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Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors

2015Journal article Open access
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dc.contributor.authorMachado, Vera A.
dc.contributor.authorPeixoto, Daniela
dc.contributor.authorCosta, Raquel
dc.contributor.authorFroufe, Hugo J.C.
dc.contributor.authorCalhelha, Ricardo C.
dc.contributor.authorAbreu, Rui M.V.
dc.contributor.authorFerreira, Isabel C.F.R.
dc.contributor.authorSoares, Raquel
dc.contributor.authorQueiroz, Maria João R.P.
dc.date.accessioned2015-12-01T10:03:46Z
dc.date.available2015-12-01T10:03:46Z
dc.date.issued2015
dc.description.abstractThe synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl] ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]- pyridin-7-ylthio)phenyl]ureas 4a–4h, with the arylurea in the meta position to the thioether, showed the lowest IC50 values in enzymatic assays (10–206 nM), the most potent compounds 4d–4h (IC50 10– 28 nM) bearing hydrophobic groups (Me, F, CF3 and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 lM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.pt_PT
dc.description.sponsorshipTo the Foundation for Science and Technology (FCT–Portugal) for financial support through the NMR Portuguese network (Bruker 400 Avance III-Univ Minho). FCT and FEDER (European Fund for Regional Development)-COMPETE/QREN/EU for financial support through the research unities PEst-C/QUI/UI686/2013-2014, PEst- OE/SAU/UI0038/2013 and 2014 and PEst-OE/AGR/UI0690/2013 and 2014, the research project PTDC/QUI-QUI/111060/2009, the PhD grant attributed to V.M. (SFRH/BD/77373/2011) and the post-Doctoral grant attributed to R.C.C. (SFRH/BPD/68344/2010), also financed by the POPH and FSE.pt_PT
dc.identifier.citationMachado, Vera A.; Peixoto, Daniela; Costa, Raquel T.; Froufe, Hugo J.C.; Calhelha, Ricardo C.; Abreu, Rui M.V.; Ferreira, Isabel C.F.R.; Soares, Raquel; Queiroz, Maria João R.P. (2015). Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 23:19, p. 6497-6509pt_PT
dc.identifier.doi10.1016/j.bmc.2015.08.010pt_PT
dc.identifier.eissn1464-3391
dc.identifier.issn0968-0896
dc.identifier.urihttp://hdl.handle.net/10198/12461
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationSYNTHESIS OF NOVEL HETEROCYCLIC COMPOUNDS BASED ON RATIONAL DESIGN AND EVALUATION OF THEIR ANTITUMOR AND ANTIANGIOGENIC POTENCIAL IN HUMAN ENDOTHELIAL AND TUMOR CELL LINES WITH TYROSINE KINASE MEMBRANE RECEPTORS AS TARGETS
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectThienopyridinethioether 1,3-diarylureaspt_PT
dc.subjectVEGFR-2 tyrosine kinase inhibitorspt_PT
dc.subjectEnzymatic assayspt_PT
dc.subjectMolecular dockingpt_PT
dc.subjectHUVECspt_PT
dc.subjectAntiangiogenesis assayspt_PT
dc.subjectWestern blottingpt_PT
dc.titleSynthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitorspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleSYNTHESIS OF NOVEL HETEROCYCLIC COMPOUNDS BASED ON RATIONAL DESIGN AND EVALUATION OF THEIR ANTITUMOR AND ANTIANGIOGENIC POTENCIAL IN HUMAN ENDOTHELIAL AND TUMOR CELL LINES WITH TYROSINE KINASE MEMBRANE RECEPTORS AS TARGETS
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FAGR%2F00690%2F2013/PT
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oaire.awardURIinfo:eu-repo/grantAgreement/FCT/COMPETE/PEst-C%2FQUI%2FUI0686%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/PEst-OE%2FAGR%2FUI0690%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F77373%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F68344%2F2010/PT
oaire.citation.endPage6509pt_PT
oaire.citation.startPage6497pt_PT
oaire.citation.titleBioorganic & Medicinal Chemistrypt_PT
oaire.citation.volume23pt_PT
oaire.fundingStream5876
oaire.fundingStream5876-PPCDTI
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person.familyNameCalhelha
person.familyNameAbreu
person.familyNameFerreira
person.givenNameRicardo C.
person.givenNameRui M.V.
person.givenNameIsabel C.F.R.
person.identifier144781
person.identifier.ciencia-idF313-E3CE-554E
person.identifier.ciencia-id0F19-0DE2-12A2
person.identifier.ciencia-id9418-CF95-9919
person.identifier.orcid0000-0002-6801-4578
person.identifier.orcid0000-0002-7745-8015
person.identifier.orcid0000-0003-4910-4882
person.identifier.ridJ-2172-2014
person.identifier.ridE-8500-2013
person.identifier.scopus-author-id6507978333
person.identifier.scopus-author-id7003290613
person.identifier.scopus-author-id36868826600
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
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rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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