High-volume cellular screening for anticancer agents with combinatorial chemical libraries: A new methodology

Summary A single-step cancer cell cytotoxic assay system for anticancer drug discovery has been developed which facilitates rapid screening of large combinatorial chemical libraries synthesized using the one-bead-one-compound (OBOC) methodology. Each OBOC library bead incorporates two orthogonally cleavable linkers that release the bead-bound compound at a different pH. The assay utilizes high concentrations of tumor cells mixed directly with OBOC beads and plated in soft agarose containing tissue culture medium. One of the orthogonal linkers is cleaved at neutral pH in tissue culture releasing an aliquot of compound to diffuse at a relatively high local concentration into the soft agarose immediately surrounding the bead. Active compounds are identified visually from a clear ring of tumor cell lysis which forms within 48 h around just the rare bead releasing a cytotoxic compound. The bead releasing a cytotoxin is then plucked from the agar and the remaining compound still linked to the bead can be released for structural analysis, followed by compound resynthesis and confirmatory testing. This assay system has been successfully applied to identification of lead cytotoxic compounds from model peptidic and non-peptidic combinatorial chemical libraries. Use of this methodology may facilitate anticancer drug discovery.     

Design considerations and computer modeling related to the development of molecular scaffolds and peptide mimetics for combinatorial chemistry

Summary A critical issue in drug discovery utilizing combinatorial chemistry as part of the discovery process is the choice of scaffolds to be used for a proper presentation, in a three-dimensional space, of the critical elements of structure necessary for molecular recognition (binding) and information transfer (agonist/ antagonist). In the case of polypeptide ligands, considerations related to the properties of various backbone structures (-helix, -sheets, etc.; , space) and those related to three-dimensional presentation of side-chain moieties (topography; (chi) space) must be addressed, although they often present quite different elements in the molecular recognition puzzle. We have addressed aspects of this problem by examining the three-dimensional structures of chemically different scaffolds at various distances from the scaffold to evaluate their putative diversity. We find that chemically diverse scaffolds can readily become topographically similar. We suggest a topographical approach involving design in chi space to deal with these problems.     

Editorial: Past,present and future of the combinatorial chemistry in Spain

Molecular Diversity -     

Discovery of enzyme inhibitors through combinatorial chemistry

Summary This review serves to highlight the recent examples of combinatoric methodology as applied to the discovery and optimization of enzyme inhibitors. Early research efforts focused on the identification of polypeptides from libraries as inhibitors of proteases. As solution- and solid-phase chemistries gain in sophistication, libraries containing less peptidic structural motifs have been created. A recurring design stratagem relies on the synthesis of libraries incorporating pharmacophores with known affinity for the target enzyme. Screening of these structure-based libraries has led to the discovery of small-molecule inhibitors of both proteolytic and non-proteolytic enzymes alike. Two tables are provided listing the enzyme targeted libraries through 1996. A name, generic structure and size is given for each library citation, accompanied by the enzyme screen and the structure and potency of the most active library member.     

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.     

Myxobacterial epothilones and tubulysins as promising anticancer agents

Tubulin-binding agents play a pivotal role in current cancer therapy and there are many efforts in pre-clinical and clinical development of known and novel cytotoxic agents ongoing. In this article a known class, epothilones, as well as a novel class, tubulysins, are presented.     

计算机辅助受迫振动实验

在Matlab平台下编写了图形用户界面程序，该程序利用计算机的声卡采集音叉上的压电换能器信号，精确地计算出频率值和平均振幅，通过多组数据采集及插值计算，可自动绘制出不同阻尼下的共振曲线．     

Synthetic methods for polyamine linkers and their application to combinatorial chemistry

Summary Polyamines and polyamine conjugates display a diverse range of important biological functions, ranging from antibiotics to immunosuppressants and glutamate receptor antagonists. For these reasons, polyamines provide an excellent template/scaffold for combinatorial chemistry. In this paper we present methods for the solid-phase immobilisation of polyamines for use in synthetic and combinatorial chemistry and describe how they have been employed in the preparation of a number of important polyamine conjugates and polyamine libraries. Thus, we have designed, synthesised and utilised a number of polyamine linkers for both solution and resin screening combinatorial application.     

New high-throughput material-exploration system based on combinatorial chemistry and electrostatic atomization

As a tool to facilitate future material explorations, our group has developed a new combinatorial system for the high-throughput preparation of compounds made up of more than three components. The system works in two steps: the atomization of a liquid by a high electric field followed by deposition to a grounded substrate. The combinatorial system based on this method has plural syringe pumps. The each starting materials are fed through the syringe pumps into a manifold, thoroughly mixed as they pass through the manifold, and atomized from the tip of a stainless steel nozzle onto a grounded substrate.     

Structure and properties of TentaGel resin beads: Implications for combinatorial library chemistry

Summary In view of the widespread use of TentaGel resin beads for the synthesis of combinatorial libraries, the properties of TentaGel resin have been examined using a combination of confocal laser microscopy and NMR spectroscopy. Evidence is presented that trypsin, a 23.5-kDa enzyme, can penetrate to the core of 90-m TentaGel beads, and that the matrix of such beads permits molecular motion at a similar rate to that in solution. The beads act as a separate gel phase rather than as a porous solid. These conclusions have important implications for the bioassay of on-bead combinatorial chemical libraries.     

Synthesis and evaluation of functionalized indoles as antimycobacterial and anticancer agents

A new series of 5-fluoro-N(2)-(cyclohexylidene)-3-phenyl-1H-indole-2-carbohydrazides (6a-6e) and their cyclization products 5-fluoro-N-(3-oxo-1-thia-4-azaspiro [4.5]dec-4-yl)-3-phenyl-1H-indole-2-carboxamides (7a-7e, 8a-8e) have been synthesized and evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv using the Microplate Alamar Blue Assay (MABA). Compounds showed moderate to good inhibitory activity at 6.25 μg/mL. Among them, 7b, 7d, 8b, and 8d were the most potent analogs with an inhibition range of 91-95?%. Additionally, compounds 6a, 7a, 7e, 8a, and 8e were subjected to the National Cancer Institute's (NCI) in vitro disease-oriented antitumor screening to be evaluated for antitumor activity. 8e, the most potent compound examined, displayed broad spectrum antiproliferative activity with particular selectivity against four leukemia cell lines (CCRF-CEM, HL-60 (TB), K-562, and RPMI-8226) with log (10) GI (50) values between -5.68 and -6.09.     

Reactant- and product-based approaches to the design of combinatorial libraries

Molecular Diversity -     

Crystal chemistry and structural design of iron-based superconductors

The second class of high-temperature superconductors （HTSCs）, iron-based pnictides and chalcogenides, necessarily contain Fe2X2 （＂X＂ refers to a pnictogen or a chalcogen element） layers, just like the first class of HTSCs which possess the essential CuO2 sheets. So far, dozens of iron-based HTSCs, classified into nine groups, have been discovered. In this article, the crystal-chemistry aspects of the known iron-based superconductors are reviewed and summarized by employing ＂hard and soft acids and bases （HSAB）＂ concept. Based on these understandings, we propose an alternative route to exploring new iron-based superconductors via rational structural design.     

Solid phase synthesis of functionalized biaryl ethers: Versatile scaffolds for combinatorial chemistry

4-Fluoro-3-nitrobenzoic acid attached to a solid support was shown to react under mild conditions with a wide range of functionalized phenols to yield, after cleavage, the corresponding biaryl ethers in excellent purity. In a similar fashion, biaryl thioethers could be obtained. Further elaboration of immobilized biaryl ethers demonstrates the potential for combinatorial library generation. This revised version was published online in August 2006 with corrections to the Cover Date.     

Use of combinatorial chemistry to develop photocurable thermoplastic polyurethane elastomers (TPUs)

Combinatorial chemistry was used to develop photocurable thermoplastic polyurethane elastomers through the incorporation of photoreactive diacetylene diols as chain extenders. The methodology applied allowed, in 36 experiments, the choice of the best compromise between mechanical properties and lack of colour. The combinations chosen were scaled up and their properties were evaluated in terms of mechanical properties. The combinatorial approach reduced the estimated time tenfold in developing such type of materials.     

Design,synthesis, cytotoxicity and molecular modeling studies of some novel fluorinated pyrazole-based heterocycles as anticancer and apoptosis-inducing agents

Molecular Diversity - 3,5-Diamino-4-(3-trifluoromethylphenyldiazenyl)-1H-pyrazole was used as a starting scaffold for the synthesis of new pyrazole-based heterocycles to study their effects on the...     

Application of the edge of chaos in combinatorial optimization

Many problems in science, engineering and real life are related to the combinatorial optimization. However, many combinatorial optimization problems belong to a class of the NP-hard problems, and their globally optimal solutions are usually difficult to solve. Therefore, great attention has been attracted to the algorithms of searching the globally optimal solution or near-optimal solution for the combinatorial optimization problems. As a typical combinatorial optimization problem, the traveling salesman problem(TSP) often serves as a touchstone for novel approaches. It has been found that natural systems, particularly brain nervous systems, work at the critical region between order and disorder, namely,on the edge of chaos. In this work, an algorithm for the combinatorial optimization problems is proposed based on the neural networks on the edge of chaos(ECNN). The algorithm is then applied to TSPs of 10 cities, 21 cities, 48 cities and 70 cities. The results show that ECNN algorithm has strong ability to drive the networks away from local minimums.Compared with the transiently chaotic neural network(TCNN), the stochastic chaotic neural network(SCNN) algorithms and other optimization algorithms, much higher rates of globally optimal solutions and near-optimal solutions are obtained with ECNN algorithm. To conclude, our algorithm provides an effective way for solving the combinatorial optimization problems.     

超声辅助滚压系统的设计与研究*

鉴于风力发电机组主轴的复杂工作情况和疲劳断裂失效形式,提出一种基于表面强化技术的超声辅助滚压加工系统;首先基于运动合成原理,获得了滚轮接触线的运动轨迹特征,并应用ANSYS/LS-DYNA软件分析了加工过程的特点;之后,基于一维振动理论、等效波长理论与牛顿迭代理论,推导了并求解了复合变幅杆的频率方程,实现了该复合变幅杆的纵向振动。通过对该变幅杆进行有限元仿真分析与振动特性测试,结果表明二者相对设计频率的偏差仅在0.817％以内。最后,通过对40Cr主轴进行超声辅助滚压测试,结果获得了粗糙度Ra 0.085μm和表面硬度32.2HRC的加工表面,较普通滚压加工粗糙度降低了69.1％,显微硬度提高了60％。