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.

Meneghetti, F., Villa, S., Masciocchi, D., Barlocco, D., Toma, L., Han, D., et al. (2015). Ureido-Pyridazinone Derivatives: Insights into the Structural and Conformational Properties for STAT3 Inhibition. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2015(22), 4907-4912 [10.1002/ejoc.201500599].

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

Legnani L.;
2015

Abstract

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.
Articolo in rivista - Articolo scientifico
Cancer; Conformation analysis; Inhibitors; Medicinal chemistry; Proteins; Signal transduction;
English
4907
4912
6
Meneghetti, F., Villa, S., Masciocchi, D., Barlocco, D., Toma, L., Han, D., et al. (2015). Ureido-Pyridazinone Derivatives: Insights into the Structural and Conformational Properties for STAT3 Inhibition. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2015(22), 4907-4912 [10.1002/ejoc.201500599].
Meneghetti, F; Villa, S; Masciocchi, D; Barlocco, D; Toma, L; Han, D; Kwon, B; Ogo, N; Asai, A; Legnani, L; Gelain, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/352049
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