Ureido‐Pyridazinone Derivatives: Insights into the Structural and Conformational Properties for STAT3 Inhibition. Issue 22 (30th June 2015)

• Record Type: Journal Article
• 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
• Is Part Of: European journal of organic chemistry. Issue 22(2015)
• Page Start: 4907
• Page End: 4912
• Publication Date: 2015-06-30
• Subjects: Medicinal chemistry -- Cancer -- Inhibitors -- Signal transduction -- Conformation analysis -- Proteins; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201500599
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract: Three new ureido‐pyridazinone derivatives, which are structurally related to the known STAT3 inhibitorAVS‐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 and6b ), which molecular structures were confirmed by means of X‐ray diffraction data on6a . 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. Abstract : 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.