Class Of Substrates Research Articles

Defect-Engineered Coordination Compound Nanoparticles Based on Prussian Blue Analogues for Surface-Enhanced Raman Spectroscopy.

Surface-enhanced Raman spectroscopy (SERS) is a powerful tool for label-free chemical analysis. The emergence of nonmetallic materials as SERS substrates, offering chemical signal enhancements, presents an exciting direction for achieving reproducible and biocompatible SERS, a challenge with traditional metallic substrates. Despite the potential, the realm of nonmetallic SERS substrates, particularly nanoparticles, remains largely untapped. Here, we present defect-engineered coordination compounds (DECCs) based on Prussian blue analogues (PBAs) as a class of nonmetallic nanoparticle-based SERS substrates. We demonstrate the utility and flexibility of the DECC template by incorporating various metal (M) elements into PBAs to synthesize nanoparticles that deliver substantial chemical mechanism (CM)-based enhancements to the Raman signal with a ∼ 108-fold increase. The introduction of the M-PBA-based DECC nanoparticles as a class of SERS substrates represents a pioneering stride, enabling the straightforward and systematic exploration of a library of compounds for SERS-based analysis of a wide range of target molecules, especially biomolecules.

Isothiourea‐Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols

AbstractThe development of methods for the selective acylative kinetic resolution (KR) of tertiary alcohols is a recognised synthetic challenge with relatively few successful substrate classes reported to date. In this manuscript, a highly enantioselective isothiourea‐catalysed acylative KR of tertiary pyrazolone alcohols is reported. The scope and limitations of this methodology have been developed, with high selectivity observed across a broad range of substrate derivatives incorporating varying substitution at N(2)‐, C(4)‐ and C(5)‐, as well as bicyclic constraints within the pyrazolone scaffold (30 examples, selectivity factors (s) typically >100) at generally low catalyst loadings (1 mol %). The application of this KR method to tertiary alcohols derived directly from a natural product (geraniol), alongside pharmaceutically relevant drug compounds (indomethacin, gemfibrozil and probenecid), with high efficiency (s >100) is also described. The KR process is readily amenable to scale up using bench grade solvents and reagents, with effective resolution on a 50 g (0.22 mol) scale demonstrated. The key structural motif leading to excellent selectivity in this KR process has been probed through computation, with an NC=O⋅⋅⋅isothiouronium interaction from substrate to acylated catalyst observed within the favoured transition state. Similarly, the effect of C(5)‐aryl substitution that leads to reduced experimental selectivity is probed, with a competitive π–isothiouronium interaction identified as leading to reduced selectivity.

Quantitative Reactivity Models for Oxidative Addition to L2Pd(0): Additional Substrate Classes, Solvents, and Mechanistic Insights.

Quantitative molecular structure-reactivity models are useful for generating predictions to guide synthesis design, and in formulating and testing mechanistic hypotheses. We report an expanded multivariate linear regression (MLR) model for the rate of (hetero)aryl (pseudo)halide oxidative addition to L2Pd(0), here exemplified by Pd(PCy3)2. This builds on a prior model from our group, with additional substrate classes (aryl chlorides and iodides) and reaction solvents (THF, toluene, THF/DMF mixture). Overall solvent effects across the entire substrate set are minimal under these conditions, enabling a unified MLR model without introduction of new molecular descriptors beyond the original five. Examining the mechanistic origin of the two molecular electrostatic potential (ESP) descriptors led to generation of a simpler, four descriptor model that is suitable for aryl halides, but not for 2-halopyridines. Using this model we identified a mechanistic outlier, 2-pyridyl triflate, which undergoes a nucleophilic displacement oxidative addition that does not involve the adjacent nitrogen atom. Finally, we discuss the relationship between C-X bond strength and oxidative addition rates, and compare the intrinsic bond strength index (IBSI) to bond dissociation enthalpy (BDE) as a bond strength descriptor.

Highly Acidic Electron-Rich Brønsted Acids Accelerate Asymmetric Pictet-Spengler Reactions by Virtue of Stabilizing Cation-π Interactions.

Electron-rich heteroaromatic imidodiphosphorimidates (IDPis) catalyze the asymmetric Pictet-Spengler reaction of N-carbamoyl-β-arylethylamines with high stereochemical precision. This particular class of catalysts furthermore provides a vital rate enhancement compared to related Brønsted acids. Here we present experimental studies on the underlying reaction kinetics that shed light on the specific origins of rate acceleration. Analysis of Hammett plots, kinetic isotope effects, reaction orders, Eyring plots, and isotopic scrambling experiments, allowed us to gather insights into the molecular interactions between the chiral Brønsted acid and catalytically formed intermediates. Based on rigorously determined pKa values as well as the experimental evidence, we propose that attractive intermolecular forces offered by electron-rich π-surfaces of the chiral counteranion enthalpically stabilize cationic intermediates and transition states by way of cation-π interactions. This view is furthermore supported by in-depth density functional theory calculations. Our deepened understanding of the reaction mechanism allowed us to develop a method for accessing 1-aryltetrahydroisoquinolines from aromatic dimethyl acetals, a substrate class that was thus far inaccessible via catalytic asymmetric Pictet-Spengler reactions.

Reaction of acetylenic carbanions with C=N bond: dynamics of development, synthetic divergence, environmental safety

This review highlights dynamics of development and synthetic application of the recently discovered reaction of acetylenic carbanions, generated in superbase media, with C=N bond of different classes of substrates. A fundamental feature of this reaction is its synthetic divergence, i.e. its ability to proceed in various directions that manifests in novel transformations to selectively deliver (depending on structure of the acetylenes and substrates with C=N bond) structurally different synthetically important products. The review also discusses cascade processes, in which the key intermediates containing the C=N bond add acetylenes thereby participating in the self-organization of diverse and potentially useful compounds. The competitive advantage of the reaction and its daughter branches is environmental safety (neutrality), based on the fundamental chemical nature of these reactions as addition processes that occur without the release of by-products.<br> The bibliography includes 133 references.

Enantioselective Transfer Hydrogenation of α-Methoxyimino-β-keto Esters.

α-Methoxyimino-β-keto esters are reported to undergo highly enantioselective catalytic transfer hydrogenation using the Noyori-Ikariya complex RuCl(p-cymene)[(S,S)-Ts-DPEN] in a mixture of formic acid-triethylamine and dimethylformamide at 25 °C. The experimental study performed on over 25 substrates combined with computational analysis revealed that a Z-configured methoxyimino group positioned alpha to a ketone carbonyl leads to higher reactivity and mostly excellent enantioselectivity within this substrate class. Density functional theory calculations of competing transition states were used in rationalizing the origins of enantioselectivity and the possible role of the methoxyimino group in the reaction outcome.

Isothiourea-Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols.

The development of methods for the selective acylative kinetic resolution (KR) of tertiary alcohols is a recognised synthetic challenge with relatively few successful substrate classes reported to date. In this manuscript, a highly enantioselective isothiourea-catalysed acylative KR of tertiary pyrazolone alcohols is reported. The scope and limitations of this methodology have been developed, with high selectivity observed across a broad range of substrate derivatives incorporating varying substitution at N(2)-, C(4)- and C(5)-, as well as bicyclic constraints within the pyrazolone scaffold (30 examples, selectivity factors (s) typically >100) at generally low catalyst loadings (1 mol%). The application of this KR method to tertiary alcohols derived from a natural product (geraniol), alongside pharmaceutically relevant drug compounds (indomethacin, gemfibrozil and probenecid), with high efficiency (s > 100) is also described. The KR process is readily amenable to scale up, with effective resolution on a 50 g (0.22 mol) scale demonstrated. The key structural motif leading to excellent selectivity in this KR process has been probed through computation, with an NC=O•••isothiouronium interaction observed within the favoured transition state. Similarly, the effect of C(5)-aryl substitution that leads to reduced experimental selectivity is probed, with a competitive π-isothiouronium interaction identified as leading to reduced selectivity.

Raman enhancement via double optical resonances in all-dielectric photonic crystal slabs

All-dielectric photonic structures are an important class of substrates in surface-enhanced Raman spectroscopy (SERS), utilizing optical resonant modes to significantly enhance the electromagnetic field and amplify the Raman signals. In this study, we demonstrate the double-resonance approach to realize significant Raman enhancement using all-dielectric photonic crystal (PhC) slab. The double-resonance condition is satisfied by designing optical resonant modes in photonic bands to match frequencies of both excitation laser and Raman signals. By the fabricated PhC slab, the significant enhancement for the Raman signal of silicon is demonstrated. The enhanced Raman signals exhibit a uniform distribution on the PhC slab. The method of Raman enhancement via double optical resonances can advance the field of all-dielectric SERS and holds potential for future SERS applications.

Sulfotransferase-mediated phase II drug metabolism prediction of substrates and sites using accessibility and reactivity-based algorithms.

Sulphotransferases (SULTs) are a major phase II metabolic enzyme class contributing ~20 % to the Phase II metabolism of FDA-approved drugs. Ignoring the potential for SULT-mediated metabolism leaves a strong potential for drug-drug interactions, often causing late-stage drug discovery failures or black-boxed warnings on FDA labels. The existing models use only accessibility descriptors and machine learning (ML) methods for class and site of sulfonation (SOS) predictions for SULT. In this study, a variety of accessibility, reactivity, and hybrid models and algorithms have been developed to make accurate substrate and SOS predictions. Unlike the literature models, reactivity parameters for the aliphatic or aromatic hydroxyl groups (R/Ar-O-H), the Bond Dissociation Energy (BDE) gave accurate models with a True Positive Rate (TPR)=0.84 for SOS predictions. We offer mechanistic insights to explain these novel findings that are not recognized in the literature. The accessibility parameters like the ratio of Chemgauss4 Score (CGS) and Molecular Weight (MW) CGS/MW and distance from cofactor (Dis) were essential for class predictions and showed TPR=0.72. Substrates consistently had lower BDE, Dis, and CGS/MW than non-substrates. Hybrid models also performed acceptablely for SOS predictions. Using the best models, Algorithms gave an acceptable performance in class prediction: TPR=0.62, False Positive Rate (FPR)=0.24, Balanced accuracy (BA)=0.69, and SOS prediction: TPR=0.98, FPR=0.60, and BA=0.69. A rule-based method was added to improve the predictive performance, which improved the algorithm TPR, FPR, and BA. Validation using an external dataset of drug-like compounds gave class prediction: TPR=0.67, FPR=0.00, and SOS prediction: TPR=0.80 and FPR=0.44 for the best Algorithm. Comparisons with standard ML models also show that our algorithm shows higher predictive performance for classification on external datasets. Overall, these models and algorithms (SOS predictor) give accurate substrate class and site (SOS) predictions for SULT-mediated Phase II metabolism and will be valuable to the drug discovery community in academia and industry. The SOS predictor is freely available for academic/non-profit research via the GitHub link.

Nature-Inspired Radical Pyridoxal-Mediated C-C Bond Formation.

Pyridoxal-5'-phosphate (PLP) and derivatives of this cofactor enable a plethora of reactions in both enzyme-mediated and free-in-solution transformations. With few exceptions in each category, such chemistry has predominantly involved two-electron processes. This sometimes poses a significant challenge for using PLP to build tetrasubstituted carbon centers, especially when the reaction is reversible. The ability to access radical pathways is paramount to broadening the scope of reactions catalyzed by this coenzyme. In this study, we demonstrate the ability to access a radical PLP-based intermediate and engage this radical intermediate in a number of C-C bond-forming reactions. By selection of an appropriate oxidant, single-electron oxidation of the quinonoid intermediate can be achieved, which can subsequently be applied to C-C bond-forming reactions. Through this radical reaction pathway, we synthesized a series of α-tertiary amino acids and esters to investigate the substrate scope and identify nonproductive reaction pathways. Beyond the amino acid model system, we demonstrate that other classes of amine substrates can be applied in this reaction and that a range of small molecule reagents can serve as coupling partners to the semiquinone radical. We anticipate that this versatile semiquinone radical species will be central to the development of a range of novel reactions.

Chemogenetic Evolution of Diversified Photoenzymes for Enantioselective [2 + 2] Cycloadditions in Whole Cells.

Artificial photoenzymes with novel catalytic modes not found in nature are in high demand; yet, they also present significant challenges in the field of biocatalysis. In this study, a chemogenetic modification strategy is developed to facilitate the rapid diversification of photoenzymes. This strategy integrates site-specific chemical conjugation of various artificial photosensitizers into natural protein cavities and the iterative mutagenesis in cell lysates. Through rounds of directed evolution, prominent visible-light-activatable photoenzyme variants were developed, featuring a thioxanthone chromophore. They successfully enabled the enantioselective [2 + 2] photocycloaddition of 2-carboxamide indoles, a class of UV-sensitive substrates that are traditionally challenging for known photoenzymes. Furthermore, the versatility of this photoenzyme is demonstrated in enantioselective whole-cell photobiocatalysis, enabling the efficient synthesis of enantioenriched cyclobutane-fused indoline tetracycles. These findings significantly expand the photophysical properties of artificial photoenzymes, a critical factor in enhancing their potential for harnessing excited-state reactivity in stereoselective transformations.

MECHANISM OF DEPROTONATION OF THE AMINO GROUP OF GLUTAMATE UPON BINDING TO N-ACETYLGLUTAMATE SYNTHASE

Gcn5-related N-acetyltransferases catalyze the transfer of an acetyl group to a primary amino group of a wide class of substrates. Protonation of the amino group upon binding to the enzyme is necessary to activate the nucleophilic attack on the substrate. The process of glutamate binding to N-acetylglutamate synthase is considered using molecular modeling and quantum chemistry methods. It has been shown that deprotonation of the primary amino group of glutamate occurs upon binding to the active site of the enzyme with the participation of the side chain of the aspartate residue.

Engineering of Rieske dioxygenase variants with improved cis-dihydroxylation activity for benzoates.

Rieske dioxygenases have a long history of being utilized as green chemical tools in the organic synthesis of high-value compounds, due to their capacity to perform the cis-dihydroxylation of a wide variety of aromatic substrates. The practical utility of these enzymes has been hampered however by steric and electronic constraints on their substrate scopes, resulting in limited reactivity with certain substrate classes. Herein, we report the engineering of a widely used member of the Rieske dioxygenase class of enzymes, toluene dioxygenase (TDO), to produce improved variants with greatly increased activity for the cis-dihydroxylation of benzoates. Through rational mutagenesis and screening, TDO variants with substantially improved activity over the wild-type enzyme were identified. Homology modeling, docking studies, molecular dynamics simulations, and substrate tunnel analysis were applied in an effort to elucidate how the identified mutations resulted in improved activity for this polar substrate class. These analyses revealed modification of the substrate tunnel as the likely cause of the improved activity observed with the best-performing enzyme variants.

Phosphorus Content of Several Plant-Based Yogurts

ObjectiveIn people with chronic kidney disease (CKD), hyperphosphatemia is an independent risk factor for mortality in observational studies. Despite not having proven benefit, dietary control of phosphorus is thought to be essential in CKD. Though dietary and serum phosphorus are correlated, ingested phosphate is less bioavailable from plant-foods rich in phytate than from animal and processed foods. Yogurt is considered a useful food due to its relatively low phosphorus and high protein content but may be detrimental since the protein content is from animal sources. Instead, plant-based yogurts (PBYs) may offer similar benefits without the associated downsides of animal protein in kidney disease, but little is known about the phosphorus contents of PBYs. Design and MethodsProtein contents and phosphorus additives were obtained from nutrition labels of several, widely available PBYs of almond, cashew, oat, coconut, and soy substrates. Phosphorus content was measured via emission spectrometry by Eurofins (Madison, WI). Based on these data, phosphorus-to-protein ratio (PPR) for each PBY was calculated. ResultsPhosphorus was highest in Silk Soy Strawberry, then Silk Almond Strawberry and Siggi’s Coconut Mixed Berries. Phosphorus was lowest in So Delicious Coconut Strawberry, then Oatly Oat Strawberry, Forager Cashew Strawberry, and Kite Hill Almond Strawberry. According to the ingredient labels, Silk Soy Strawberry, Silk Almond Strawberry, and Oatly Oat Strawberry contained phosphorus additives while Siggi’s Coconut Mixed Berries contained pea protein additives. Of PBYs from the same substrate class, So Delicious Coconut Strawberry and Siggi’s Coconut Mixed Berries had the largest differences in their phosphorus and protein contents. These seven samples’ PPR ratios were higher than that of dairy yogurt values reported from the literature, including Stonyfield Organic Oikos Strawberry, Chobani Nonfat Strawberry, and Yoplait Greek Strawberry. ConclusionLow phosphorus-to-protein ratio (PPR) foods are emphasized for people with CKD. Siggi’s Coconut Mixed Berries had the lowest PPR. However, So Delicious Coconut Strawberry had the highest ratio which underscores product variability despite both using the same PBY substrate. Of the samples analyzed, Siggi’s Coconut Mixed Berries may be the most desirable for patients with CKD because its PPR was the lowest.

The Arabidopsis AtSWEET13 transporter discriminates sugars by selective facial and positional substrate recognition

Transporters are targeted by endogenous metabolites and exogenous molecules to reach cellular destinations, but it is generally not understood how different substrate classes exploit the same transporter’s mechanism. Any disclosure of plasticity in transporter mechanism when treated with different substrates becomes critical for developing general selectivity principles in membrane transport catalysis. Using extensive molecular dynamics simulations with an enhanced sampling approach, we select the Arabidopsis sugar transporter AtSWEET13 as a model system to identify the basis for glucose versus sucrose molecular recognition and transport. Here we find that AtSWEET13 chemical selectivity originates from a conserved substrate facial selectivity demonstrated when committing alternate access, despite mono-/di-saccharides experiencing differing degrees of conformational and positional freedom throughout other stages of transport. However, substrate interactions with structural hallmarks associated with known functional annotations can help reinforce selective preferences in molecular transport.

An alternative broad-specificity pathway for glycan breakdown in bacteria.

The vast majority of glycosidases characterized to date follow one of the variations of the 'Koshland' mechanisms1 to hydrolyse glycosidic bonds through substitution reactions. Here we describe a large-scale screen of a human gut microbiome metagenomic library using an assay that selectively identifies non-Koshland glycosidase activities2. Using this, we identify a cluster of enzymes with extremely broad substrate specificities and thoroughly characterize these, mechanistically and structurally. These enzymes not only break glycosidic linkages of both α and β stereochemistry and multiple connectivities, but also cleave substrates that are not hydrolysed by standard glycosidases. These include thioglycosides, such as the glucosinolates from plants, and pseudoglycosidic bonds of pharmaceuticals such as acarbose. This is achieved through a distinct mechanism of hydrolysis that involves oxidation/reduction and elimination/hydration steps, each catalysed by enzyme modules that are in many cases interchangeable between organisms and substrate classes. Homologues of these enzymes occur in both Gram-positive and Gram-negative bacteria associated with the gut microbiome and other body parts, as well as other environments, such as soil and sea. Such alternative step-wise mechanisms appear to constitute largely unrecognized but abundant pathways for glycan degradation as part of the metabolism of carbohydrates in bacteria.

Linking eucalyptus stump decomposition to microbial diversity, community composition, and metabolites

In terrestrial ecosystems, microorganisms serve as primary decomposers of stumps, influencing carbon and nutrient cycling. However, our understanding of alterations in microbial communities driven by microbial-mediated metabolites within eucalyptus stump substrates of varying decay classes remains limited. Therefore, we conducted a 90-day laboratory incubation experiment using eucalyptus stump substrates representing five decay classes. Employing high-throughput sequencing and metabolomics, we evaluated microbial metabolites, community composition, diversity, and their interconnections. In the different decay classes of substrates, Proteobacteria, Actinobacteria, and Bacteroidetes were the dominant bacterial phyla. Despite the gradual increase of Basidiomycota across decay classes, Ascomycota persisted as the dominant fungal phylum. Acidothermus and Talaromyces genera were identified as primary microorganisms strongly associated with microbial metabolites. Partial least squares path modelling (PLS-PM) analysis revealed that microbial communities were primarily influenced by microbe-mediated metabolites, and available resource stoichiometry directly affected microbial alpha and beta diversity. The variations in stump bacterial and fungal community structures were explained by the presence of dissolved organic carbon (DOC) and ellagic acid. Random forest analysis indicated that total carbon (TC) of the stump was the most significant predictor of bacterial diversity. Moreover, total carbon to total phosphorus (TC:TP) and total nitrogen to total phosphorus (TN:TP) ratios of stumps were identified as pivotal factors influencing fungal diversity. Overall, our findings suggest that stump decomposition involves dynamic cross-kingdom succession and is significantly influenced by changes in substrate quality, with microbial-mediated metabolites exerting a pronounced and direct impact on microbial community diversity during the process.

Persistent organonickel complexes as general platforms for Csp2-Csp3 coupling reactions.

The importance of constructing Csp2-Csp3 bonds has motivated the development of electrochemical, photochemical and thermal activation methods to reductively couple abundant aryl and alkyl electrophiles. However, these methodologies are limited to couplings of very specific substrate classes and require specialized sets of catalysts and reaction set-ups. Here we show a consolidation of these myriad strategies into a single set of conditions that enable reliable alkyl-aryl couplings, including those that were previously unknown. These reactions rely on the discovery of unusually persistent organonickel complexes that serve as stoichiometric platforms for C(sp2)-C(sp3) coupling. Aryl, heteroaryl or vinyl complexes of Ni can be inexpensively prepared on a multigram scale by mild electroreduction from the corresponding C(sp2) electrophile. Organonickel complexes can be isolated and stored or telescoped directly to reliably diversify drug-like molecules. Finally, the procedure was miniaturized to micromole scales by integrating soluble battery chemistries as redox initiators, enabling a high-throughput exploration of substrate diversity.

Alkyl Cyclopropyl Ketones in Catalytic Formal [3 + 2] Cycloadditions: The Role of SmI2 Catalyst Stabilization.

Alkyl cyclopropyl ketones are introduced as versatile substrates for catalytic formal [3 + 2] cycloadditions with alkenes and alkynes and previously unexplored enyne partners, efficiently delivering complex, sp3-rich products. The key to effectively engaging this relatively unreactive new substrate class is the use of SmI2 as a catalyst in combination with substoichiometric amounts of Sm0; the latter likely acting to prevent catalyst deactivation by returning SmIII to the catalytic cycle. In the absence of Sm0, background degradation of the SmI2 catalyst can outrun product formation. For the most recalcitrant alkyl cyclopropyl ketones, catalysis is "switched-on" using these new robust conditions, and otherwise unattainable products are delivered. Combined experimental and computational studies have been used to identify and probe reactivity trends among alkyl cyclopropyl ketones, including more complex bicyclic alkyl cyclopropyl ketones, which react quickly with various partners to give complex products. In addition to establishing alkyl cyclopropyl ketones as a new substrate class in a burgeoning field of catalysis, our study provides vital mechanistic insight and robust, practical approaches for the nascent field of catalysis with SmI2.

Sensitive, Stable, and Recyclable ZnO/Ag Nanohybrid Substrates for Surface-Enhanced Raman Scattering Metrology.

Surface-enhanced Raman scattering is a practical, noninvasive spectroscopic technique that measures chemical fingerprints for varieties of molecules in multiple applications. However, synthesizing appropriate substrates for practical, long-term applications of this method has always been a challenging task. In the present study, we show that ZnO/Ag nanohybrid substrates may act as highly stable, sensitive, and recyclable substrates for surface-enhanced Raman scattering, as illustrated by the detection of methylene blue, selected as a test dye molecule with self-cleaning functionalities. Specifically, we demonstrate the detection enhancement factor of 3.7 × 107 along with exceptional long-term stability explained in terms of the localized surface plasmon resonance from the Ag nanocrystals embedded into the chemically inert ZnO nanoparticles, constituting the nanohybrid. Significantly, these substrates can be efficiently cleaned and regenerated while maintaining their high performance upon recycling. As a result, using these substrates, up to 10-12 M detection sensitivity has been demonstrated, enabling the accuracy required in modern environmental monitoring, bioassays, and analytical chemistry. Thus, ZnO nanoparticles with embedded Ag nanocrystals constitute a novel class of advanced nanohybrid substrates for use in multiple applications of surface-enhanced Raman scattering metrology.