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Title 

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

 

피리다지논 계열의 스탯3 저해제의 구조-활성 연구

Authors 

F MeneghettiS VillaD MasciocchiD BarloccoL TomaDong Cho HanByoung-Mog KwonN OgoA AsaiL LegnaniA Gelain

Publisher 

Wiley-VCH Verlag

Issue Date 

2015

Citation 

European Journal of Organic Chemistry, vol. 2015, no. 22, pp. 4907-4912

Keywords 

CancerConformation analysisInhibitorsMedicinal chemistryProteinsSignal transduction

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.

ISSN 

1434-193X

Link 

http://dx.doi.org/10.1002/ejoc.201500599

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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