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Synthesis, molecular Docking and biological evaluation of new 1-Aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenylureas as Potent Type II VEGFR-2 Tyrosine Kinase inhibitors

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dc.contributor.authorMachado, Vera A.
dc.contributor.authorPeixoto, Daniela
dc.contributor.authorCosta, Raquel
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.accessioned2015-11-04T17:50:25Z
dc.date.available2015-11-04T17:50:25Z
dc.date.issued2014
dc.description.abstractThe vascular endothelial growth factor receptor 2 (VEGFR-2) is a tyrosine kinase receptor, expressed primarily in endothelial cells, and is activated by the specific binding of VEGF to the VEGFR-2 extracellular regulatory domain. Once activated, VEGFR-2 undergoes autophosphorylation, triggering signaling pathways leading to endothelial cell proliferation and subsequent angiogenesisY1 Small molecules may act as inhibitors by competing for the ATP-binding s'1te of the VEGFR-2 intracellular tyrosine kinase domain, thereby preventing the intracellular signa ling that leads to angiogenesis. [ZJ Here, we present the synthesis of new 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas la-c, as potent type 11 VEGFR-2 inhibitors based on molecular docking (Figure A) and biological evaluation including enzymatic assays using the VEGFR-2 tyrosine kinase domain (ICso=l0-28 nM) and studies in human umbilical vein endothelial cells (HUVECs). The latter included cell viability (MTS), proliferation (BrdU) and Western blot for total and phosphorylated VEGFR-2 (Figure B). The predicted docked poses were analyzed in detail and a plausible explanation for compounds 1 potency was obtained base9 on the simultaneous presence of a S-linker and the arylurea moiety in the meta position as a new substitution pattern for the type 11 VEGFR-2 inhibitors. These chemical features place the thieno[3,2-b]pyridine and the terminal aryl ring in close superimposition to a pyrrolo[3,2-d]pyrimidine derivative. The presence of hydrofobic substituents (F and Me) in the terminal aryl ring is also important. For these compounds a significant inhibition in HUVECs proliferation upon VEGF stimulation was observed at low concentrations (0.5-1.0 IJ.M) without affecting cell viability. Westernblot analysis demonstrated that compounds 1 significantly the inhibited VEGFR-2 phosphorylation at 1.0 jlM, thus confirming their anti-angiogenic potential.pt_PT
dc.identifier.citationMachado, Vera A.; Peixoto, Daniela; Costa, Raquel; Calhelha, Ricardo C.; Abreu, Rui M.V.; Ferreira, Isabel C.F.R.; Soares, Raquel; Queiroz, Maria João R.P. (2014). Synthesis, molecular Docking and biological evaluation of new 1-Aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenylureas as Potent Type II VEGFR-2 Tyrosine Kinase inhibitors. In International Symposium of Medicinal Chemistry. Lisboapt_PT
dc.identifier.urihttp://hdl.handle.net/10198/12280
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationPEst-OE/SAU/UI0038/2013pt_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.titleSynthesis, molecular Docking and biological evaluation of new 1-Aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenylureas as Potent Type II VEGFR-2 Tyrosine Kinase inhibitorspt_PT
dc.typeconference object
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-PPCDTI/PTDC%2FQUI-QUI%2F111060%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/COMPETE/PEst-C%2FQUI%2FUI0686%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FAGR%2F00690%2F2013/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.titleInternational Symposium of Medicinal Chemistrypt_PT
oaire.fundingStream5876-PPCDTI
oaire.fundingStreamCOMPETE
oaire.fundingStream5876
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.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
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typeconferenceObjectpt_PT
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