-redox disordered rocksalt cathodes
Authors: McColl Kit , House Robert A. , Rees Gregory J. , Squires Alexander G. , Coles Samuel W. , Bruce Peter G. , Morgan Benjamin J. , Islam M. Saiful
Published: February 2022

Lithium-rich disordered rocksalt cathodes display high capacities arising from redox chemistry on both transition-metal and oxygen ions and are potential candidates for next-generation lithium-ion batteries. The atomic-scale mechanisms governing this O-redox behaviour, however, are not fully understood. In particular, it is not clear to what extent transition metal migration is required for O-redox and what role this may play in explaining voltage hysteresis in these materials. Here, we reveal an O-redox mechanism linking transition metal migration and O2 formation in the disordered rocksalt Li2MnO2F. At high states of charge, O-ions dimerise to form molecular O2 trapped in the bulk structure, leaving vacant O sites surrounding neighbouring Mn ions. This undercoordination drives Mn movement into new fully-coordinated octahedral sites. Mn displacement can occur irreversibly, which results in voltage hysteresis, with a lower voltage upon discharge as observed experimentally. Alternatively, Mn displacement may take place into interstitial octahedral sites, which permits a reversible return of the Mn ion to its original site upon discharge, recovering the original Li2MnO2F structure and resulting in reversible O-redox without voltage loss. These new findings suggest that reversible transition metal ion migration provides a possible design route to retain the high energy density of O-redox disordered rocksalt cathodes on cycling.
Structured Liquid Batteries
Authors: Yan Jiajun , Russell Thomas , Helms Brett
Published: February 2022

Here we describe structured liquid batteries, whose membranes self-form via coacervation of polyelectrolytes. The membrane serves as an ion conductor, a physical barrier, and a structural support. Complexation of redox-active small molecules with their complementary polyelectrolyte also mitigates the crossover. The reconfigurability of liquids allows the cell to conform to prescribed patterns and the cells are rechargeable for hundreds of hours.
Synthesis of stereoenriched piperidines via chemo-enzymatic dearomatization of activated pyridines
Authors: Harawa Vanessa , Thorpe Thomas , Marshall James , Gilio Amelia , Heath Rachel , Angelastro Antonio , Finnigan James , Charnock Simon , Grogan Gideon , Whitehead Roger , Turner Nicholas
Published: February 2022

The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature has yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of the antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.
Online tools to easily build augmented reality models of biomolecules that run right on the web
Authors: Cortés Rodríguez Fabio , Dal Peraro Matteo , Abriata Luciano
Published: February 2022

Abstract. Several groups developed in the last years augmented and virtual reality (AR/VR) programs and apps to visualize 3D molecules, most rather static, limited in content, and requiring software installs, some even requiring expensive hardware. During the Covid-19 pandemic, our team launched moleculARweb (https://molecularweb.epfl.ch), a website that offers interactive content for chemistry and structural biology education through commodity web-based AR that works on consumer devices like smartphones, tablets and laptops. Among thousands of users, teachers increasingly request more biological macromolecules to be available, a demand that we cannot satisfy individually. Therefore, to allow users to build their own material, we built a web interface where any user can build any online AR experience in few steps starting from a PDB structure or from virtual objects/scenes exported from VMD. The website also returns a WebXR session for viewing and manipulating the model in high-end immersive VR headsets with web browsers, here tested on the ~400 USD Oculus Quest 2. The tool is accessible at https://molecularweb.epfl.ch/pages/pdb2ar.html.