Application Of Combinatorial Chemistry Research Articles

SOLVENT-FREE RAPID MICROWAVE SYNTHESIS AND ANTIVIRAL ACTIVITY OF 2,4-(I H, 3H)PYRIMIDINEDIONE

Microwave-assisted method has wide application in combinatorial chemistry. It has become a powerful tool in building the bioactive and pharmaceutical important compounds library within a short time. In view of a pronounced effect of Microwave-assisted methods in synthetic chemistry and their importance in drug discovery, a systematic work on the solvent-free synthesis of 2,4-(IH,3H)Pyrimidinedione(uracil) was carried out. Comparison was made between classic (conventional) and Novel (microwave-assisted) methods and it was found that compounds synthesized by microwave-assisted method showed better yield and reduced reaction time under safe and environment-friendly conditions, while conventional methods were tedious and time consuming. The structure elucidation of synthesized compounds was done by its melting/boiling points, solubility, thin layer chromatography (TLC) techniques and spectral analysis i.e ultraviolet (UV), Fourier transform infrared spectroscopy (FTIR) and Gas chromatography–mass spectrometry (GC-MS) were used to get the results. The pharmacological evaluation of synthesized compound was investigated by its antiviral activities against Lasota strain of NDV (ranikhait disease virus) and it showed the positive activity

The Use of Plant Fibers for Oligosaccharide Production with Libraries Constructed by Combinatorial Enzyme Technology

: Combinatorial chemistry involves the chemical or biological synthesis of libraries of the diverse structural population of a template molecule and the screening for the variants expressing desirable target properties. The approach has been a focus of research activity in modern drug discovery and biotechnology for accelerating the discovery and development of novel therapeutic and bioactive compounds. This review describes the application of combinatorial chemistry in enzyme technology as a novel technique and invention developed in our laboratory to construct oligosaccharide libraries in the conversion of plant fibers. The theory, mechanism, development, and application of this combinatorial enzyme approach are presented for the first time. The potential food and non-food uses of oligosaccharides are described. Citrus pectin and wheat insoluble fiber have been used as substrates for combinatorial enzyme reactions. Generation of libraries of structural variants of pectic oligosaccharides (oligoGalA) and feruloyl oligosaccharides (FOS) demonstrates the feasibility and usefulness of the technique in the transformation of plant biomass to value- added products.

Identifying superionic conductors by materials informatics and high-throughput synthesis

Combinatorial chemistry has been proven effective in the search for novel functional materials, especially in the field of organic chemistry, and is being used to identify functional inorganic compounds. However, there is a growing need for approaches that predict and experimentally realize new materials, beyond composition optimization of known systems. Application of combinatorial chemistry to materials discovery is typically hindered by a limited ability to search a wide chemical composition space, and by our ability to experimentally screen promising compounds. Here, a combinatorial scheme is proposed that combines a materials informatics technique to define a chemical search space with high-throughput synthesis and evaluation. We identify high-performance superionic conductors in the Ca-(Nb,Ta)-Bi-O system, demonstrating the effectiveness of this approach for accelerated materials discovery.

A Novel Strategy of Ugi-4CR/Huisgen 1,3-Dipolar Synthesis of 1H-1,2,3-Triazole-Modified Peptidoimetics

In this protocol, we report a novel approach for the synthesis of a new class of heterocyclic 1H-1,2,3-triazole-modified peptidomimetic compounds. The process consists of an Ugi four-component condensation reaction of amines, an isocyanide, an aldehyde and acids followed by a Huisgen 1,3-dipolar cycloaddition reaction with an azide group in the presence of a catalytic amount of CuSO4.5H2O/sodium ascorbate. The copper-catalyzed Huisgen cycloaddition reactions provide such a general synthetic method, with the resulting 1,2,3-triazoles being good peptide bond mimics. This protocol was highly efficient for structurally diverse heterocyclic molecules containing an active aldehyde group and will find applications in combinatorial chemistry, diversity-oriented synthesis, and drug discovery.

A composite element bit design for magnetically encoded microcarriers for future combinatorial chemistry applications

A composite element (CE) bit design for magnetically encoded microcarriers provides an increased coercivity range for longer bit codes as well as significant improvements to encoding density, reliability and read-out.

Biomolecule Arrays Using Functional Combinatorial Particle Patterning on Microchips

AbstractBiofunctionalization of surfaces in a microarray format has revolutionized biological assay applications. Here, a microarray system based on a microelectronic chip is presented that allows for a versatile combinatorial in situ molecule synthesis with very high density. Successfully demonstrating an application for peptide array synthesis, the method offers a compact approach, high combinatorial freedom, and, due to the intrinsic alignment, high and reproducible precision. Patterning the chip surface with different microparticle types which imbed different monomers, several thousand different molecule types can be simultaneously elongated layer‐by‐layer by coupling the particle imbedded monomers to the molecules growing on the chip surface. This technique has the potential for a wide application in combinatorial chemistry, as long as the desired monomeric building blocks are compatible with the chemical process.

Investigating vesicular selection: A selection operator in in vitro evolution

Abstract Directed protein evolution has led to major advances in organic chemistry, enabling the development of highly optimised proteins. The SELEX method has also been highly effective in evolving ribose nucleic acid (RNA) or deoxy-ribose nucleic acid (DNA) molecules; variants have been proposed which allow SELEX to be used in protein evolution. All of these methods can be viewed as evolutionary algorithms implemented in chemistry. A number of methods rely on selection of natural cells, or of artificial bubbles. These methods result in a new form of selection mechanism, which we call vesicular selection (VS). It is not, prima facie, clear whether VS is an effective selection mechanism, or how its performance is affected by changes in vesicle size. It is difficult to investigate this in vitro, so we use in silico methods derived from evolutionary computation. The primary aim is to test whether this selection method hinders biochemical evolutionary search (in which case, it might be worth investing research effort in discovering alternative selection methods). An in silico implementation of this selection method, embedded in an otherwise-typical evolutionary computation system, shows reasonable ability to solve tough optimisation problems, together with an acceptable ability to concentrate the solutions found. We compare it with tournament selection (TS), a standard evolutionary computation method, which can be finely tuned for high selection pressure, but only coarsely tuned for low selection pressure. By contrast, the new selection mechanism VS is highly tunable at low selection pressures. It is thus particularly suited to problem domains where extensive exploration capabilities are required. Since there is very good reason to believe that protein search spaces require highly exploratory search, the selection mechanism is well matched to its application in combinatorial chemistry.

In Silico Prediction of Cytochrome P450-Mediated Drug Metabolism

The application of combinatorial chemistry and high-throughput screening technique enables the large number of chemicals to be generated and tested simultaneously, which will facilitate the drug development and discovery. At the same time, it brings about a challenge of how to efficiently identify the potential drug candidates from thousands of compounds. A way used to deal with the challenge is to consider the drug pharmacokinetic properties, such as absorption, distribution, metabolism and excretion (ADME), in the early stage of drug development. Among ADME properties, metabolism is of importance due to the strong association with efficacy and safety of drug. The review will focus on in silico approaches for prediction of Cytochrome P450-mediated drug metabolism. We will describe these predictive methods from two aspects, structure-based and data-based. Moreover, the applications and limitations of various methods will be discussed. Finally, we provide further direction toward improving the predictive accuracy of these in silico methods.

Improvement in Aqueous Solubility in Small Molecule Drug Discovery Programs by Disruption of Molecular Planarity and Symmetry

Aqueous solubility is essential for drug candidates. Poor aqueous solubility is likely to result in poor absorption, even if the permeation rate is high, since the flux of a drug across the intestinal membrane is proportional to the concentration gradient between the intestinal lumen and the blood. The Biopharmaceutical Classification System (BCS) was introduced in the mid-1990s to classify drug substances with respect to their aqueous solubility and membrane permeability. Drug substrates, for which solubility enhancement can improve the oral bioavailability, are classified in class 2 (poorly soluble/ permeable) and class 4 (poorly soluble/poorly permeable). The FDA regulations concerning oral medications require more extensive investigation of compounds with low solubility, and low solubility may have an even greater impact in the case of iv dosage forms. In addition, risk assessment of poorly soluble compounds is challenging because exposure may be difficult to define and test sensitivity may be reduced. Further, high concentrations of poorly soluble drugs in organisms may result in crystallization and acute toxicity, as in the case of uric acid and gout. Overall, poor solubility of drug candidates has been identified as the cause of numerous drug development failures. According to the simplest definition, the thermodynamic solubility of a compound in a solvent is the maximum amount of the most stable crystalline form of the compound that can remain in solution under equilibrium conditions. The most stable form is invariably the form that has the highest melting point. The importance of thermodynamic assessment is greater in late discovery/early development, when it is useful to confirm earlier kinetic solubility results, to rule out potential artifacts, and to generate high-quality solubility data. The kinetic solubility of a molecule depends on its crystal form, and crystal polymorphs of a molecule can show different kinetic solubility. Therefore, crystal modification can produce an increase in dissolution rate and a temporary or apparent increase of solubility. However, it cannot produce a permanent alteration of solubility. Given sufficient time, the undissolved solute will revert to its most stable crystal form, and the solubility will approach the true thermodynamic solubility. Therefore, the role of crystal modification is confined to increasing the dissolution rate of drugs. Appropriate formulation can help in addressing these problems, but the extent of absorption and solubility enhancement that can realistically be achieved is severely limited. Stability and manufacturing problems also have to be taken into account, since it is likely that an insoluble drug candidate may not be formulated as a conventional tablet or capsule and will require a less conventional approach such as, for example, a soft gel capsule. Thus, it would be better to generate drug candidates with sufficient aqueous solubility at the drug discovery stage. In other words, it is much better to improve solubility by chemical means, i.e., by modification of the molecule itself. But on the other hand, application of combinatorial chemistry and highthroughput screening (HTS) systems has tended to change the profile of compound libraries in the direction of greater hydrophobicity and higher molecular weight, and this in turn has resulted in a profile of lower solubility. This is a problem for medicinal chemists, and improvement of the aqueous solubility of bioactive molecules is a major and common issue in medicinal chemistry. In general, the aqueous solubility of small molecules depends on their hydrophobicity (log P). The partition coefficient, logP, is defined as follows: logP = log[(solute in n-octanol)/ (solute in water)]. Increase of aqueous solubility leads to an increase of the denominator of the above equation and a decrease of log P. Thus, decrease of log P by chemical modification, i.e., introduction of hydrophilic group(s) into molecules, is a classical and general strategy for improving aqueous solubility. But this approach is not universally effective because the introduced hydrophilic group(s) sometimes interferes with the target proteindrug interaction. In addition, this strategy is not effective when both solubility and hydrophobicity need to be increased, for example, to improve the oral bioavailability of highly hydrophilic compounds with insufficient solubility. Furthermore, compounds with poor solubility in both octanol and water sometimes retain poor absolute values of aqueous solubility despite a decrease of log P values, because log P values are just ratios. Therefore, a novel and general strategy to increase the aqueous solubility of drug candidates would have a great impact on drug discovery and medicinal chemistry. Here, we review an alternative strategy for improving aqueous solubility by means of disruption of molecular planarity and symmetry.

ChemInform Abstract: Multisubstituted Urea Derivatives of Hydrazines by a Flexible Approach with Potential Application in Combinatorial Chemistry.

ChemInform Abstract: Multisubstituted Urea Derivatives of Hydrazines by a Flexible Approach with Potential Application in Combinatorial Chemistry.

ChemInform Abstract: Peptidomimetic Building Blocks for the Synthesis of Sulfonamide Peptoids.

There is a constant demand for novel building blocks for combinatorial chemistry applications. A one-pot synthesis of a novel class of peptidomimetic building blocks to be used for the preparation of sulfonamide peptoids, is presented here. Furthermore, it is shown that these compounds can be incorporated in a peptide sequence.

連続反応および多成分反応を基盤とする多置換シクロブタンの迅速合成法の開発

A large variety of organic substances having complicated polycyclic structures and a wide assortment of stereogenic centers are found in nature. These compounds often exhibit attractive and specific biological activities. Ideal strategies for preparing these structurally complex substances would involve sequences in which stereocontrolled formation of multiple carbon-carbon bonds occur in a single step starting with simple, readily available materials. Great attention has been given to the development of intermolecular cascade reactions and multi-component reactions owing to their high degree of atom economy and their applications in combinatorial chemistry as well as diversity-oriented syntheses. Herein we describe a new class of catalytic reaction of polycyclic structures including cyclobutane ring by utilizing cascade reaction and multi-component reaction, and its related catalytic reaction as well as their application to biologically activesubstances.

Generation of Molecular Graphs for QSAR Studies: An Approach Based on Supergraphs

A new algorithm for generation of substituted derivatives of a given structure and its software implementation are described. The program has deterministic and stochastic generation modes and efficiently supports various types of structural constraints. The problem of exhaustive and irredundant generation is discussed, and a new algorithm of the complete rejection of isomorphic molecular graphs is proposed. The main application of the generator is QSAR studies; however, applications in combinatorial chemistry are also possible.

Poly (amino ester) Composed of Poly (ethylene glycol) and Aminosilane Prepared by Combinatorial Chemistry as a Gene Carrier

Application of combinatorial chemistry and high throughput screening for the synthesis and evaluation of mini-library of novel biodegradable poly (beta-amino ester)s (PAE)s composed of gamma-aminopropyl-triethoxysilane (APES) and poly (ethylene glycol) diacrylate (PEGDA) for gene delivery efficiency and safety in 293T and HeLa cells in the presence of and absence of serum. PAEs were synthesized at different mole ratios of APES and PEGDA by Michael addition reaction and synthesis was confirmed by 1H nuclear magnetic resonance (1H-NMR). Ninety six ratios of polyplexes were evaluated for luciferase and MTS assay in 293T and HeLa cells in the presence of and absence of serum. Relationship between transfection efficiency and DNA binding ability of PAEs was studied by gel electrophoresis. Particle sizes and molecular weight of selected PAEs were measured by dynamic light scattering and gel permeation chromatography multi-angle light scattering, respectively. 1H-NMR confirmed the synthesis of PAEs. In both cell lines, transfection efficiency and cell viability were increased for PAEs obtained from R106 (0.7:1, APES:PEGDA) to R121 (6:1, APES:PEGDA) with a marginal increase in APES concentration. Transfection pattern was uniform in the absence of and presence of serum. In both cell lines, PAE obtained from R121 demonstrated high transfection efficiency and low cytotoxicity as compared to polyethylenimine (25 KDa) and Lipofectamine. PAE obtained from R121 showed good DNA binding and condensation with average particle sizes of 133 nm. Addition of PEGDA over APES resulted in a novel PAE which has high safety and transfection efficiency. Transfection and cytotoxicity are very sensitive to monomer ratios and mainly governed by concentration of amine monomer.

Applications of Combinatorial Chemistry in the Agrosciences

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Chemical and metabolic transformations of selected bile acids

This article surveys chemical transformations of selected bile acids. Chemical transformations were initially carried out with the aim of determining the structure of bile acids. More recently they have been concerned with bile acid interconversions as well as with the synthesis of steroid hormones, vitamins and therapeutc agents. Studies of similarities and differences in the biosynthesis of bile acids from cholesterol have occupied many researches. However, this article reviews only papers dealing with the synthesis of potential intermediates in the biosynthesis of bile acids. Steroid hormones such as pregnenolone, progesterone and testosterone are synthesized from methyl thiodeoxycholate whereas cortisone is synthesized from methyl deoxycholiate. Numerous papers and patents devoted to the synthesis of ursodeoxycholic acid from cholic or chenodeoxycholic acid testify to its effectiveness in the treatment of cholelithiasis. Chenodeoxycholic acid appears to be an excellent precursor in the synthesis of steroid plant growth regulators, as well as in the synthesis of metabolites and vitamin D analogues. Chirality of bile acids has been exploited in the synthesis of cyclic and acyclic receptors and solvents. Cholic and deoxycholic acids have been used to create new macrocyclic structures which show different capacities to bind and transport other compounds. Another important trend in the chemistry of bile acids is their application in combinatorial chemistry.

Combinatorial Chemistry in Glycobiology

AbstractFor Abstract see ChemInform Abstract in Full Text.

Applications of Combinatorial Chemistry in the AgroSciences

During the past ten years combinatorial chemistry developed from a powerful synthetic methodology, providing large libraries of usually simple new chemical entities, to a comprehensive strategy presently covering a multitude of technologies across the whole workflow from hit generation to lead optimization. Thus combinatorial chemistry had a major impact not only on the pharmaceutical research but also with some delay on the agrochemical research. The agrochemical discovery environment is different from that of the pharmaceutical research in that it relies mainly on whole organism screenings. This review summarizes some recent applications of combinatorial chemistry in the agrosciences, covering all the three major fields of research: fungicides, herbicides, and insecticides. The article focuses on libraries with published biological activities and thus highlights some characteristic features of successful agrochemical libraries, which may be fundamentally different from pharmaceutical libraries.

Prospects for Combinatorial Chemistry in the Agrosciences

The recent progress and future prospects for the successful application of combinatorial chemistry and high throughput screening within the agrochemical lead discovery process are outlined and discussed. Solid and solution phase library synthesis technologies are reviewed and compared, and the role and importance of bioavailability, diversity and virtual screening in rational library design are detailed.

Combinatorial Chemistry in Glycobiology

The application of combinatorial chemistry to glycobiology historically has proven challenging due to numerous synthetic hurdles. The advent of novel methodologies has enabled the production of natural as well as mimetic analogues for proof-of-concept experiments and SAR. This review highlights some of the recent synthetic advances in combinatorial carbohydrate synthesis. The application of carbohydrate libraries in glycobiology is also discussed.