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Meneghetti, Fiorella,Villa, Stefania,Masciocchi, Daniela,Barlocco, Daniela,Toma, Lucio,Han, Dong‐,Cho,Kwon, Byoung‐,Mog,Ogo, Naohisa,Asai, Akira,Legnani, Laura,Gelain, Arianna WILEY‐VCH Verlag 2015 EUROPEAN JOURNAL OF ORGANIC CHEMISTRY Vol.2015 No.22
<P><B>Abstract</B></P><P>Three new ureido‐pyridazinone derivatives, which are structurally related to the known STAT3 inhibitor <B>AVS‐0288</B>, 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 (<B>6a</B> and <B>6b</B>), which molecular structures were confirmed by means of X‐ray diffraction data on <B>6a</B>. 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 <I>ZZ</I> arrangement are essential and probably act in a synergistic way to confer significant activity against STAT3.</P>