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

Fiorella Meneghetti, Stefania Villa, Daniela Masciocchi, Daniela Barlocco, Lucio Toma, Dong Cho Han, Byoung Mog Kwon, Naohisa Ogo, Akira Asai, Laura Legnani, Arianna Gelain

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)4907-4912
Number of pages6
JournalEuropean Journal of Organic Chemistry
Volume2015
Issue number22
DOIs
Publication statusPublished - Aug 1 2015

    Fingerprint

Keywords

  • Cancer
  • Conformation analysis
  • Inhibitors
  • Medicinal chemistry
  • Proteins
  • Signal transduction

ASJC Scopus subject areas

  • Organic Chemistry
  • Physical and Theoretical Chemistry

Cite this

Meneghetti, F., Villa, S., Masciocchi, D., Barlocco, D., Toma, L., Han, D. C., Kwon, B. M., Ogo, N., Asai, A., Legnani, L., & Gelain, A. (2015). Ureido-Pyridazinone Derivatives: Insights into the Structural and Conformational Properties for STAT3 Inhibition. European Journal of Organic Chemistry, 2015(22), 4907-4912. https://doi.org/10.1002/ejoc.201500599