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.     

Synthesis of Substituted 2-Azolyl-1-pyridylethan-1-ols

Through the reaction of (2-aryloxiran-2-yl)pyridines with triazole or imidazole a series of novel 2-azolyl-1-pyridylethan-1-ols has been synthesized with different positioning of the nitrogen atom in the pyridine fragment for pharmacological and agrochemical screening. The compounds prepared showed high fungicidal activity.     

High throughput screening in agrochemical research

The demand for new herbicides, insecticides and fungicides led to a steady increase in the number of compounds being tested to find novel market products. To keep pace with the rising workload, high throughput screening (HTS) technologies have been introduced. In agrochemical research miniaturised in vivo tests on whole real target organisms are now possible and are an integral part of the screening cascade. A complementary target based in vitro HTS has also been established in agrochemical research. Target based HTS allows a directed approach towards untouched market shares by novel modes of action. Selection of the best suited targets is the most crucial issue in this approach. Genomic methods thereby deliver many essential genes as candidate targets. Consideration of further criteria such as druggability notably narrows down the number of promising targets. Though target to hit to lead progression still is as in pharmaceutical research a complex and therefore risky process, the implementation of novel bioscience technologies has entailed the transition to an integrated innovative agrochemical research perspective.     

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.     

Synthesis and high performance liquid chromatography/electrospray mass spectrometry single-bead decoding of split-pool structural libraries of polyamines supported on polystyrene and polystyrene/ethylene glycol resins

Natural polyamines are ubiquitous biomolecules present in all living cells. These cationic compounds play essential roles in both cell growth and differentiation and are known to interact in complex ways with polyanionic biomolecules. Consequently, there is significant interest in expanding nature's polyamine diversity using combinatorial synthesis and screening strategies. This article describes an efficient split-pool solid-phase synthetic strategy toward the generation of encoded libraries of polyamines via the exhaustive borane-promoted reduction of trityl-linked, resin-bound polyamides. Model structural libraries of tetra- and pentaamines were designed from a set of geometrically diverse amino acid building blocks. To encode the libraries, a partial termination synthesis approach was employed at the polyamide stage, allowing each library to be analyzed from single beads by HPLC/ESMS under two sets of conditions featuring both pH extremes. Determination of the sequence of polyamine residues was simply achieved by the mass differences observed between the full oligomers and the terminated ones. Both polystyrene- and TentaGel-supported libraries, including a library of 4913 pentaamines, were prepared and successfully decoded. For the TentaGel-supported libraries, suitable for on-bead aqueous screening of biomolecules, a novel trityl-derivatized resin was prepared in which the trityl group is anchored to the poly(ethylene glycol) chains via a methylene group. The resulting resin is much more resistant than other commercially available polystyrene-poly(ethylene glycol) trityl resins to the harsh borane reduction conditions required. Two workup conditions for the cleavage of the resultant borane-amine adducts were evaluated on the TentaGel bound polyamide 14. Although the two methods showed a comparable efficiency when using the polystyrene support, with 14 it was found that the piperidine-exchange method afforded polyamines of higher purity than the iodine-based oxidative method previously developed in our laboratory.     

Polymeric nanoparticles for protein kinase activity

Nanoparticles were prepared from poly-ion complexes, possessing both PEI-FITC-(PKA-specific substrate) (kemptide) and PAA-TRITC, which produce intermolecular FRET; the nanoparticles were dissociated by phosphorylation, presented a strong FITC intensity and can be applied to high-throughput screening for large chemical libraries, for drug discovery of kinase inhibitors.     

Applications of Polymeric Reagents in Organic Synthesis

Summary. Polymer supported reagents have found many applications in recent years. Scientists in research laboratories of agrochemical and pharmaceutical industries now routinely utilize these compounds to prepare ensembles of small organic molecules for screening. This review is aimed to highlight some of the most important applications of these promising materials in organic synthesis. Furthermore, an extensive listing of polymeric reagents that were recently used in organic synthesis is included.     

Applications of Polymeric Reagents in Organic Synthesis

Polymer supported reagents have found many applications in recent years. Scientists in research laboratories of agrochemical and pharmaceutical industries now routinely utilize these compounds to prepare ensembles of small organic molecules for screening. This review is aimed to highlight some of the most important applications of these promising materials in organic synthesis. Furthermore, an extensive listing of polymeric reagents that were recently used in organic synthesis is included.     

药物发现中常用化合物库特征描述与对比分析

随着计算技术的发展和分子模拟软件的日趋成熟, 虚拟筛选已经在药物发现过程中发挥着越来越重要的作用. 在虚拟筛选过程中, 所使用化合物库的质量对先导化合物发现的成功率起着至关重要的作用. 本文通过对已知药物库、天然产物库、中药原植物化学成分库、筛选常用商业化合物库以及研究者所在实验室建立的化合物库的分析比较, 从化合物库的分子多样性、化学空间和分子骨架等多个方面提取并对比每一种化合物库的特征, 发现了已知药物库与中药原植物化学成分库的特征相似性, 揭示了中药原植物化学成分库作为筛选库的类药性优势, 并且深化了对几种筛选用化合物库特征的认识和理解.     

Solid-phase synthesis of five-dimensional libraries via a tandem Petasis-Ugi multi-component condensation reaction

Five-dimensional libraries of dipeptide amides are readily prepared using a solid-phase tandem Petasis-Ugi multi-component condensation protocol on either a RINK amine or Universal RINK isonitrile resin. The method is practical and can be automated to prepare a large number of compounds useful for high throughput biological screening.     

Efficient Formation of Luminescent Lanthanide(III) Complexes by Solid‐Phase Synthesis and On‐Resin Screening

Time‐resolved luminescence measurements of luminescent lanthanide complexes have advantages in biological assays and high‐throughput screening, owing to their high sensitivity. In spite of the recent advances in their energy‐transfer mechanism and molecular‐orbital‐based computational molecular design, it is still difficult to estimate the quantum yields of new luminescent lanthanide complexes. Herein, solid‐phase libraries of luminescent lanthanide complexes were prepared through amide‐condensation and Pd‐catalyzed coupling reactions and their luminescent properties were screened with a microplate reader. Good correlation was observed between the time‐resolved luminescence intensities of the solid‐phase libraries and those of the corresponding complexes that were synthesized by using liquid‐phase chemistry. This method enabled the rapid and efficient development of new sensitizers for Sm^III, Eu^III, and Tb^III luminescence. Thus, solid‐phase combinatorial synthesis combined with on‐resin screening led to the discovery of a wide variety of luminescent sensitizers.     

Synthesis and fungicidal activity of substituted 2-(4-chlorophenoxy)-1-(3-pyridyl)ethan-1-ols

A series of new substituted 2-(4-chlorophenoxy)-1-(3-pyridyl)ethan-1-ols has been obtained by the interaction of substituted 3-(oxiranyl)pyridines with 4-chlorophenol or sodium 4-chlorophenoxide for pharmacological and agrochemical screening. Fungicidal activity has been shown for the obtained compounds.     

Effect of the Coating of the Polymer Blend (Polyacrylamide/PEG 6000) on the Efficiency of Rice Husk as a Pesticide Carrier

In recent years the utilization of fibers and powders derived from agricultural sources has become a subject of interest. However, they have been exploited only from an engineering point of view, and the strong ability of agricultural wastes as a carrier for agrochemical formulations has been ignored. A study has been made on the possibility of using such an agrochemical waste, namely rice husk, which is readily available and biodegradable, as a carrier for pesticide formulation. The solid formulations were prepared by adsorbing deltamethrin on the rice husk. The deltamethrin‐adsorbed rice husk is then coated with the polymer blend of Polyacrylamide and PEG 6000 in varying ratios between the deltamethrin‐adsorbed rice husk and the polymer blend. The formulations were characterized by analytical methods such as FTIR and XRD techniques. Important physical properties from the formulation standpoint, such as solubility, dispersion stability, and wettability, were studied.     

Library fingerprints: a novel approach to the screening of virtual libraries

We propose a novel method to prioritize libraries for combinatorial synthesis and high-throughput screening that assesses the viability of a particular library on the basis of the aggregate physical-chemical properties of the compounds using a na?ve Bayesian classifier. This approach prioritizes collections of related compounds according to the aggregate values of their physical-chemical parameters in contrast to single-compound screening. The method is also shown to be useful in screening existing noncombinatorial libraries when the compounds in these libraries have been previously clustered according to their molecular graphs. We show that the method used here is comparable or superior to the single-compound virtual screening of combinatorial libraries and noncombinatorial libraries and is superior to the pairwise Tanimoto similarity searching of a collection of combinatorial libraries.     

The development of a semiautomated procedure for the synthesis and screening of a large group of molecularly imprinted polymers

A method for synthesis and evaluation of molecularly imprinted polymers (MIPs) on a semiautomated miniature scale is reported. This technique combines molecular imprinting with the combinatorial chemistry approach, allowing rapid screening and optimizations of libraries of MIPs. The polymers were prepared and evaluated in situ by rebinding utilizing powder dispensing and liquid handling systems. MIPs were prepared by a combinatorial approach using methacrylic acid (MAA), 4-vinylpyridine (4-VP), acrylamide, and styrene as functional monomers, and acetonitrile and toluene as porogenic solvents. A drug substance having aromatic, hydroxyl, -O-CONH2 functional groups was selected as the template molecule for this study. The MIP library results demonstrated that the polymer prepared with MAA as functional monomer shows the strongest binding affinity, and therefore, is preferred for the preparation of this particular template molecule. Due to the low consumption of reagents, and more importantly, the demonstrated ability of this method to effectively identify optimal imprinting conditions, this small-scale combinatorial protocol is well suited for fast and efficient screening and optimizations of MIPs.     

Comparison of resin and solution screening methodologies in combinatorial chemistry and the identification of a 100 nM inhibitor of trypanothione reductase

Two identical polyamine peptide conjugate libraries were screened against the parasitic enzyme trypanothione reductase. One of these libraries was in a solution format, while the other was resin-based and was used in two resin-based screens (a diminution assay and a direct bead screening). Potent inhibitors (100 nM) of trypanothione reductase were identified both in the solution screen and in the resin-based screens when using the PEGA resin of Meldal. Resin screening of both types failed to work with TentaGel resin. Importantly there was excellent agreement between the solution and resin-based assays, suggesting both methods are reliable for the screening of combinatorial libraries.     

Development of (S)-Malimide as A Versatile Chiron for the Synthesis of 2-Pyrrolidinone-related Compounds

Selectivity, efficiency and flexibility are three major goals in organic synthesis. A good flexible synthetic method would allow the preparation of different class of compounds as well as their homologous in a straightforward way. The development of flexible synthetic methodology is particularly important in view of both providing compounds for screening ligands, bioactive compounds, drugs candidates, agrochemical candidates, etc. and providing methods for combinatorial chemistry.     

Functionalized Polymers-Emerging Versatile Tools for Solution-Phase Chemistry and Automated Parallel Synthesis

As part of the dramatic changes associated with the need for preparing compound libraries in pharmaceutical and agrochemical research laboratories, industry searches for new technologies that allow for the automation of synthetic processes. Since the pioneering work by Merrifield polymeric supports have been identified to play a key role in this field however, polymer-assisted solution-phase synthesis which utilizes immobilized reagents and catalysts has only recently begun to flourish. Polymer-assisted solution-phase synthesis has various advantages over conventional solution-phase chemistry, such as the ease of separation of the supported species from a reaction mixture by filtration and washing, the opportunity to use an excess of the reagent to force the reaction to completion without causing workup problems, and the adaptability to continuous-flow processes. Various strategies for employing functionalized polymers stoichiometrically have been developed. Apart from reagents that are covalently or ionically attached to the polymeric backbone and which are released into solution in the presence of a suitable substrate, scavenger reagents play an increasingly important role in purifying reaction mixtures. Employing functionalized polymers in solution-phase synthesis has been shown to be extremely useful in automated parallel synthesis and multistep sequences. So far, compound libraries containing as many as 88 members have been generated by using several polymer-bound reagents one after another. Furthermore, it has been demonstrated that complex natural products like the alkaloids (+/-)-oxomaritidine and (+/-)-epimaritidine can be prepared by a sequence of five and six consecutive polymer-assisted steps, respectively, and the potent analgesic compound (+/-)-epibatidine in twelve linear steps ten of which are based on functionalized polymers. These developments reveal the great future prospects of polymer-assisted solution-phase synthesis.     

Capillary electrophoresis using immobilized whole cells with overexpressed endothelin receptor for specific ligand screening

A new capillary electrophoresis method using immobilized cells as the stationary phase has been developed. The power of this method is demonstrated by the separation and identification of endothelin antagonists on a capillary column coated by the transfected Chinese hamster ovary (CHO) cells with overexpressing endothelin receptors. The screening results are validated by functional assays suppressing the increase of intracellular calcium concentration induced by endothelin-1. Instead of making efforts in isolating protein receptors, the easily prepared whole-cell capillary column provides a superior tool on the basis of ligand/receptor affinity for a rapid screening of potent drug candidates from compound libraries.     

Optimizing photo-embossed gratings: a gradient library approach

Methodologies for the rapid screening of coating systems were developed and applied to photopolymer lacquers for photoembossing applications. Continuous and discrete gradient libraries were prepared with a gradient in grating period along the short axis and along the long axis, a gradient in exposure energy, development temperature, film thickness, photoinitiator concentration, or monomer to polymer mass ratio. Discrete gradient libraries consisted of arrays of rectangular films made by pipetting a certain amount of sample onto a chemically patterned substrate consisting of hydrophilic patches surrounded by hydrophobic, fluorinated barriers. The shape and height of the photoembossed gratings were measured using an automated AFM. Optimum grating height was obtained for a 20-microm period at intermediate exposure energies, photoinitiator concentrations, or both. Height improves with development temperature (max 110 degrees C), monomer-to-polymer ratio (max 55 wt % monomer), and film thickness. Surface topography can also be optimized, depending on any specific application.