- Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease
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Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK2-selective ligands using radiolabelled binding assays. CCK antagonism was confirmed for the ligands in isolated tissue preparations.
- Lattmann,Sattayasai,Narayanan,Ngoc,Burrell,Balaram,Palizdar,Lattmann
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supporting information
p. 680 - 685
(2017/03/30)
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- Cholecystokinin-1 receptor antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anticancer agents
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A new class of 5-arylated 5-hydroxypyrrolones was derived from mucochloric acid in 2 synthetic steps and the chemical structure was confirmed additionally by X-ray analysis. Using a radiolabelled binding assay, potent CCK1 selective ligands were identified (CCK1: 12 nM) and the antagonism was confirmed by using isolated tissue preparations. A series of isobutyl derivatives displayed unsurmountable CCK antagonistic properties and in vitro excellent inhibition of proliferation was obtained in cholecystokinin related cancer cell lines in the nanomolar range. Finally, using xenograft studies in nude mice, two selected pyrrolone derivatives, X = H and X = F a fluorinated analogue (PNB-028), showed a strong inhibition of tumour growth in a chemo-resistant colon cancer-(MAC 16) and a human pancreatic cell line (MIAPACA) at 50 mg kg-1 by oral administration.
- Lattmann,Russell,Schwalbe,Shortt,Balaram,Theochari,Alharbi,Narayanan,Lattmann
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supporting information
p. 1138 - 1145
(2016/07/06)
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- Ureido-Pyridazinone Derivatives: Insights into the Structural and Conformational Properties for STAT3 Inhibition
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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, Fiorella,Villa, Stefania,Masciocchi, Daniela,Barlocco, Daniela,Toma, Lucio,Han, Dong-Cho,Kwon, Byoung-Mog,Ogo, Naohisa,Asai, Akira,Legnani, Laura,Gelain, Arianna
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supporting information
p. 4907 - 4912
(2015/08/03)
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