High-Throughput Synthesis and Characterization of Aryl Silicones by Using the Piers–Rubinsztajn Reaction

Arylsilicones are widely exploited for their thermal and optical properties. The creation of phenylsilicone elastomers with specific physical properties is typically done by a “one-off” formulation and test process. Herein, it is demonstrated that high-throughput synthesis methods can be used to rapidly prepare a series of arylsilicone elastomers and then the relative impact of different aryl groups on their physical properties is assessed. Aromatic groups were incorporated into polydimethylsiloxane (PDMS) elastomers by exploiting the relative reactivity of different functional groups in the Piers–Rubinsztajn reaction. To analyze trends in the silicone mechanical properties as a function of increasing aryl concentration—structure/property relationships—libraries of elastomers were both quickly synthesized and characterized by using high-throughput suites starting from low viscosity silicone oils/monomers in 96-well plates. Liquid handling parameters were optimized to effectively work with the silicones. Incorporating aryl instead of alkyl crosslinkers into the PDMS backbone increased the silicone elastomer modulus by approximately 50 % (at a crosslink density of 6 %); elastomers prepared with an aromatic crosslinker with three contact points led to much higher moduli compared with those with one contact point at the same crosslink density. When located at precise rather than random points on the silicone chains, diphenylsilicones had lower moduli than analogous monophenylsilicones.     

Development and Molecular Understanding of a Pd-Catalyzed Cyanation of Aryl Boronic Acids Enabled by High-Throughput Experimentation and Data Analysis

A synthetic method for the palladium-catalyzed cyanation of aryl boronic acids using bench stable and non-toxic N-cyanosuccinimide has been developed. High-throughput experimentation facilitated the screen of 90 different ligands and the resultant statistical data analysis identified that ligand σ-donation, π-acidity and sterics are key drivers that govern yield. Categorization into three ligand groups – monophosphines, bisphosphines and miscellaneous – was performed before the analysis. For the monophosphines, the yield of the reaction increases for strong σ-donating, weak π-accepting ligands, with flexible pendant substituents. For the bisphosphines, the yield predominantly correlates with ligand lability. The applicability of the designed reaction to a wider substrate scope was investigated, showing good functional group tolerance in particular with boronic acids bearing electron-withdrawing substituents. This work outlines the development of a novel reaction, coupled with a fast and efficient workflow to gain understanding of the optimal ligand properties for the design of improved palladium cross-coupling catalysts.     

Identification of Compounds that Selectively Stabilize Specific G‐Quadruplex Structures by Using a Thioflavin T‐Displacement Assay as a Tool

Small molecules are used in the G‐quadruplex (G4) research field in vivo and in vitro, and there are increasing demands for ligands that selectively stabilize different G4 structures. Thioflavin T (ThT) emits an enhanced fluorescence signal when binding to G4 structures. Herein, we show that ThT can be competitively displaced by the binding of small molecules to G4 structures and develop a ThT‐displacement high‐throughput screening assay to find novel and selective G4‐binding compounds. We screened approximately 28 000 compounds by using three different G4 structures and identified eight novel G4 binders. Analysis of the structural conformation and stability of the G4 structures in presence of these compounds demonstrated that the four compounds enhance the thermal stabilization of the structures without affecting their structural conformation. In addition, all four compounds also increased the G4‐structure block of DNA synthesis by Taq DNA polymerase. Also, two of these compounds showed selectivity between certain Schizosaccharomyces pombe G4 structures, thus suggesting that these compounds or their analogues can be used as selective tools for G4 DNA studies.     

Mass Activated Droplet Sorting (MADS) Enables High‐Throughput Screening of Enzymatic Reactions at Nanoliter Scale

Microfluidic droplet sorting enables the high‐throughput screening and selection of water‐in‐oil microreactors at speeds and volumes unparalleled by traditional well‐plate approaches. Most such systems sort using fluorescent reporters on modified substrates or reactions that are rarely industrially relevant. We describe a microfluidic system for high‐throughput sorting of nanoliter droplets based on direct detection using electrospray ionization mass spectrometry (ESI‐MS). Droplets are split, one portion is analyzed by ESI‐MS, and the second portion is sorted based on the MS result. Throughput of 0.7 samples s^?1 is achieved with 98 % accuracy using a self‐correcting and adaptive sorting algorithm. We use the system to screen ≈15 000 samples in 6 h and demonstrate its utility by sorting 25 nL droplets containing transaminase expressed in vitro. Label‐free ESI‐MS droplet screening expands the toolbox for droplet detection and recovery, improving the applicability of droplet sorting to protein engineering, drug discovery, and diagnostic workflows.     

Discovery of Chemicals to Either Clear or Indicate Amyloid Aggregates by Targeting Memory‐Impairing Anti‐Parallel Aβ Dimers

Amyloid‐β (Aβ) oligomers are implicated in Alzheimer disease (AD). However, their unstable nature and heterogeneous state disrupts elucidation of their explicit role in AD progression, impeding the development of tools targeting soluble Aβ oligomers. Herein parallel and anti‐parallel variants of Aβ(1–40) dimers were designed and synthesized, and their pathogenic properties in AD models characterized. Anti‐parallel dimers induced cognitive impairments with increased amyloidogenesis and cytotoxicity, and this dimer was then used in a screening platform. Through screening, two FDA‐approved drugs, Oxytetracycline and Sunitinib, were identified to dissociate Aβ oligomers and plaques to monomers in 5XFAD transgenic mice. In addition, fluorescent Astrophloxine was shown to detect aggregated Aβ in brain tissue and cerebrospinal fluid samples of AD mice. This screening platform provides a stable and homogeneous environment for observing Aβ interactions with dimer‐specific molecules.     

费托反应本征动力学中合成气分压对反应速率的影响

利用高通量动力学反应器测量了本征条件下钴基费托催化剂上反应物消耗速率rCO和产物生成速率rCH4随固定床床层的分布,并考察了它们在不同入口分压(p0CO,p0H2)条件下的变化.结果表明,入口氢碳比(H/C)0=p0H2/p0CO为影响速率的敏感外部变量,反应速率随(H/C)0的增加而加快;而合成气总压p0H2+CO则...     

面向丙烯/丙烷吸附分离的金属有机骨架材料的高通量计算筛选

丙烯、丙烷作为分子尺寸相近的共沸物,其分离一直是化工领域研究热点。金属有机骨架(MOFs)材料因其高度可调的孔道结构,在丙烯/丙烷分离应用上已展现出诱人潜能。本文基于Core MOF 2019数据库,采用巨正则蒙特卡洛基高通量计算筛选技术,获得了分离性优异的MOFs结构,发现其拥有适中的丙烯吸附量和较弱的丙烷吸附能力,且骨架孔径为3.70～4.10?、孔隙率中等(0.35～0.44),并揭示了孔道中心吸附位的选择性与丙烯/丙烷分离系数间关系。本研究阐明了高丙烯/丙烷分离性的骨架材料的结构和性能特征,为设计MOFs实现丙烯/丙烷的高效分离提供理论指导和数据支撑。     

Design,Synthesis, and Phenotypic Profiling of Pyrano‐Furo‐Pyridone Pseudo Natural Products

Natural products (NPs) inspire the design and synthesis of novel biologically relevant chemical matter, for instance through biology‐oriented synthesis (BIOS). However, BIOS is limited by the partial coverage of NP‐like chemical space by the guiding NPs. The design and synthesis of “pseudo NPs” overcomes these limitations by combining NP‐inspired strategies with fragment‐based compound design through de novo combination of NP‐derived fragments to unprecedented compound classes not accessible through biosynthesis. We describe the development and biological evaluation of pyrano‐furo‐pyridone (PFP) pseudo NPs, which combine pyridone‐ and dihydropyran NP fragments in three isomeric arrangements. Cheminformatic analysis indicates that the PFPs reside in an area of NP‐like chemical space not covered by existing NPs but rather by drugs and related compounds. Phenotypic profiling in a target‐agnostic “cell painting” assay revealed that PFPs induce formation of reactive oxygen species and are structurally novel inhibitors of mitochondrial complex I.     

Application of FTIR Microscopy in Combinatorial Experimentation on Polymer Blends

Summary: A novel combinatorial, high-throughput experimentation (HTE) setup has been developed, which allows for rapid mapping of the phase behavior of blends of homopolymers and block copolymers. The principle is based on the preparation of composition (ϕ)-temperature (T) gradient films. Linear ϕ gradients were obtained over a large composition range, as shown by FTIR microscopy. The applicability of this combinatorial approach was demonstrated by studying the phase behavior of a poly(styrene-co-acrylonitrile) (SAN)/poly(methyl methacrylate-co-ethyl acrylate) (PMMA-EA) blend with varying EA content and a poly(styrene-b-butadiene-b-methyl methacrylate) (SBM) triblock copolymer.     

Preparation and evaluation of ammonia decomposition catalysts by high-throughput technique

The high-throughput technique has been successfully employed to investigate systematically NH₃ decomposition catalysts for COx-free hydrogen production. Supported γ-Mo₂N catalysts not only could be prepared and evaluated by the high-throughput experiment, but are also active for NH₃ decomposition luke supported Ni and Co catalysts. Additionally, the preparation process and support play important roles on the catalytic performance of supported γ-Mo₂N catalysts.