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New di(heteroaryl)thioethers 1,3-diarylureas in the thieno[3,2-b]pyridine series as VEGFR2 tyrosine kinase inhibitors: docking, synthesis, enzymatic and cellular assays

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dc.contributor.authorMachado, Vera A.
dc.contributor.authorCosta, Raquel
dc.contributor.authorPeixoto, Daniela
dc.contributor.authorAbreu, Rui M.V.
dc.contributor.authorCalhelha, Ricardo C.
dc.contributor.authorFerreira, Isabel C.F.R.
dc.contributor.authorSoares, Raquel
dc.contributor.authorQueiroz, Maria João R.P.
dc.date.accessioned2015-11-04T17:22:00Z
dc.date.available2015-11-04T17:22:00Z
dc.date.issued2013
dc.description.abstractVascular Endothelial Growth Factor Receptor 2 (VEGFR2) is a tyrosine kinase receptor, expressed primarily in endothelial cells, and is activated by the specific binding of VEGF, produced and released by the tumor, to the VEGFR2 extracellular regulatory domain, undergoing autophosphorylation, triggering signaling pathways leading to endothelial cell proliferation towards the tumor [!].Small molecules may act as inhibitors by competing for the ATP-binding site of the VEGFR2 intracellular tyrosine kinase domain, thereby preventing the intracellular signaling that leads to angiogenesis [2]. Herein, we report the synthesis using rational design of new 1-aryl-3-[3-thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas (la-c) as VEGFR2 tyrosine kinase inhibitors. The compounds presented, with the arylurea in the meta position to the thioether and with F or a Me group, showed very low !Cso values (11-28 nM) in enzymatic assays as predicted by molecular docking. To examine the activity of compounds 1 in endothelial cells, VEGF-stimulated (60 ng/mL) Human Umbilical Vein Endothelial Cells (HUVECs) were cultured in M199 medium in the absence (C) or presence of each compound at different concentrations. A remarkable reduction in the proliferation of HUVECs using the BrdU incorporation assay was observed for all compounds at I !JM, for compound la being observed a higher antiproliferative effect. Further studies are ongoing to examine whether these molecules affect the expression and activity of VEGFR2 and the signaling pathways, using western blotting assays. Given the established role of VEGFR2 in proliferation and migration of endothelial cells, these molecules are promising anti-angiogenic agents that can be used for therapeutic purposes in pathological conditions where angiogenesis is exacerbated, such as cancer.pt_PT
dc.identifier.citationMachado, Vera; Costa, Raquel; Peixoto, Daniela; Abreu, Rui M.V.; Calhelha, Ricardo C.; Ferreira, Isabel C.F.R.; Soares, Raquel T.; Queiroz, Maria João R.P. (2013). New di(heteroaryl)thioethers 1,3-diarylureas in the thieno[3,2-b]pyridine series as VEGFR2 tyrosine kinase inhibitors: docking, synthesis, enzymatic and cellular assays. In 49th International Conference on Medicinal Chemistry (RICT 2013). Nicept_PT
dc.identifier.urihttp://hdl.handle.net/10198/12279
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationPEst-C/QUI/UI686/2011pt_PT
dc.relationPEst-OE/SAUIUI0038/2011pt_PT
dc.relationStrategic Project - UI 690 - 2011-2012
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.titleNew di(heteroaryl)thioethers 1,3-diarylureas in the thieno[3,2-b]pyridine series as VEGFR2 tyrosine kinase inhibitors: docking, synthesis, enzymatic and cellular assayspt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.awardTitleStrategic Project - UI 690 - 2011-2012
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-PPCDTI/PTDC%2FQUI-QUI%2F111060%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/PEst-OE%2FAGR%2FUI0690%2F2011/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.title49th International Conference on Medicinal Chemistry (RICT 2013)pt_PT
oaire.fundingStream5876-PPCDTI
oaire.fundingStream6817 - DCRRNI ID
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.rightsopenAccesspt_PT
rcaap.typeconferenceObjectpt_PT
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