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Modeling, synthesis and NMR characterization of novel chimera compounds targeting STAT3

Signal Transducer and Activator of Transcription 3 (STAT3) is a cytoplasmic factor that mediates intracellular signaling commonly generated at cell surface receptors and transmits it to the nucleus. In previous research studies we synthesized several molecules inhibiting STAT3 and among them oxadiaz...

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Bibliographic Details
Published in:MedChemComm 2014-11, Vol.5 (11), p.1651-1657
Main Authors: Dell'Orto, Silvia, Masciocchi, Daniela, Villa, Stefania, Meneghetti, Fiorella, Celentano, Giuseppe, Barlocco, Daniela, Colombo, Diego, Legnani, Laura, Toma, Lucio, Jeon, Yoon Jung, Kwon, Byoung-Mog, Asai, Akira, Gelain, Arianna
Format: Article
Language:English
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Summary:Signal Transducer and Activator of Transcription 3 (STAT3) is a cytoplasmic factor that mediates intracellular signaling commonly generated at cell surface receptors and transmits it to the nucleus. In previous research studies we synthesized several molecules inhibiting STAT3 and among them oxadiazole MD77 and pyridazinone I showed an interesting activity. For the first one, a direct inhibition mechanism was determined, while I interfered within the STAT3 pathway at a different level. In order to discover novel compounds possibly endowed with an improved activity, we decided to merge their scaffolds on the basis of their calculated conformational properties. Therefore we designed and synthesized the chimera diastereomers 3-oxo- N -(4-(trifluoromethyl)phenyl)-2,3,4,4a,5,6-hexahydrobenzo[ h ]cinnoline-6-carboxamide ( 1 , 2 ) and 3-oxo- N -(4-(trifluoromethyl)phenyl)-2,3,5,6-tetrahydrobenzo[ h ]cinnoline-6-carboxamide ( 3 ) as racemate and their enantiomeric separation was performed. Modeling studies and theoretical prediction of [ α ] D values were carried out beside NMR studies which allowed us to assign 1 and 2 relative configurations.
ISSN:2040-2503
2040-2511
DOI:10.1039/C4MD00177J