Synthesis Of Combinatorial Libraries Research Articles

Defining privileged reagents using subsimilarity comparison.

We have developed a new method for assigning a drug-like score to reagents. This algorithm uses topological torsion (TT) 2D descriptors to compute the subsimilarity of any given reagent to a substructural element of any compound in the CMC. The utility of this approach is demonstrated by scoring a test set of reagents derived from the "Comprehensive Survey of Combinatorial Library Synthesis: 2000" (J. Comb. Chem.). R-groups were extracted from the most-active compounds found in each of the reviewed libraries, and the distribution of the subsimilarity scores for these monomers were compared to the ACD. This comparison showed a dramatic shift in the distribution of the JCC R-group subset toward higher subsimilarity scores in comparison to the entire ACD database. The ACD was also used to examine the relationship between molecular weight and various subsimilarity scoring algorithms. This analysis was used to derive a subsimilarity score that is less biased by molecular weight.

Regiospecific solid-phase synthesis of substituted 1,2,3-triazoles

A traceless and regiospecific solid-phase synthesis of substituted 1,2,3-triazoles is developed using polystyrene-sulfonyl hydrazide resin. The chemistry is applicable to combinatorial library synthesis.

Dendrimers and combinatorial chemistry—tools for fluorescent enhancement in protease assays

FRET based systems are some of the best methods available to detect and monitor proteolytic activity. To enhance fluorescent signals and hence assay sensitivity, two different systems were developed using two different dendrimeric constructs. In the first case, a triple branched dendrimer bearing three dansyl groups was used to enhance assay sensitivity and showed a significant enhancement of fluorescence following enzymatic cleavage. In another example, a tris-fluorescein probe, that undergoes self-quenching, was utilized in a combinatorial library synthesis to map the substrate specificity of proteases.

DNA display II. Genetic manipulation of combinatorial chemistry libraries for small-molecule evolution.

Biological in vitro selection techniques, such as RNA aptamer methods and mRNA display, have proven to be powerful approaches for engineering molecules with novel functions. These techniques are based on iterative amplification of biopolymer libraries, interposed by selection for a desired functional property. Rare, promising compounds are enriched over multiple generations of a constantly replicating molecular population, and subsequently identified. The restriction of such methods to DNA, RNA, and polypeptides precludes their use for small-molecule discovery. To overcome this limitation, we have directed the synthesis of combinatorial chemistry libraries with DNA “genes,” making possible iterative amplification of a nonbiological molecular species. By differential hybridization during the course of a traditional split-and-pool combinatorial synthesis, the DNA sequence of each gene is read out and translated into a unique small-molecule structure. This “chemical translation” provides practical access to synthetic compound populations 1 million-fold more complex than state-of-the-art combinatorial libraries. We carried out an in vitro selection experiment (iterated chemical translation, selection, and amplification) on a library of 106 nonnatural peptides. The library converged over three generations to a high-affinity protein ligand. The ability to genetically encode diverse classes of synthetic transformations enables the in vitro selection and potential evolution of an essentially limitless collection of compound families, opening new avenues to drug discovery, catalyst design, and the development of a materials science “biology.”

The Pictet—Spengler Reaction in Solid‐Phase Combinatorial Chemistry

AbstractFor Abstract see ChemInform Abstract in Full Text.

Antibodies and genetically engineered related molecules: production and purification.

Antibodies and antibody derivatives constitute 20 % of biopharmaceutical products currently in development, and despite early failures of murine products, chimeric and humanized monoclonal antibodies are now viable therapeutics. A number of genetically engineered antibody constructions have emerged, including molecular hybrids or chimeras that can deliver a powerful toxin to a target such as a tumor cell. However, the general use in clinical practice of antibody therapeutics is dependent not only on the availability of products with required efficacy but also on the costs of therapy. As a rule, a significant percentage (50-80%) of the total manufacturing cost of a therapeutic antibody is incurred during downstream processing. The critical challenges posed by the production of novel antibody therapeutics include improving process economics and efficiency, to reduce costs, and fulfilling increasingly demanding quality criteria for Food and Drug Administration (FDA) approval. It is anticipated that novel affinity-based separations will emerge from the development of synthetic ligands tailored to specific biotechnological needs. These synthetic affinity ligands include peptides obtained by synthesis and screening of peptide combinatorial libraries and artificial non-peptidic ligands generated by a de novo process design and synthesis. The exceptional stability, improved selectivity, and low cost of these ligands can lead to more efficient, less expensive, and safer procedures for antibody purification at manufacturing scales. This review aims to highlight the current trends in the design and construction of genetically engineered antibodies and related molecules, the recombinant systems used for their production, and the development of novel affinity-based strategies for antibody recovery and purification.

Combinatorial chemistry: libraries from libraries, the art of the diversity-oriented transformation of resin-bound peptides and chiral polyamides to low molecular weight acyclic and heterocyclic compounds.

Combinatorial chemistry has deeply impacted the drug discovery process by accelerating the synthesis and screening of large numbers of compounds having therapeutic and/or diagnostic potential. These techniques offer unique enhancement in the potential identification of new and/or therapeutic candidates. Our efforts over the past 10 years in the design and diversity-oriented synthesis of low molecular weight acyclic and heterocyclic combinatorial libraries derived from amino acids, peptides, and/or peptidomimetics are described. Employing a "toolbox" of various chemical transformations, including alkylation, oxidation, reduction, acylation, and the use of a variety of multifunctional reagents, the "libraries from libraries" concept has enabled the continued development of an ever-expanding, structurally varied series of organic chemical libraries.

ToF-SIMS imaging with cluster ion beams

Molecule-specific imaging using focused ion beams is one of the most powerful applications of ToF-SIMS and offers unique surface characterization information. However, many experiments lack the necessary sensitivity to properly take advantage of the sub-100 nm probe size typical of liquid metal ion sources. The yield of biomolecules using Ga + ions, for example, is very small when compared to that obtained using Cs + ion or SF 5 + cluster ion sources. Most recently, a C 60 + source with a probe size approaching 1×10 −6 m has become available and offers promise to expand imaging applications dramatically. Here, we report on imaging experiments on 50×10 −6 m polystyrene resin particles used in solid phase synthesis of combinatorial libraries and on the assay of the membrane chemistry of single biological cells. Both of these examples allow much higher quality images to be acquired with, in some cases, almost no sample damage. This latter effect opens the possibility of three-dimensional molecule-specific imaging.

Molecule-specific imaging with mass spectrometry and a buckminsterfullerene probe: application to characterizing solid-phase synthesized combinatorial libraries.

We employ a newly developed buckminsterfullerene (C(60)) primary ion beam with time-of-flight secondary ion mass spectrometry to create molecule-specific images of resin particles employed in the solid-phase synthesis of peptide combinatorial libraries. This new cluster ion source, when operated at an incident energy of 20 keV, is remarkably effective at desorbing small peptides directly from a polymer surface and opens new possibilities for characterizing large arrays of diverse sets of molecules. In addition, the C(60) ion beam may be focused to a spot of 1.5 microm in diameter, enabling molecule-specific images of single 100 microm resin particles to be acquired. We report three significant aspects associated with utilizing the C(60) projectile that show how this technology can be taken to a more advanced level, especially when compared to results obtained with more conventional atomic primary ions. First, the useful yield of molecular ions is generally observed to be enhanced by at least 3 orders of magnitude over those previously possible. Second, the energy dissipation process associated with the C(60) impact is most efficient at desorbing molecules on soft substrates such as polymer surfaces rather than harder substrates such as metals or semiconductors. Third, there is a greatly reduced tendency for insulating surfaces to build up excess charge, obviating the need for charge compensation. Using a small five-member peptide library as a model, we show that by utilizing the focusing properties of the C(60) beam, it is possible to assay the surface composition of 100-microm polymer beads at a rate of up to 10 particles/s. Moreover, even at the picomole level, there are enough sequence ions in the mass spectrum to determine a unique composition. The results illustrate the ability to quickly assay large libraries without the use of tags and suggest the strategy may be applicable to a range of high-throughput experiments.

Elimination Chemistry in the Solution‐ and Solid‐Phase Synthesis of Combinatorial Libraries

AbstractFor Abstract see ChemInform Abstract in Full Text.

Catalysis of Nucleophilic Aromatic Substitutions in the 2,6,8‐Trisubstituted Purines and Application in the Synthesis of Combinatorial Libraries

AbstractFor Abstract see ChemInform Abstract in Full Text.

Articles selected by Faculty of 1000: culturing novel soil bacteria; profiling biofilm formation; regulatory role for miRNA:miRNA duplexes; synthesis of combinatorial libraries; phylogenetic analysis of coelomata

Articles selected by Faculty of 1000: culturing novel soil bacteria; profiling biofilm formation; regulatory role for miRNA:miRNA duplexes; synthesis of combinatorial libraries; phylogenetic analysis of coelomata

From Solution‐Phase Studies to Solid‐Phase Synthesis: A New Indole‐Based Scaffold for Combinatorial Chemistry

AbstractFor Abstract see ChemInform Abstract in Full Text.

Combinatorial synthesis of benztropine libraries and their evaluation as monoamine transporter inhibitors.

A combinatorial synthesis of benztropine analogues is presented. Radical azidonation of 3-benzyloxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 3 to 3-(1-azidobenzyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 4 was used as a key step in the synthesis. This step was optimized by adding 10% DMF to the reaction. Reaction of 4 with phenyl magnesium bromide followed by Boc removal and N-methylation gave benztropine 1. Reaction of five-component Grignard reagents with 4 was used to create a two-dimensional library of 25 N-normethylbenztropine analogues. Further reaction of this library with five alkyl bromides was carried out to create a three-dimensional library containing 125 compounds. Screening of the libraries towards binding and inhibition of uptake of the human dopamine (hDAT), serotonin (hSERT) and norepinephrine transporters (hNET) was carried out. None of the synthesized compounds were found to be stronger than benztropine, and none were selective for inhibition of binding over monoamine uptake.

8 Chemical genetics

Chemical genetics is based on the ability of small molecules to bind reversibly to biological molecules resulting in a phenotypic change in cells. Recent advances in the synthesis of combinatorial libraries of diverse skeletal structure along with the use of cell-based high throughput screening has led to the identification of novel molecules highly targeted towards specific pathways. Screening of pharmaceutical libraries has revealed novel and unexpected combinations of molecules effective against cancer and other diseases. The number of possible molecules less than 3000 daltons is truly vast and it is with chemical genetics that “chemical space” can be fully explored.

Combinatorial library synthesis of two- and three-ring benzenoid amides on solid support

A liquid crystalline library of 100 molecules with three benzene rings and 18 molecules with two benzene rings was synthesized on solid support by means of benzoylation or acylation and palladium(0)-catalyzed carbonylation of a secondary amine obtained by a reductive amination of 4-iodoaniline and a backbone amide linker. The conversion and purity of the final products are high enough to investigate the mesomorphic properties.

Química combinatória: moderna ferramenta para a obtenção de candidatos a protótipos de novos fármacos

A Quimica Combinatoria (QC) e atualmente uma das mais promissoras ferramentas para a descoberta e o desenvolvimento de novas moleculas com potencialidades terapeuticas. Nesta metodologia de sintese os produtos sao formados simultaneamente e podem ser testados biologicamente em uma so vez, seja em forma de misturas ou separadamente. A principal meta desta nova metodologia e reduzir o tempo necessario para a obtencao de um novo farmaco. A sintese de quimiotecas pode ser realizada atraves da utilizacao de polimeros insoluveis, soluveis ou pela tradicional sintese em solucao, sendo que cada uma delas apresenta caracteristicas que podem ser vantajosas ou nao, dependendo da metodologia utilizada. O desenvolvimento de tecnicas de high throughput screening (HTS) devido as suas caracteristicas peculiares necessita de tempo, razao pela qual a sintese de quimiotecas pequenas e racionais e enfatizada.

Leveraging structural approaches: applications of NMR-based screening and X-ray crystallography for inhibitor design

In the last several years, NMR strategies in drug discovery have evolved from a primarily structural focus to a set of technologies that are non-structural in nature but that have a much greater impact on the identification and optimization of real drug leads. NMR-based screening methods, such as the SHAPES strategy, help rapidly identify good starting points for drug design in a relatively high throughput implementation. The SHAPES method uses simple NMR techniques to detect binding of a limited, but diverse library of low molecular weight, soluble compounds to a potential drug target. SHAPES library compounds are derived largely from molecular frameworks most commonly found in known therapeutic agents. The NMR experiments used in these protocols are based on the well-known NMR techniques, and may be applied to targets with no limitation on molecular weight and no requirement for isotope labeling. Following screening, SHAPES hits may be used to guide virtual screening, synthesis of combinatorial libraries, and bias the first compounds that undergo high throughput screening. Integration of the SHAPES strategy with iterative X-ray crystallographic structure determination can be very useful in deriving an initial structural pharmacophore model and achieving significant in vitro potency in a short time frame. Here, examples are provided of how the combination of NMR SHAPES screening, virtual screening, molecular modeling and X-ray crystallography has led to novel drug scaffolds in several drug discovery programs: JNK3 MAP kinase and the fatty acid binding protein, aP2.

PEG based resins for protease drug discovery synthesis, screening and analysis of combinatorial on-bead libraries.

This review will cover the entire hit identification process performed with biocompatible, aqueous solvated, poly[ethylene glycol] (PEG) based resins - from synthesis, through screening, to analysis. The different types of resins (including their preparation) will be discussed and compared individually. Examples of one-bead-one-compound substrate libraries will be presented, as will one-bead-two-compounds libraries used for the discovery of enzyme inhibitors. The review includes a section covering organic and bio-organic reactions performed on all-PEG resins and discusses on-bead screening of the libraries with biomolecules. Finally, analysis of compounds on single beads, either via investigation by on-bead NMR or by ladder-coding of the combinatorial compound is covered. In general, the review will focus on chemistry, libraries, synthesis, screening, and analysis, using all-PEG based resins.

Microwave-Assisted Polymer-Supported Combinatorial Synthesis

Lead identification and optimization is always a challenge to the medicinal chemists in drug discovery. Numbers of simple to complex and smaller to bigger organic compounds are prepared to meet the screening purpose of biological targets. Conventional solution phase synthetic methodologies are lacking the speed to run along with the need of medicinally interesting compounds due to their long reaction time, tedious work-up and purification problems. Alternatively opted polymer-supported synthesis of combinatorial libraries has been emerged as a promising tool in generating large numbers of structurally diverse molecules in a manner rapid and parallel. Microwave-assisted solid/liquid phase combinatorial synthetic techniques have been proved efficient in reducing the reaction time from days & hours to minutes & seconds and more promisingly to produce improved yields with high purities. This review briefs about the theory behind microwave chemical technology and glimpses of recent advancements in its application on polymer supported combinatorial synthesis.