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.

Ureido-pyridazinone derivatives : insights into the structural and conformational properties for STAT3 inhibition / F. Meneghetti, S. Villa, D. Masciocchi, D. Barlocco, L. Toma, D-C. Han, B-M. Kwon, N. Ogo, A. Asai, L. Legnani, A. Gelain. - In: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY. - ISSN 1099-0690. - 2015:22(2015 Jun 30), pp. 4907-4912.

Ureido-pyridazinone derivatives : insights into the structural and conformational properties for STAT3 inhibition

F. Meneghetti
Primo
;
S. Villa
;
D. Masciocchi;D. Barlocco;A. Gelain
Ultimo
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.
Medicinal chemistry; Cancer;Inhibitors; Signal transduction; Conformation analysis; Proteins
Settore CHIM/08 - Chimica Farmaceutica
Settore CHIM/06 - Chimica Organica
30-giu-2015
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/286967
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