Synthesis and Evaluation of [2-(4-Quinolyloxy)phenyl]methanone Derivatives: Novel Selective Inhibitors of Transforming Growth Factor-β Kinase

We synthesized and evaluated various [2-(4-quinolyloxy)phenyl]methanone derivatives. These compounds had novel chemical structures that were distinct from those of previously reported inhibitors. Biological data suggested that these compounds inhibited transforming growth factor-β signaling by inter...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 51; no. 11; pp. 3326 - 3329
Main Authors:	Shimizu, Toshiyuki, Kimura, Kaname, Sakai, Teruyuki, Kawakami, Kazuki, Miyazaki, Tetsuko, Nakouji, Masayoshi, Ogawa, Akira, Ohuchi, Hitomi, Shimizu, Kiyoshi
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 12-06-2008
Subjects:	Activin Receptors, Type I - antagonists & inhibitors Activin Receptors, Type I - metabolism Biological and medical sciences Cell Line, Tumor Genes, Reporter Humans Luciferases - biosynthesis Luciferases - genetics Medical sciences Miscellaneous Pharmacology. Drug treatments Phosphorylation Quinolines - chemical synthesis Quinolines - chemistry Quinolines - pharmacology Smad2 Protein - genetics Smad2 Protein - metabolism Smad3 Protein - genetics Smad3 Protein - metabolism Structure-Activity Relationship Transforming Growth Factor beta - metabolism Transforming Growth Factor beta - pharmacology Benzophenone derivatives Smad protein Enzyme Transforming growth factor β Transferases Cytokine Quinoline derivatives Selectivity Ketone In vitro Signal transduction Structure activity relation Inhibitor Chemical synthesis
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Summary:	We synthesized and evaluated various [2-(4-quinolyloxy)phenyl]methanone derivatives. These compounds had novel chemical structures that were distinct from those of previously reported inhibitors. Biological data suggested that these compounds inhibited transforming growth factor-β signaling by interacting with the ATP-binding pocket of the transforming growth factor-β type I receptor kinase domain. Here, we report on the synthesis and structure−activity relationships of the compounds in this series.
Bibliography:	ark:/67375/TPS-1WCM7XGK-4 Details on general experimental methods, biological assays, the synthesis of 9c−ae, and their analytical data. This material is available free of charge via the Internet at http://pubs.acs.org. istex:50FCD61DBEB42A6FD8DB9AB1D430D98186134F3A ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm701626z