Synthesis and Applications of Small Molecule Libraries

Thompson, Lorin A.; Ellman, Jonathan A.

doi:10.1021/cr9402081

Cited by 1,467 publications

(520 citation statements)

References 225 publications

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“…The residue was purified by silica gel chromatography, eluting with 7:3-6:4 hexane/ethyl acetate, to yield 599 mg (63%) of 12 as a clear oil. 1 N-(3-Bromobenzyl)-(aminooxy)acetamide (13). Compound 12 (457 mg, 1.3 mmol) was dissolved in a solution of 95:2.5:2.5 trifluoroacetic acid/triisopropylsilane/water (v/v/v) (9.0 mL) and stirred at room temperature for 1 h. The reaction was concentrated in vacuo and purified by reversed-phase HPLC on a C4 column and lyophilized to yield 206 mg (63%) of 13 as a white powder.…”

Section: Capping and Deprotection Of Resin 4 (5)mentioning

confidence: 99%

“…Compound 12 (457 mg, 1.3 mmol) was dissolved in a solution of 95:2.5:2.5 trifluoroacetic acid/triisopropylsilane/water (v/v/v) (9.0 mL) and stirred at room temperature for 1 h. The reaction was concentrated in vacuo and purified by reversed-phase HPLC on a C4 column and lyophilized to yield 206 mg (63%) of 13 as a white powder. 1 Peptoid Synthesis. The peptoid oligomers were synthesized on an automated peptoid/peptide synthesizer.…”

Section: Capping and Deprotection Of Resin 4 (5)mentioning

confidence: 99%

“…Combinatorial chemistry allows for the rapid synthesis of a large collection of diverse molecules. 1 The majority of the compound libraries that have been prepared to date have been synthesized using high-yielding general reactions and solidphase synthesis techniques. The solid phase facilitates the handling of large numbers of reactions, allowing the use of excess reagents and simple washing procedures to isolate the desired product.…”

Section: Introductionmentioning

confidence: 99%

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Cleavable Hydrophilic Linker for One-Bead-One-Compound Sequencing of Oligomer Libraries by Tandem Mass Spectrometry

Paulick¹,

Hart²,

Brinner³

et al. 2006

J. Comb. Chem.

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We have developed a method for the rapid and unambiguous identification of sequences of hit compounds from one-bead-one-compound combinatorial libraries of peptide and peptoid ligands. The approach uses a cleavable linker that is hydrophilic to help reduce nonspecific binding to biological samples and allows for the attachment of a halogen tag, which greatly facilitates post-screening sequencing by tandem mass spectrometry (MS/MS). The linker is based on a tartaric acid unit, which, upon cleavage from resin, generates a C-terminal aldehyde. This aldehyde can then be derivatized with a bromine-containing amino-oxy compound that serves as an isotope tag for subsequent MS/MS analysis of y-ion fragments. We have applied this linker and method to the syntheses of a number of peptoids that vary in sequence and length and have also demonstrated single-bead sequencing of a peptoid pentamer. The linker is also shown to have very low levels of nonspecific binding to proteins.

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Section: Capping and Deprotection Of Resin 4 (5)mentioning

confidence: 99%

Section: Capping and Deprotection Of Resin 4 (5)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cleavable Hydrophilic Linker for One-Bead-One-Compound Sequencing of Oligomer Libraries by Tandem Mass Spectrometry

Paulick¹,

Hart²,

Brinner³

et al. 2006

J. Comb. Chem.

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“…The generation of diverse combinatorial libraries has been shown to be a valuable tool for lead compound identification in the drug discovery process 1,2 . However, lead compound optimization and traditional medicinal chemistry remain the bottlenecks in this high-throughput discipline.…”

Section: Introductionmentioning

confidence: 99%

Automated generation of a dihydropyrimidine compound library using microwave-assisted processing

Dallinger

Kappe

2007

Nat Protoc

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Here we report the generation of a small focused library of 12 diversely functionalized dihydropyrimidine (DHPM) derivatives via one-pot three-component Biginelli cyclocondensation of b-ketoesters, aldehydes and (thio)ureas. By applying controlled microwave heating under sealed vessel conditions using a fully automated microwave instrument including a gripper and liquid handler, the sequential synthesis of DHPMs can be performed in a shorter reaction time (10-20 min per one DHPM derivative) compared to conventional heating methods, which normally require several hours of reflux heating. The solid products either crystallize directly upon cooling or can be precipitated upon addition of water, requiring only filtration for isolation. In this way, the DHPM derivatives are obtained in high purity and no further purification by recrystallization or chromatography is necessary. This can be ascribed to the microwave heating technology where less side-product formation is often seen. The preparation of this 12-membered DHPM library can be carried out within B9 h.

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“…The application of combinatorial chemistry [1,2] and high throughput screening [3] to drug discovery has altered the traditional serial process of lead identification and optimization that traditionally preceded investigations of drug development. Instead, vast numbers of new compounds are synthesized in parallel using combinatorial chemistry and tested rapidly using high throughput screening.…”

Section: Introductionmentioning

confidence: 99%

Analysis and screening of combinatorial libraries using mass spectrometry

Shin

Breemen

2001

Biopharm & Drug Disp

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Mass spectrometry is a highly selective and high throughput analytical technique that is ideally suited for the identification and purity determination of large numbers of compounds prepared using combinatorial chemistry or for the dereplication of natural products. Compounds may be characterized based on molecular weight, elemental composition and structural features based on fragmentation patterns. When coupled to a separation technique such as highperformance liquid chromatography (HPLC) or capillary electrophoresis, mass spectrometric applications may be expanded to include analysis of complex mixtures. However, the slower speed of the separation step reduces the throughput of the analysis. This review concerns the application of mass spectrometry to the characterization of combinatorial libraries and the screening of library and natural product mixtures. Strategies to enhance the throughput of LC-MS are discussed including fast HPLC and parallel LC-MS. Also, mass spectrometry-based screening methods are described including frontal affinity chromatography-mass spectrometry, gel permeation chromatography LC-MS, direct electrospray mass spectrometry of receptor-ligand complexes, affinity chromatography-mass spectrometry, and pulsed ultrafiltration mass spectrometry.

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Synthesis and Applications of Small Molecule Libraries

Cited by 1,467 publications

References 225 publications

Cleavable Hydrophilic Linker for One-Bead-One-Compound Sequencing of Oligomer Libraries by Tandem Mass Spectrometry

Cleavable Hydrophilic Linker for One-Bead-One-Compound Sequencing of Oligomer Libraries by Tandem Mass Spectrometry

Automated generation of a dihydropyrimidine compound library using microwave-assisted processing

Analysis and screening of combinatorial libraries using mass spectrometry

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