Approaches for introducing high molecular diversity in scaffolds: Fast parallel synthesis of highly substituted 1H-quinolin-4-one libraries

We have developed a two steps strategy for the parallel synthesis of highly diversified quinolin-ones. In the first step we have combined and improved different synthetic methods for generating quinolin-4-ones bearing four different substitutions at specific positions using round bottomed flasks. The synthesis was assessed for a large number of substituted quinolin-4-ones. In the second step, the improved method was adapted to a parallel array synthesis using a 12 positions carrousel as demonstrated for the synthesis of 42-variable quinolin-4-ones. The first combinatorial library set 14(a-x) was obtained with a chemical purity of more than 95% without purification, the second library set 15(a-r), which included two synthetic steps, needed combinatorial purification using an innovative parallel purifier. The proposed approach contributes to a more extensive diversification of molecular scaffolds in general and provides access to highly substituted quinolinones in particular.     

Microwave heating in high pressure reaction vessels

Abstract

We report the use of microwave -hydrothermal processing to synthesize various ceramic powders. Microwave-hydrothermal processing is compared with conventional hydrothermal processing in the crystallisation of MoO₂. The presence of microwave field leads to accelerated kinetics of crystallization of the finely divided molybdenum dioxide particles. Existing microwave heated pressure vessels for chemical synthesis cannot be used above 250 MPa and 270°C because they contain parts made of polymeric materials. The objective of this work is to associate a microwave source to a high pressure vessel in a way such that it might be used to carry out reactions in aqueous media at pressures around 100 MPa and temperatures above the critical point of water.     

Parallel microwave chemistry in silicon carbide microtiter platforms: a review

In this review, applications of silicon carbide-based microtiter platforms designed for use in combination with dedicated multimode microwave reactors are described. These platforms are employed not only for the efficient parallel synthesis of compound libraries, but also in the context of high-throughput reaction screening/optimization and a number of other (bio)analytical and biomedical applications. Since the semiconducting plate material (silicon carbide) is strongly microwave absorbing and possesses high thermal conductivity, no temperature gradients across the microtiter plate exist. Therefore, many of the disadvantages experienced in attempting to perform microtiter plate chemistry under conventional microwave conditions can be eliminated. In general, the silicon carbide-based microtiter platforms allow sealed vessel processing (either directly in the well or in glass vials placed into the wells) of volumes ranging from 0.02–3.0 mL at a maximum temperature/pressure limit of 200°C/20 bar. Depending on the specific plate and rotor configuration, a maximum of 80–192 transformations can be carried out in parallel in a single microwave irradiation experiment under strict temperature control. A platform type utilizing HPLC/GC vials as reaction vessels allows analysis directly from the reaction vessel eliminating the need for a transfer step from the reaction to the analysis vial. The latter system is particularly useful for analytical applications as well as reaction optimization/screening.     

Advances in Microwave-Assisted Combinatorial Chemistry Without Polymer-Supported Reagents

Summary Combinatorial methodologies have dramatically changed the chemical research and discovery process, offering an unlimited source of new molecule entities to be screened for activity. The application of microwave irradiation in Combinatorial Chemistry and high-throughput synthesis has become increasingly popular. By taking advantage of this energy source, compound libraries for lead generation can be assembled in a fraction of time required by conventional thermal heating. This review focuses on the advances in developing synthetic methodologies in microwave without polymer-supported reagents suitable for combinatorial chemistry, including the advances in microwave-assisted fluorous synthesis technology.     

Parallel fabrication of artificially designed superlattices by combinatorial laser MBE

A system for parallel synthesis of atomically regulated lattices and nano-structured heterojunctions has been developed. This combinatorial laser MBE system is composed of a UHV-PLD chamber, scanning RHEED for in situ diagnostics of reactions at various areas of substrate surface, a pair of fixed and moving masks to define the film deposition area, and a computer for controlling the operation conditions as functions of deposition area and time. In this system, oxide layered lattice strips were deposited in parallel on a SrTiO₃ substrate under RHEED observation of individual strips with different compositions and/or layer thickness.     

Application of computer assisted combinatorial chemistry in antivirial,antimalarial and anticancer agents design

Combinatorial chemistry and technologies have been developed to a stage where synthetic schemes are available for generation of a large variety of organic molecules. The innovative concept of combinatorial design assumes that screening of a large and diverse library of compounds will increase the probability of finding an active analogue among the compounds tested. Since the rate at which libraries are screened for activity currently constitutes a limitation to the use of combinatorial technologies, it is important to be selective about the number of compounds to be synthesized. Early experience with combinatorial chemistry indicated that chemical diversity alone did not result in a significant increase in the number of generated lead compounds. Emphasis has therefore been increasingly put on the use of computer assisted combinatorial chemical techniques. Computational methods are valuable in the design of virtual libraries of molecular models. Selection strategies based on computed physicochemical properties of the models or of a target compound are introduced to reduce the time and costs of library synthesis and screening. In addition, computational structure-based library focusing methods can be used to perform in silico screening of the activity of Compounds against a target receptor by docking the ligands into the receptor model. Three case studies are discussed dealing with the design of targeted combinatorial libraries of inhibitors of HIV-1 protease, P. falciparum plasmepsin and human urokinase as potential antivirial, antimalarial and anti-cancer drugs. These illustrate library focusing strategies.     

一种大气微波环形波导等离子体设备

 微波等离子体相对其它等离子体而言有很多的优点，具有极高的工业应用价值。但在大气条件下，大体积的微波等离子体较难获得。为达到产生该种微波等离子体并将之应用的目的，特设计了一台环形波导反应腔设备并从事了等离子体激发的相关研究。介绍了该设备的设计思路，给出了常用的非磁化微波等离子体工作气体的击穿曲线，通过软件仿真得到了反应腔内的电场分布，并陈述了微波等离子体反应的基本现象。结合试验的结果，证明了软件仿真的正确性和装置的有效性。目前，该装置可在大气压下顺利激发一定体积的氦、氩等离子体。     

110 GHz微波电离大气产生等离子体过程的理论研究

将描述电磁波的Maxwell方程组和简化的等离子体流体方程组耦合数值求解,对110 GHz微波电离大气产生等离子体的过程进行了理论研究. 研究发现:在高气压下等离子体成丝状;中等气压下等离子体先成丝状,在向微波源移动的过程中逐渐向连续的等离子体区域过渡;低气压下电离产生连续的等离子体区域. 不同气压下等离子体区域都向微波源方向移动. 初始电子数密度分布只影响放电初始阶段的等离子体区域形状,不会影响成丝与否. 等离子体区域在垂直于电场方向和平行于电场方向的移动规律不同. 当电场平行于计算平面时,由于沿着电场方向等离子体两端存在强场区,等离子体区域被拉长,在较低的气压下会出现等离子体丝阵. 关键词： 110 GHz微波 大气电离 等离子体丝阵     

Solid phase synthesis of combinatorial libraries using anhydrides as templates

A simple and general approach to the synthesis of chemical libraries based on a universal anhydride template allows the preparation of large number of compounds. Various cyclic/acyclic amines, primary/secondary amines, differentially protected bifunctional amines were used as nucleophiles to react with anhydrides. The free carboxylic acid generated was then coupled with solid-bound amines. The facile and rapid generation of compounds through this multi-component assembly can be accomplished in a combinatorial parallel synthesis. This revised version was published online in August 2006 with corrections to the Cover Date.     

Future pathways for combinatorial chemistry

Summary Investment in combinatorial chemistry (combichem) in the pharmaceutical industry is being driven by the need for increased efficiency. Results from pioneers in the field have demonstrated where mixture or discrete compound synthesis is useful, and what mixture sizes and compound concentrations are appropriate. To make the techniques of combichem of general utility in drug discovery, a broad range of advances is still required. Conversion of organic chemistry to solid phase conditions is key, as are developments in linkers and resins. Library design methodology requires further development. Combinatorial biosynthesis of focused libraries of natural products holds great promise for capitalising on hardwon natural product leads. Miniaturisation of screens is required to reduce the cost of screening combinatorial libraries. Developments in the processes preceding and following synthesis are required to enable the flow of increased numbers of compounds without new bottlenecks developing. The impact of combinatorial chemistry will be greatly enhanced by synergy with ongoing parallel developments in genetic technologies, screening technologies and bioinformatics.     

High-throughput experimentation in synthetic polymer chemistry: From RAFT and anionic polymerizations to process development

The application of combinatorial and high-throughput approaches in polymer research is described. An overview of the utilized synthesis robots is given, including different parallel synthesizers and a process development robot. In addition, the application of the parallel synthesis robots to reversible addition fragmentation termination (RAFT) radical polymerizations and ionic copolymerizations is overviewed. Moreover, first results concerning the process development of semi-batch free radical polymerizations are described.     

Microwave breakdown of air initiated by a short electromagnetic vibrator

The electrical breakdown of air (under a pressure from several tens of Torr to several hundreds of Torr) is initiated in a linearly polarized quasi-optical microwave beam using a rounded-end cylindrical metallic electromagnetic vibrator placed parallel to the electric component of the microwave field. The vibrator is much shorter than the wavelength of the field. The field strength at the top of the vibrator as a function of its length is determined. An empiric expression relating the field strength at the top with the vibrator length-to-diameter ratio is found for the vibrator length range studied. The practicability of locally measuring the field in a quasioptical microwave beam is substantiated. The idea is to determine the maximal air pressure at which electrical breakdown of air initiated by a short vibrator placed at a given point of the beam takes place.     

Ø500 mm阵列透镜波前采样器的研制

 设计加工了一个由484块单透镜组成的大口径阵列透镜,并设计了一套光束波前采样及测量实验系统。在实验过程中,合理匹配了阵列透镜波前采样器、CCD、成像屏和图像采集处理各系统参数,并讨论了该系统的动态范围和采样精度。利用平行光标定了该系统,且测量了大口径波前的像差,测量值与理论值相吻合。实验证明了阵列透镜波前采样器用于波前采样的技术可行性。     

大气压微波等离子体射流装置放电特性研究

基于同轴传输线结构设计了两种不同喷嘴结构的大气压微波等离子体射流(MW-APPJ)装置,其工作频率2.45 GHz,工作气体为氩气,分别研究了两种不同喷嘴结构对等离子体放电特性产生的影响。仿真结果表明,MW-APPJ在气体喷嘴处会产生高强度的电场,经过优化结构,实现在频率2.45 GHz下,喷嘴处的场强满足氩气电离的击穿场强阈值要求。同时,利用多物理场耦合仿真软件对装置的气流分布进行了稳态模拟,并通过实验对比分析了两种喷嘴结构下大气压氩等离子体射流的基本特性。实验结果表明,不同的喷嘴结构会影响等离子体装置的反射系数随输入功率的变化规律,但并不影响等离子体射流长度随输入功率的变化规律和反射功率随进气流量的变化规律;同时,在大气压下,稳态微波等离子体射流呈现出类金属性,等离子体中的电子只能在很薄的区域中吸收微波能量,因而造成微波的反射功率较大。     

一种准光反射聚焦微波放电大气等离子体装置

设计了一种准光反射聚焦方式的微波放电大气等离子体实验装置,装置包括大气环境模拟室和微波辐射聚焦系统。辐射微波在腔室中心形成kV/cm量级的非均匀强场,击穿大气产生等离子体。通过仿真计算了腔室内的空间辐射场分布,并利用小信号传递的方式进行测量,测量结果与仿真相符,形成的等离子体形态与辐射场分布强弱一致。电磁场在聚焦区域形成驻波,等离子体出现明显分层现象。实验通过拍照记录了不同参数条件下的等离子体图样,等离子体形态随气压升高而收缩,放电区域受场强和气压共同影响。对实验结果进行分析,验证了该装置的能力。     

Frequency dependence of microwave-assisted electron-transfer chemical reactions

In this paper, the electron transfer reactions in the microwave field are studied. A classical theory is developed for a mix of reagents and polar frequency-dispersive and lossy solvent filling vessels excited by microwaves. These reactors are described by a system of non-linear partial self-consistent differential equations for non-stationary microwave field, heat and liquid dynamics, and chemical molecular kinetics. A particular solution of this system is considered for the isothermic electron-transfer reactions in the microwave field varying its frequency with the calculation of the normalised Marcus rate coefficient. It is found that for the small normalised reaction free energy, the chemical reactions are supported by microwaves in a wide frequency band with an increased value of the exponent in the Marcus rate coefficient. At higher values of this energy, these reactions are driven only by conventional microwave heating. The restrictions for the given theory are reviewed, and further experimental and semi-classical and quantum-mechanical studies are found essential for practical applications of these findings.     

Advances in diversity profiling and combinatorial series design

Rapid advances in synthetic and screening technology have recently enabled the simultaneous synthesis and biological evaluation of large chemical libraries containing hundreds to tens of thousands of compounds, using molecular diversity as a means to design and prioritize experiments. This paper reviews some of the most important computational work in the field of diversity profiling and combinatorial library design, with particular emphasis on methodology and applications. It is divided into four sections that address issues related to molecular representation, dimensionality reduction, compound selection, and visualization.     

Velocity auto-correlation and hot-electron diffusion constant in GaAs and InP

Auto-correlation functions of the fluctuations in the electron velocities transverse and parallel to the applied electric field are calculated by the Monte Carlo method for GaAs and InP at three different values of field strength which are around three times the threshold field for negative differential mobility in each case. From these the frequency-dependent diffusion coefficients transverse and parallel to the applied field and the figure of merit for noise performance when used in a microwave amplifying device are determined. The results indicate that the transverse auto-correlation functionC _t (s) falls nearly exponentially to zero with increasing intervals while the parallel functionC _p (s) falls sharply, attains a minimum and then rises towards zero. In each case a higher field gives a higher rate of fall and makes the correlation functions zero within a shorter interval. The transverses diffusion coefficient falls monotonically with the frequency but the parallel diffusion coefficient generally starts with a low value at low frequencies, rises to a maximum and then falls. InP, with a larger separation between the central and the satellite valleys, has a higher value of the low frequency transverse diffusion coefficient and a lower value of its parallel counterpart. The noise performance of microwave semiconductor amplifying devices depends mainly on the low frequency parallel diffusion constant and consequently devices made out of materials like InP with a large separation between valleys are likely to have better noise characteristics.     

Initiation of dusty structures in chain reactions under the action of gyrotron radiation on a mixture of metal and dielectric powders with an open boundary

A dusty plasma formed in chain exothermal reactions initiated by radiation of a high-power gyrotron in mixtures of metal and dielectric powders has been described. An oscillatory character of such chain reactions, as well as the appearance of dust particles at the first (explosive) stage, has been detected. The tracks, velocities, and sizes of dust particles have been measured. It has been revealed that ensembles of dust particles appear in a reactor after switching-off of the gyrotron against the background of development of chemical reactions. The time of existence of these ensembles is three or four orders of magnitude larger than the duration of a microwave radiation pulse. The quasistationary state of the low-temperature plasma with charged macroparticles appears because of both the chemical heating of the mixture in the reactor and thermophoresis. It has been shown that dust particles are necessary as crystallization nuclei for the creation (or deposition) of complex composites of nano- and micromaterials produced in secondary plasma chemical synthesis.     

A dual-mode microwave resonator for double electron-electron spin resonance spectroscopy at W-band microwave frequencies

We present a dual-mode resonator operating at/near 94 GHz (W-band) microwave frequencies and supporting two microwave modes with the same field polarization at the sample position. Numerical analysis shows that the frequencies of both modes as well as their frequency separation can be tuned in a broad range up to GHz. The resonator was constructed to perform pulsed ELDOR experiments with a variable separation of "pump" and "detection" frequencies up to Δν=350 MHz. To examine its performance, test ESE/PELDOR experiments were performed on a representative biradical system.