Ureido-Pyridazinone Derivatives: Insights into the Structural and Conformational Properties for STAT3 Inhibition

Three new ureido‐pyridazinone derivatives, which are structurally related to the known STAT3 inhibitor AVS‐0288, were designed by taking into account the structure–activity relationships determined for several ureido‐oxadiazole derivatives previously studied by our group. Their synthesis was first a...

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Bibliographic Details
Published in:European journal of organic chemistry 2015-08, Vol.2015 (22), p.4907-4912
Main Authors: Meneghetti, Fiorella, Villa, Stefania, Masciocchi, Daniela, Barlocco, Daniela, Toma, Lucio, Han, Dong-Cho, Kwon, Byoung-Mog, Ogo, Naohisa, Asai, Akira, Legnani, Laura, Gelain, Arianna
Format: Article
Language:English
Subjects:
Cancer
Conformation analysis
Diffraction
Inhibitors
Medicinal chemistry
Proteins
Signal transduction
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Summary:Three new ureido‐pyridazinone derivatives, which are structurally related to the known STAT3 inhibitor AVS‐0288, were designed by taking into account the structure–activity relationships determined for several ureido‐oxadiazole derivatives previously studied by our group. Their synthesis was first attempted through suitable 5‐aminopyridazinone intermediates (6a and 6b), which molecular structures were confirmed by means of X‐ray diffraction data on 6a. Amine functionalization was unsuccessful, therefore, an alternative method was devised. Dual‐luciferase and AlphaScreen‐based assays were used to test their activity. The obtained data were rationalized on the basis of a modeling study, which focused our attention on the geometrical preferences of the ureido moiety. Computational results seem to indicate that both the 1,2,5‐oxadiazole ring and the extended ZZ arrangement are essential and probably act in a synergistic way to confer significant activity against STAT3. The design, synthesis and biological properties of new potential STAT3 inhibitors with a pyridazinone ring, which replaces the 1,2,5‐oxadiazole of previous investigated compounds, are described. A complete modeling study rationalized the results obtained and helped elucidate the structural and conformational properties needed for STAT3 inhibition.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.201500599