Regioselective alkylation at the N4 positionof a 3-oxo-1,4-benzodiazepine on solid support

An efficient solid phase regioselective alkylation at the N4 positionof a 3-oxo-1,4-benzodiazepine template exemplified by 4-H-2,3,4,5-tetrahydro-7-iodo-3-oxo-1H-1,4-benzodiazepine-2-acetate-polymerester is described. Further chemical elaboration atposition 7, utilizing a modified Heck reaction, allows the incorporationof amides from primary or secondary amines. The two diversity points atpositions 4 and 7 were utilized tosynthesize a 28-membered, combinatorial array on Sasrin® resin in moderate yields and >80% purity. Having validated the chemistry on solid support, acombine and splitapproach to prepare a bead-bound combinatorial library is achievableutilizing similar experimental practices and procedures as in thearray synthesis.     

Atom and ion recombination in spurs

The proportion of singlets generated during a recombination of atoms or ions in a radiolytic spur reaction is examined from the viewpoint of a combinatorial analysis. The results obtained differ from other, already conflicting, published work. The problem is formulated in a way that enables spin relaxation effects to be incorporated.     

Discovery of a herbicidal lead using polymer-bound activated esters in generating a combinatorial library of amides and esters

Summary A combinatorial library containing mixtures of amides and esters was prepared through solid-phase chemistry. The advantages of using solid-phase chemistry over solution-phase chemistry to prepare this library are discussed. The library was screened through a high-throughput whole organism herbicidal assay upon which a mixture containing amides was found to have herbicidal activity. Deconvolution of the mixture providedN-(3-benzoylphenyl)-3-(1,1-dimethylethyl)-1-methyl)-1H-pyrazole-5-carboxamide as a herbicidal lead with broadleaf and narrowleaf pre-emergence herbicidal activity as low as 100 g/ha on some weed species. This study represents the first report of an agrochemical discovered using a combinatorial approach. Supplementary Material, comprising experimental procedures for the preparation of resin II and the reaction of II with nucleophiles, GC/MS and LC/MS data for the reaction ofII with morpholine, and a detailed experimental for the preparation of 2 with characterization data, is available upon request.     

A new efficient synthetic methodology for tetrahydroisoquinoline and tetrahydro-β-carboline derivatives using the Pictet–Spengler reaction

A new solution-phase methodology microwave-assisted for improving the Pictet-Spengler reaction in the synthesis of the tetrahydroisoquinoline and beta-carboline derivatives has been reported. This methodology was applied to obtain a small library of tetrahydroisoquinoline and beta-carboline derivatives using L-Dopa, dopamine, and tryptophan, as well as a variety of commercially available aldehydes as starting material. The use of such nonconventional reaction conditions reveals several features like a short reaction time compared to conventional eating, ease of isolation of the products after work-up, and improvement of the yields. This new one-pot protocol would be an ideal and rapid method to synthesize compounds in a combinatorial context.     

Reaction of isocyanides with thiophenols and gem-diactivated olefins: a one-pot synthesis of substituted 2-aminopyrroles

A novel multicomponent reaction of isocyanides with thiophenols and gem-diactivated olefins has been discovered. Depending on the choice of isocyanides, substituted 2-aminopyrroles or thioimidates have been prepared. The obtained scaffolds bearing four points of diversity can directly be used in combinatorial syntheses.     

A multi-component reaction (MCR) approach to the synthesis of highly diverse polymers with polypeptide-like features

A new strategy for the combinatorial synthesis of new materials has been developed through the consecutive application of an Ugi 4CC reaction and a ring-opening metathesis polymerization (ROMP) reaction. Norbornenyl aldehydes and carboxylic acids could be used in the Ugi MCR to give highly diverse monomers that were converted to the corresponding polymers by exposure to the second-generation Grubbs' catalyst. These polymers have structural features reminiscent of polypeptides and the process could be extended to the preparation of chiral materials.     

Combinatorial screening of fuel cell cathode catalyst compositions

An improved fuel cell cathode catalyst composition was pursued by fabricating and screening thin film combinatorial libraries. Results from the Pt-Ru, Pt-Co-Ti, Pt-Co-Cu and Pt-Co-Cr systems are reported. The discrete composition combinatorial libraries were fabricated by plasma sputtering through shadow masks. Each combinatorial library was tested by cyclic voltammetry in a multichannel electrochemical cell. Compositions were ranked based on the onset potential of the oxygen reduction reaction. Several compositions exhibited better onset potentials than pure Pt. The optimum composition from the Pt-Co-Ti system was Pt₄₄Ti₁₂Co₄₄ but showed signs of corrosion after prolonged testing. A wide range of Pt-Co-Cu compositions also outperformed Pt initially, but ultimately failed due to poor corrosion resistance. Among all of the compositions that were screened, the best performance was demonstrated by Pt₂₈Co₃₆Cr₃₆, with an onset potential 107 mV higher than pure Pt and no sign of corrosion.     

Relevance of sonochemistry or ultrasound (US) as a proficient means for the synthesis of fused heterocycles

Medicinal chemistry has been benefited by combinatorial chemistry and high throughput parallel synthesis. The use of sonochemistry under controlled conditions has been proved beneficial for medicinal chemistry and drug discovery process since it dramatically reduces reaction times, from days or hours to minutes. In addition, sonochemistry synthesis provides higher yields, lower cost, easy workups and greater purity as compared to lower yields, tedious workups, longer reaction times, lesser purity and termination of many by-products in the conventional thermal methods.     

The Gewald multicomponent reaction

The Gewald reaction of sulfur, cyanoacetic acid derivatives, and oxo-component (G-3CR) yielding highly substituted 2-aminothiophene derivatives has seen diverse applications in combinatorial and medicinal chemistry. Its products are of great use in pharmaceutical industry mainly as small molecular weight inhibitors. We herein review synthetic scope and variations, usage, and structural biology of Gewald products.     

Six new photolabile linkers for solid phase synthesis. 2. Coupling of various building blocks and photolytic cleavage

Photolabile linkers are very useful in the generation of combinatorial libraries as they offer compound cleavage under mild conditions directly into a solvent suitable for biological testing. Six new photolabile linkers have been developed which allow coupling of building blocks with a carboxy, amino, hydroxy and sulfonyl group. Photolytic cleavage of these building blocks will give libraries with carboxy, amido, methylamido, amino, ureido, hydroxy, aminocarbonyloxy and aminosulfonyl terminal groups. Coupling conditions for these reactions were elucidated and the photolytic cleavage reaction was studied.     

Design,synthesis and use of binary encoded synthetic chemical libraries

Summary With the advent of combinatorial chemistry a new paradigm is evolving in the field of drug discovery. The approach is based on an integration of chemistry, high-throughput screening and automation engineering. The chemistry arm is usually based on solid-phase synthesis technology as the preferred approach to library construction. One of the most powerful of the solid-phase methods is encoded split synthesis, in which the reaction history experience by each polymeric bead is unambiguously recorded. This split-and-pool approach, employing chemically robust tags, was used to construct a 85 000-membered dihydrobenzopyran library.     

Ultrasound-promoted an efficient method for one-pot synthesis of 2-amino-4,6-diphenylnicotinonitriles in water: a rapid procedure without catalyst

A green and convenient approach to the synthesis of 2-amino-4,6-diphenylnicotinonitriles via four-component reaction of malononitrile, aromatic aldehydes, acetophenone derivatives and ammonium acetate in water under ultrasound irradiation is described. The combinatorial synthesis was achieved for this methodology with applying ultrasound irradiation while making use of water as green solvent. In comparison to conventional methods, experimental simplicity, good functional group tolerance, excellent yields, short routine, and selectivity without the need for a transition metal or base catalyst are prominent features of this sonocatalyzed procedure.     

Sonochemically synthesis of pyrazolones using reusable catalyst CuI nanoparticles that was prepared by sonication

A simple and green process to prepare copper iodide in nano scale via sonication was carried out. Subsequently, this nanoparticles was used as an efficient catalyst for the synthesis of 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones via four-component reaction of hydrazine, ethyl acetoacetate, aldehyde and β-naphthol in water under ultrasound irradiation. The combinatorial synthesis was attained for this procedure with applying ultrasound irradiation while making use of water as green ambient. Simple work-up, excellent yield of products and short reaction times are some of the important features of this protocol. Notably, this catalyst could be recycled and reused for five times without noticeably decreasing the catalytic activity.     

Ultrasound promoted one-pot synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile scaffolds in aqueous media: A complementary ‘green chemistry’ tool to organic synthesis

A green and simple approach to assembling of 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile scaffolds via three-component reaction of kojic acid, malononitrile, and aromatic aldehydes in aqueous media under ultrasound irradiation is described. The combinatorial synthesis was achieved for this methodology with applying ultrasound irradiation while making use of water as green solvent. In comparison to conventional methods, experimental simplicity, good functional group tolerance, excellent yields, short routine, and selectivity without the need for a transition metal or base catalyst are prominent features of this green procedure.     

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.     

迎风凹腔与逆向喷流组合热防护系统冷却效果研究

对迎风凹腔与逆向喷流组合热防护系统的冷却效果进行了分析, 研究了相同总压不同流速的逆向喷流对组合结构的流场、气动受力及壁面传热的影响. 通过与相关的实验结果对比, 验证了数值方法的可靠性. 研究发现:该结构能够有效地对飞行器鼻锥表面进行冷却, 引入很小总压的逆向喷流(逆喷总压比 PR=0.1), 组合结构的冷却效果就可以远远优于单一的迎风凹腔; 相同逆向喷流总压下, 逆喷速度越高, 逆喷流量越大, 外壁面的冷却效果越好; 随逆喷流速提高, 气动阻力也进一步减小. 本文研究的组合结构非常适用于远程、 需长时间飞行的高超声速飞行器的热防护.     

Single bead parallel synthesis and screening

Microstructured silicon wafers were employed as miniaturized solid-phase reaction vessels as well as miniaturized micro titer plates. Employing piezoelectric drop-on-demand liquid jets, a combinatorial library of 256 Peptides was synthesized on single beads. The synthesis protocol was associated to the location in the silicon nano-well arrangement. Products were photolytically cleaved in the same well that was used for synthesis and subsequently interrogated for thrombin inhibition in a homogeneous competition assay. The assay procedure was based on drop-on-demand liquid delivery and laser induced fluorescence imaging. The novel format proved useful for the integration of both synthesis and screening into one platform, a prerequisite for an iterative, evolutionary approach towards drug discovery.     

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.     

迎风凹腔与逆向喷流组合热防护系统冷却效果研究

对迎风凹腔与逆向喷流组合热防护系统的冷却效果进行了分析, 研究了相同总压不同流速的逆向喷流对组合结构的流场、气动受力及壁面传热的影响. 通过与相关的实验结果对比, 验证了数值方法的可靠性. 研究发现:该结构能够有效地对飞行器鼻锥表面进行冷却, 引入很小总压的逆向喷流(逆喷总压比 PR=0.1), 组合结构的冷却效果就可以远远优于单一的迎风凹腔; 相同逆向喷流总压下, 逆喷速度越高, 逆喷流量越大, 外壁面的冷却效果越好; 随逆喷流速提高, 气动阻力也进一步减小. 本文研究的组合结构非常适用于