Synthesis Of Combinatorial Libraries Research Articles

Analytical Techniques Applied in the Combinatorial Synthesis of Large Drug Discovery Libraries

Analytical Techniques Applied in the Combinatorial Synthesis of Large Drug Discovery Libraries

ChemInform Abstract: Combinatorial Library Synthesis Using Polymer‐Supported Catalysts

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Identification of novel Ah receptor agonists using a high-throughput green fluorescent protein-based recombinant cell bioassay.

The Ah receptor is a ligand-dependent transcription factor that mediates the biological and toxic effects of polycyclic aromatic hydrocarbons and halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). Recent evidence also suggests a role for the AhR in normal physiology and development. Although a variety of structurally diverse chemicals are reported to bind to and activate the AhR, the full spectrum of structural chemical classes that can interact with the AhR remains to be elucidated. Large-scale analysis of the ligand binding specificity of the AhR requires the use of a high-throughput AhR bioassay system for chemical screening. We have utilized a recombinant mouse hepatoma cell line (H1G1.1c3) containing a stably integrated TCDD- and AhR-responsive enhanced green fluorescent protein (EGFP) reporter gene to screen a 1,5-dialkylamino-2,4-dinitrobenzene combinatorial chemical library consisting of 155 parental amines and up to 12 090 combinatorial products in less than 7 days for novel AhR agonists. These analyses have identified numerous parental amines as relatively potent inducers of EGFP (with EC(50)s between 8 and 1000 microM) and also have revealed several novel products of the combinatorial chemical library synthesis with EC(50)s between 10 and 100 microM. Overall, these results have not only allowed the identification of novel activators of the AhR but also demonstrate the utility of the recombinant H1G1.1c3 cell bioassay for high-throughput chemical screening.

Universal solid-phase approach for the immobilization, derivatization, and resin-to-resin transfer reactions of boronic acids.

Boronic acid-containing molecules are employed in a broad range of biological, medicinal, and synthetic applications. These compounds, however, tend to be difficult to handle by solution-phase methods. Herein, this problem is addressed with the development of the first general solid-phase approach for the derivatization of functionalized boronic acids. This approach is based on the use of a diethanolamine resin anchor that facilitates boronic acid immobilization by avoiding the need for exhaustive removal of water in the esterification process. The immobilization of a wide variety of boronic acids onto N,N-diethanolaminomethyl polystyrene (DEAM-PS, 1) can be performed within minutes by simple stirring in anhydrous solvents at room temperature. Evidence for the formation of a bicyclic diethanolamine boronate with putative N-B coordination was shown by (1)H NMR analysis of DEAM-PS-supported p-tolylboronic acid. The hydrolytic cleavage of the same model boronic acid from the DEAM-PS resin was studied by UV spectroscopy. Hydrolysis and attachment were shown to occur under a rapidly attained equilibrium, and a large excess of water (>32 equiv) is required to effect a practically quantitative release of boronic acids from DEAM-PS. Despite their relative sensitivity to water and alcohols, DEAM-PS-bound arylboronic acids functionalized with a formyl, a bromomethyl, a carboxyl, or an amino group can be transformed in good to excellent yields into a wide variety of amines, amides, anilides, and ureas, respectively. Ugi multicomponent reactions on DEAM-PS-supported aminobenzeneboronic acids, derivatization of multifunctional arylboronic acids, and sequential reactions can also be carried out efficiently. These new DEAM-PS-supported arylboronic acids can be employed directly into resin-to-resin transfer reactions (RRTR). This type of multiresin process helps eliminate time-consuming cleavage and transfer operations, thereby considerably simplifying the outlook of combinatorial library synthesis by manual or automated means. This concept was illustrated by a set of optimized procedures for the Suzuki cross-coupling and the borono-Mannich reactions.

A selectively deprotectable triazacyclophane scaffold for the construction of artificial receptors.

[reaction: see text]. The synthesis of a triazacylclophane scaffold bearing a set of selectively removable protecting groups is described. This versatile scaffold, which can be linked to a solid support, allows the attachment of three different side chains and can therefore be used for the combinatorial synthesis of libraries of artificial receptor molecules of high structural diversity.

Identification of B cell and T cell epitopes using synthetic peptide combinatorial libraries.

This unit presents a combinatorial library method that consists of the synthesis and screening of mixture-based synthetic combinatorial libraries (SCL) of peptide molecules. The protocols employ peptide SCL to identify peptides recognized by mAbs and T cells. The first protocol uses a positional scanning SCL (PS-SCL) made up of hexapeptides to identify antigenic determinants recognized by mAbs. The 120 mixtures in the hexapeptide PS-SCL are tested for their inhibitory activity in a competitive ELISA. The second protocol uses a decapeptide PS-SCL to identify T cell peptide ligands. The 200 mixtures of the decapeptide PS-SCL are tested for their ability to induce proliferation. Support protocols cover optimization of the assay conditions for each mAb or T cell, to achieve the best level of sensitivity and reproducibility, and preparation of a hexapeptide PS-SCL, along with deconvolution approaches.

A useful bicyclic topological decapeptide template for solution-phase combinatorial synthesis of tetrapodal libraries

An orthogonally protected bicyclic decapeptide has been constructed and evaluated as a template for combinatorial synthesis. This template is found most useful for solution-phase combinatorial synthesis of tetrapodal libraries.

Identification of novel polyphenol oxidase inhibitors by enzymatic one-pot synthesis and deconvolution of combinatorial libraries.

The feasibility of enzymatic synthesis of combinatorial libraries using multifunctional starting materials [i.e., 2,4-dihydroxy-N-(2-hydroxyethyl)benzamide, 1; 4-hydroxyphenethyl alcohol, 2; 3,5-dihydroxybenzyl alcohol, 3; and 4-hydroxybenzyl alcohol, 4] with six vinyl esters, in a one-pot reaction, was investigated. Candida antarctica lipase was employed as a biocatalyst. The resulting 24-compound library contained all the expected species with no significant bias toward particular combinations of substrates. As expected, the library contained a substance(s) that showed significant inhibition of polyphenol oxidase, which was used as a model target. The deconvolution was accomplished via resynthesis of ten partial libraries, which were prepared with either an equimolar mixture of the four alcohols and a single vinyl ester, or a single alcohol and equimolar mixture of the activated esters. Analysis of the inhibition pattern observed with these partial libraries suggested that 4-hydroxybenzyl benzoate (4e) should be the most potent inhibitor. This conclusion was confirmed by the preparation and comparison of all 24 components of the initial library. Finally, it was shown that 4e was a competitive inhibitor of polyphenol oxidase, with a K(i) of 40 microM. This value compared favorably with a K(i) of 400 microM, which was determined for parent phenol 4.

ChemInform Abstract: Synthesis of Combinatorial Libraries Using the Portioning‐Mixing Procedure

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Synthesis and Screening of Positional Scanning Synthetic Combinatorial Libraries

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Parallel solid-phase synthesis of nucleoside phosphoramidate libraries

Combinatorial chemistry is playing an increasingly prominent role in the process of drug discovery. A nucleic acid-based (NAB TM) scaffold can be engineered to create functional group and topological diversity in a library. Described herein is the parallel solid-phase synthesis of combinatorial libraries of nucleoside phosphoramidates, and the first evaluation of antiviral activity against hepatitis B virus (HBV).

Combinatorial synthesis of libraries of indole derivatives

The synthesis of two indole derivative libraries is described. 2-Acyl-3-amino-indoles 4 can easily be accessed by treatment of the intermediates 3 with bases in a one-pot reaction sequence whereas the reaction of the isolated intermediates 5 (R 3=aromatic-, heteroaromatic, or cycloalkyl) with acid chlorides yielded the novel indole derivatives 6. The products were purified by reversed phase column chromatography and obtained in multi-milligram quantities in acceptable yields.

Click Chemistry: Diverse Chemical Function from a Few Good Reactions.

Examination of nature's favorite molecules reveals a striking preference for making carbon-heteroatom bonds over carbon-carbon bonds-surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon-heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C-C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

Click Chemistry: Diverse Chemical Function from a Few Good Reactions.

Examination of nature's favorite molecules reveals a striking preference for making carbon-heteroatom bonds over carbon-carbon bonds-surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon-heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C-C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

Large-Scale Syntheses of FMOC-Protected Non-Proteogenic Amino Acids: Useful Building Blocks for Combinatorial Libraries

Convenient and reliable large-scale procedures for the protection of various amino acids with N-(9-fluorenylmethoxycarbonyl)oxysuccinimide (FMOC-OSu) are described. Commercially available 4-aminomethylbenzoic acid and trans-4-(aminomethyl)cyclohexanecarboxylic acid were converted into their corresponding FMOC-derivatives in excellent yields without the need for an extractive workup. In addition, FMOC-cis-β-amino acids were also prepared, employing a [2 + 2]-cycloaddition strategy between a cyclic olefin and N-chlorosulfonyl isocyanate (CSI). The resulting N-chlorosulfonyl β-lactams were reduced to the parent β-lactams with sodium sulfite and then converted to the cis-β-amino acid hydrochlorides by exposure to aqueous hydrochloric acid. The resulting cis-β-amino acids were converted to their FMOC-derivatives under conditions similar to those developed for the commercially available amino acids. Differences in the conditions employed between these β-amino acids and the commercial derivatives were observed, primarily in the nature of the base required for the reaction. A possible rationale for the differences in behavior is described. These FMOC-amino acid derivatives are valuable intermediates for the solid-phase synthesis of combinatorial libraries.

Click Chemistry: Diverse Chemical Function from a Few Good Reactions

Examination of nature's favorite molecules reveals a striking preference for making carbon-heteroatom bonds over carbon-carbon bonds-surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon-heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C-C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

Regioselective solid-phase 4-amino-de-chlorination of 2,4,6-trichloropyrimidine by resin-supported N-potassium carbamates

The first regioselective resin-anchoring reaction of 2,4,6-trichloropyrimidine has been achieved through 4-amino-de-chlorination by solid-supported Boc-like N-potassium carbamates. Excellent regioselectivities together with high coupling efficiency were obtained with aliphatic, aromatic and α-amino-ester derived carbamates. The scope and limits of the reaction are described with the view of its applications to the solid-phase synthesis of combinatorial libraries of aminopyrimidine-based structures.

Solid phase synthesis of mixture-based acyclic and heterocyclic small molecule combinatorial libraries from resin-bound polyamides.

The development of soluble mixture-based heterocyclic combinatorial libraries derived from amino acids and peptides is described. Starting with a "toolbox" of various chemical transformations, including alkylations, reductions, acylations, and the use of a variety of bifunctional reagents, the "libraries from libraries" concept has been expanded to encompass the development of more than fifty positional scanning combinatorial libraries each composed of tens of thousands of low molecular weight acyclic and heterocyclic compounds.

Solid-Phase Traceless Synthesis of Selected Nitrogen-Containing Heterocyclic Compounds. The Encore Technique for Directed Sorting of Modular Solid Support

The acid lability of electron-rich N-benzylanilines has been exploited in a linker for the traceless solid-phase synthesis of benzimidazoles, 2-aminobenzimidazoles, quinoxalinones and tetrahydroquinoxalines. The target compound precursors were assembled on a solid-phase support derivatized with either a benzylamine or a benzhydrylamine linker. Exposure to an acidic reagent caused cleavage of the C(benzyl)-N(aniline) bond, releasing the product with only a hydrogen atom on the descending nitrogen. The Encore technique for directed sorting on SynPhase Lanterns has been developed and applied to combinatorial synthesis of generic drug discovery libraries.

The combinatorial synthesis of racemic homosilatecan libraries via a cascade radical annulation.

The combinatorial synthesis of racemic homosilatecan libraries via a cascade radical annulation.