Publicação
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
| dc.contributor.author | Machado, Vera A. | |
| dc.contributor.author | Peixoto, Daniela | |
| dc.contributor.author | Costa, Raquel | |
| dc.contributor.author | Calhelha, Ricardo C. | |
| dc.contributor.author | Abreu, Rui M.V. | |
| dc.contributor.author | Ferreira, Isabel C.F.R. | |
| dc.contributor.author | Soares, Raquel | |
| dc.contributor.author | Queiroz, Maria João R.P. | |
| dc.date.accessioned | 2015-11-04T17:50:25Z | |
| dc.date.available | 2015-11-04T17:50:25Z | |
| dc.date.issued | 2014 | |
| dc.description.abstract | The 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.citation | Machado, 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. Lisboa | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10198/12280 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.relation | PEst-OE/SAU/UI0038/2013 | pt_PT |
| dc.relation | New antitumor and antiangiogenic heterocyclic compounds: synthesis, molecular modeling, screening of enzymatic inhibition and studies in tumor and endothelial cell lines with tyrosine kinase membrane receptors as targets | |
| dc.relation | Projecto Estratégico - UI 686 - 2013-2014 | |
| dc.relation | Synthesis 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.relation | New antitumor and/or anti-angiogenic heterocyclic compounds: Synthesis, molecular modelling and inhibition enzymatic assays using tyrosine kinase membrane growth factor receptors | |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt_PT |
| dc.title | 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 | pt_PT |
| dc.type | conference object | |
| dspace.entity.type | Publication | |
| oaire.awardNumber | PTDC/QUI-QUI/111060/2009 | |
| oaire.awardNumber | PEst-C/QUI/UI0686/2013 | |
| oaire.awardNumber | SFRH/BD/77373/2011 | |
| oaire.awardNumber | SFRH/BPD/68344/2010 | |
| oaire.awardTitle | New antitumor and antiangiogenic heterocyclic compounds: synthesis, molecular modeling, screening of enzymatic inhibition and studies in tumor and endothelial cell lines with tyrosine kinase membrane receptors as targets | |
| oaire.awardTitle | Projecto Estratégico - UI 686 - 2013-2014 | |
| oaire.awardTitle | Synthesis 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.awardTitle | New antitumor and/or anti-angiogenic heterocyclic compounds: Synthesis, molecular modelling and inhibition enzymatic assays using tyrosine kinase membrane growth factor receptors | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FQUI-QUI%2F111060%2F2009/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/COMPETE/PEst-C%2FQUI%2FUI0686%2F2013/PT | |
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| oaire.awardURI | info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F68344%2F2010/PT | |
| oaire.citation.title | International Symposium of Medicinal Chemistry | pt_PT |
| oaire.fundingStream | 5876-PPCDTI | |
| oaire.fundingStream | COMPETE | |
| oaire.fundingStream | SFRH | |
| person.familyName | Calhelha | |
| person.familyName | Abreu | |
| person.familyName | Ferreira | |
| person.givenName | Ricardo C. | |
| person.givenName | Rui M.V. | |
| person.givenName | Isabel C.F.R. | |
| person.identifier | 144781 | |
| person.identifier.ciencia-id | F313-E3CE-554E | |
| person.identifier.ciencia-id | 0F19-0DE2-12A2 | |
| person.identifier.ciencia-id | 9418-CF95-9919 | |
| person.identifier.orcid | 0000-0002-6801-4578 | |
| person.identifier.orcid | 0000-0002-7745-8015 | |
| person.identifier.orcid | 0000-0003-4910-4882 | |
| person.identifier.rid | J-2172-2014 | |
| person.identifier.rid | E-8500-2013 | |
| person.identifier.scopus-author-id | 6507978333 | |
| person.identifier.scopus-author-id | 7003290613 | |
| person.identifier.scopus-author-id | 36868826600 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | conferenceObject | pt_PT |
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