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1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR-2 tyrosine kinase inhibitors: Synthesis, biological evaluation, and molecular modelling studies

2013Journal article Open access
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dc.contributor.authorSoares, Pedro
dc.contributor.authorCosta, Raquel
dc.contributor.authorFroufe, Hugo J.C.
dc.contributor.authorCalhelha, Ricardo C.
dc.contributor.authorPeixoto, Daniela
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.accessioned2013-07-24T14:21:39Z
dc.date.available2013-07-24T14:21:39Z
dc.date.issued2013
dc.description.abstractThe Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) is a tyrosine kinase receptor involved in the growth and differentiation of endothelial cells that is implicated in tumor-associated angiogenesis. In this study novel 1-aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas were synthesized and evaluated for the VEGFR-2 tyrosine kinase inhibition. Three of these compounds showed good VEGFR-2 inhibition presenting low IC50 values (150-199 nM) in enzymatic assays. The latter promoted also significant inhibition of cell proliferation at low concentrations (0.5-1 µM), not affecting cell viability, of VEGF-stimulated Human Umbilical Vein Endothelial Cells (HUVECs) using the BrdU assay. The determination of the total and phosphorylated (active) VEGFR-2 was performed by western-blot, and it was possible to conclude that the compounds significantly inhibit the phosphorylation of the receptor at 1 µM pointing to their antiproliferative mechanism of action in HUVECs. The molecular rationale for inhibiting the tyrosine kinase domain of VEGFR-2 was also done and discussed using molecular docking studies.por
dc.description.sponsorshipFoundation for the 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/UI686/2011, PEst-OE/SAU/UI0038/2011 and PEst-OE/AGR/UI0690/2011, the research project PTDC/QUI-QUI/111060/2009 and the post-Doctoral grant attributed to R.C.C. (SFRH/BPD/68344/2010) also financed by POPH (Human Potential Operational Programme) and FSE (Social European Fund).por
dc.identifier.citationSoares, Pedro; Costa, Raquel; Froufe, Hugo J.C.; Calhelha, Ricardo C.; Peixoto, Daniela; Abreu, Rui M.V.; Ferreira, Isabel C.F.R.; Soares, Raquel; Queiroz, Maria João R.P. (2013). 1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR-2 tyrosine kinase inhibitors: Synthesis, biological evaluation, and molecular modelling studies. BioMed Research International. ISSN 2314-6141. 2013, p. 1-9por
dc.identifier.issn2314-6141
dc.identifier.urihttp://hdl.handle.net/10198/8554
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherHindawi Publishing Corporationpor
dc.relationPEst-C/QUI/UI686/2011
dc.relationStrategic Project - UI 38 - 2011-2012
dc.relationStrategic Project - UI 690 - 2011-2012
dc.subjectThienopyrimidine ether ureaspor
dc.subjectVEGFR-2 inhibitorspor
dc.subjectHUVECspor
dc.subjectWestern-blotpor
dc.subjectMolecular modellingpor
dc.title1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR-2 tyrosine kinase inhibitors: Synthesis, biological evaluation, and molecular modelling studiespor
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleStrategic Project - UI 38 - 2011-2012
oaire.awardTitleStrategic Project - UI 690 - 2011-2012
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FQUI-QUI%2F111060%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/PEst-OE%2FSAU%2FUI0038%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/PEst-OE%2FAGR%2FUI0690%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F68344%2F2010/PT
oaire.citation.endPage9por
oaire.citation.startPage1por
oaire.citation.titleBioMed Research Internationalpor
oaire.fundingStream5876-PPCDTI
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamSFRH
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
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspor
rcaap.typearticlepor
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