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1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR2 tyrosine kinase inhibitors: synthesis, docking studies, enzymatic and cellular assays

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dc.contributor.authorQueiroz, Maria João R.P.
dc.contributor.authorPeixoto, Daniela
dc.contributor.authorSoares, Pedro
dc.contributor.authorAbreu, Rui M.V.
dc.contributor.authorFroufe, Hugo J.C.
dc.contributor.authorCalhelha, Ricardo C.
dc.contributor.authorFerreira, Isabel C.F.R.
dc.contributor.authorCosta, Raquel
dc.contributor.authorSoares, Raquel
dc.date.accessioned2013-01-07T10:18:05Z
dc.date.available2013-01-07T10:18:05Z
dc.date.issued2012
dc.description.abstractA number of thienopyrimidines derivatives have shown potent vascular endothelial growth factor receptor 2 (VEGFR2) inhibition activity. Here, we present the synthesis of new 1-aryl-3-[4-(thieno[3,2-d) pyrimidin-4-yloxy)phenyl]ureas by promoting t he regioselective attack of the hydroxy group of the 4-aminophenol in the chlorine nucleophilic displacement on two 4-chlorinated thieno[3,2-d]pyrimidines, obtaining compounds la and 1b which were reacted with arylisocyanates to give t he corresponding 1,3-diarylureas 2a-f (see scheme). These compounds were evaluated for inhibition of VEGFR2 tyrosine kinase activity using enzymatic assays, and 2a- c showed good inhibition ability with IC50 values in the range of hundreds of nanomolar. The rationale for the inhibition activity is also discussed using docking. To examine the activity of 2a- c in endothelial cells, human umbilical vein endothelial cells (HUVECs) were cultured in the presence or absence of each compound in different concentrations. A decrease in the proliferation of HUVECs was observed by the incorporation of BrdU quantified by ELISA assay. Given the established role of VEGFR2 in proliferation and migration of endothelial cells, these molecules are promising antiangiogenic agents that can be used for therapeutic purposes in pathological conditions where angiogenesis is exacerbated, such as cancer.por
dc.identifier.citationQueiroz, Maria João; Peixoto, Daniela; Soares, Pedro; Abreu, Rui M.V.; Froufe, Hugo J.C.; Calhelha, Ricardo C.; Ferreira, Isabel C.F.R.; Costa, Raquel; Soares, Raquel (2012). 1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR2 tyrosine kinase inhibitors: synthesis, docking studies, enzymatic and cellular assays. In XXIInd International Symposium on Medicinal Chemistry. Berlinpor
dc.identifier.urihttp://hdl.handle.net/10198/7833
dc.language.isoengpor
dc.peerreviewedyespor
dc.relationPEst-C/QUI/UI686/2011
dc.relationStrategic Project - UI 690 - 2011-2012
dc.relationStrategic Project - UI 38 - 2011-2012
dc.title1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR2 tyrosine kinase inhibitors: synthesis, docking studies, enzymatic and cellular assayspor
dc.typeconference object
dspace.entity.typePublication
oaire.awardTitleStrategic Project - UI 690 - 2011-2012
oaire.awardTitleStrategic Project - UI 38 - 2011-2012
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/PEst-OE%2FAGR%2FUI0690%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/PEst-OE%2FSAU%2FUI0038%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FQUI-QUI%2F111060%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F68344%2F2010/PT
oaire.citation.conferencePlaceBerlim, Alemanhapor
oaire.citation.titleXXIInd International Symposium on Medicinal Chemistry, 2-6th September 2012por
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream5876-PPCDTI
oaire.fundingStreamSFRH
person.familyNameAbreu
person.familyNameCalhelha
person.familyNameFerreira
person.givenNameRui M.V.
person.givenNameRicardo C.
person.givenNameIsabel C.F.R.
person.identifier144781
person.identifier.ciencia-id0F19-0DE2-12A2
person.identifier.ciencia-idF313-E3CE-554E
person.identifier.ciencia-id9418-CF95-9919
person.identifier.orcid0000-0002-7745-8015
person.identifier.orcid0000-0002-6801-4578
person.identifier.orcid0000-0003-4910-4882
person.identifier.ridJ-2172-2014
person.identifier.ridE-8500-2013
person.identifier.scopus-author-id7003290613
person.identifier.scopus-author-id6507978333
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
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