Forward Chemical Genetics

Haggarty, Stephen J.; Schreiber, Stuart L.

doi:10.1002/9783527619375.ch6

Cited by 5 publications

(3 citation statements)

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“…Small molecule biological probes that influence protein function are useful tools for studying the cell and can also serve as lead structures in the development of new therapeutic agents [1-5]. The NIH Roadmap [6] project has created opportunities for the development of new chemical libraries for subsequent screening by the Molecular Libraries Screening Center Network (MLSCN) in a combined effort to identify unique and useful biological probes.…”

Section: Introductionmentioning

confidence: 99%

Parallel Synthesis of a Library of Symmetrically- and Dissymmetrically-disubstituted Imidazole-4,5-dicarboxamides Bearing Amino Acid Esters

2009

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The imidazole-4,5-dicarboxylic acid scaffold is readily derivatized with amino acid esters to afford symmetrically- and dissymmetrically-disubstituted imidazole-4,5-dicarboxamides with intramolecularly hydrogen bonded conformations that predispose the presentation of amino acid pharmacophores. In this work, a total of 45 imidazole-4,5-dicarboxamides bearing amino acid esters were prepared by parallel synthesis. The library members were purified by column chromatography on silica gel and the purified compounds characterized by LC-MS with LC detection at 214 nm. A selection of the final compounds was also analyzed by 1H-NMR spectroscopy. The analytically pure final products have been submitted to the Molecular Library Small Molecule Repository (MLSMR) for screening in the Molecular Library Screening Center Network (MLSCN) as part of the NIH Roadmap.

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Section: Introductionmentioning

confidence: 99%

Parallel Synthesis of a Library of Symmetrically- and Dissymmetrically-disubstituted Imidazole-4,5-dicarboxamides Bearing Amino Acid Esters

2009

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“…There remains a need for selective small molecule probes of biological processes in order to discern cellular communication and signaling pathways, as well as for potential application as therapeutic agents against diseases [ 1 , 2 , 3 , 4 ]. In general, the most useful biological probes will also meet the parameters commonly found for drugs or drug-like molecules, including Lipinski’s “rule of five” [ 5 ] and the number of rotatable bonds [ 6 ], since such parameters are indications of solubility and cellular permeability [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Parallel Synthesis of an Imidazole-4,5-dicarboxamide Library Bearing Amino Acid Esters and Alkanamines

2008

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The imidazole-4,5-dicarboxylic acid scaffold is readily derivatized with amino acid esters and alkanamines to afford compounds with intramolecularly hydrogen bonded conformations that mimic substituted purines and therefore are hypothesized to be potential inhibitors of kinases through competitive binding to the ATP site. In this work, a total of 126 dissymmetrically disubstituted imidazole-4,5-dicarboxamides with amino acid ester and alkanamide substituents were prepared by parallel synthesis. The library members were purified by column chromatography on silica gel and the purified compounds characterized by LC-MS with LC detection at 214 nm. A selection of the final compounds was also analyzed by 1H-NMR spectroscopy. The analytically pure final products have been submitted to the Molecular Library Small Molecule Repository (MLSMR) for screening in the Molecular Library Screening Center Network (MLSCN) as part of the NIH Roadmap.

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“…Many of these derivatives are natural compounds and have been identified by serendipity or through screens, e.g., for anticancer activity (Gough and Crews, 2007). In the last decade chemical genetics, the generation of "preferred structure" libraries, and sometimes computer-aided design have started to provide us with new tools to interfere with intracellular events (Breinbauer et al, 2007;Haggarty and Schreiber, 2007;Breinbauer et al, 2002;Schreiber, 1998). In the following paragraphs I will not dwell on small molecule modulators such as kinase inhibitors or effectors of the cytoskeleton.…”

Section: Molecules To Dissect Intracellular Signaling Cascadesmentioning

confidence: 99%

Molecular tools for cell and systems biology

Schultz

2007

HFSP Journal

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Forward Chemical Genetics

Cited by 5 publications

References 86 publications

Parallel Synthesis of a Library of Symmetrically- and Dissymmetrically-disubstituted Imidazole-4,5-dicarboxamides Bearing Amino Acid Esters

Parallel Synthesis of a Library of Symmetrically- and Dissymmetrically-disubstituted Imidazole-4,5-dicarboxamides Bearing Amino Acid Esters

Parallel Synthesis of an Imidazole-4,5-dicarboxamide Library Bearing Amino Acid Esters and Alkanamines

Molecular tools for cell and systems biology

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