Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors
Main Author: | |
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Publication Date: | 2015 |
Other Authors: | , , , , , , , |
Format: | Article |
Language: | eng |
Source: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Download full: | http://hdl.handle.net/1822/39853 |
Summary: | The synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 4a-4h, with the arylurea in the meta position to the thioether, showed the lowest IC50 values in enzymatic assays (10-206 nM), the most potent compounds 4d-4h (IC50 10-28 nM) bearing hydrophobic groups (Me, F, CF3 and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 microM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs. |
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Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitorsThienopyridinethioether 1,3-diarylureasVEGFR-2 tyrosine kinase inhibitorsEnzymatic assaysMolecular DockingHUVECsAntiangiogenesis assaysWestern blottingCiências Médicas::Outras Ciências MédicasCiências Naturais::Ciências QuímicasScience & TechnologyThe synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 4a-4h, with the arylurea in the meta position to the thioether, showed the lowest IC50 values in enzymatic assays (10-206 nM), the most potent compounds 4d-4h (IC50 10-28 nM) bearing hydrophobic groups (Me, F, CF3 and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 microM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.To the Foundation for 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/UI686/2013-2014, PEst-OE/SAU/UI0038/2013 and 2014 and PEst OE/AGR/UI0690/2013 and 2014, the research project PTDC/QUI-QUI/111060/2009, the PhD grant attributed to V.M. (SFRH/BD/77373/2011) and the post-Doctoral grant attributed to R.C.C. (SFRH/BPD/68344/2010), also financed by the POPH and FSE.ElsevierUniversidade do MinhoMachado, Vera A.Peixoto, D.Costa, R.Froufe, H. J. C.Calhelha, Ricardo C.Abreu, R. M. VFerreira, Isabel C. F. R.Soares, R.Queiroz, Maria João R. P.20152015-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/39853eng53. Machado, V. A., Peixoto, D., Costa, R., Froufe, H. J. C., Calhelha, R. C., Abreu, R. M. V., . . . Queiroz, M. J. R. P. (2015). Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors. Bioorganic and Medicinal Chemistry, 23(19), 6497-6509. doi: 10.1016/j.bmc.2015.08.0100968-089610.1016/j.bmc.2015.08.01026344591http://dx.doi.org/10.1016/j.bmc.2015.08.010info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:43:17Zoai:repositorium.sdum.uminho.pt:1822/39853Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:40:42.736915Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors |
title |
Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors |
spellingShingle |
Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors Machado, Vera A. Thienopyridinethioether 1,3-diarylureas VEGFR-2 tyrosine kinase inhibitors Enzymatic assays Molecular Docking HUVECs Antiangiogenesis assays Western blotting Ciências Médicas::Outras Ciências Médicas Ciências Naturais::Ciências Químicas Science & Technology |
title_short |
Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors |
title_full |
Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors |
title_fullStr |
Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors |
title_full_unstemmed |
Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors |
title_sort |
Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors |
author |
Machado, Vera A. |
author_facet |
Machado, Vera A. Peixoto, D. Costa, R. Froufe, H. J. C. Calhelha, Ricardo C. Abreu, R. M. V Ferreira, Isabel C. F. R. Soares, R. Queiroz, Maria João R. P. |
author_role |
author |
author2 |
Peixoto, D. Costa, R. Froufe, H. J. C. Calhelha, Ricardo C. Abreu, R. M. V Ferreira, Isabel C. F. R. Soares, R. Queiroz, Maria João R. P. |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Machado, Vera A. Peixoto, D. Costa, R. Froufe, H. J. C. Calhelha, Ricardo C. Abreu, R. M. V Ferreira, Isabel C. F. R. Soares, R. Queiroz, Maria João R. P. |
dc.subject.por.fl_str_mv |
Thienopyridinethioether 1,3-diarylureas VEGFR-2 tyrosine kinase inhibitors Enzymatic assays Molecular Docking HUVECs Antiangiogenesis assays Western blotting Ciências Médicas::Outras Ciências Médicas Ciências Naturais::Ciências Químicas Science & Technology |
topic |
Thienopyridinethioether 1,3-diarylureas VEGFR-2 tyrosine kinase inhibitors Enzymatic assays Molecular Docking HUVECs Antiangiogenesis assays Western blotting Ciências Médicas::Outras Ciências Médicas Ciências Naturais::Ciências Químicas Science & Technology |
description |
The synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 4a-4h, with the arylurea in the meta position to the thioether, showed the lowest IC50 values in enzymatic assays (10-206 nM), the most potent compounds 4d-4h (IC50 10-28 nM) bearing hydrophobic groups (Me, F, CF3 and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 microM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs. |
publishDate |
2015 |
dc.date.none.fl_str_mv |
2015 2015-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/39853 |
url |
http://hdl.handle.net/1822/39853 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
53. Machado, V. A., Peixoto, D., Costa, R., Froufe, H. J. C., Calhelha, R. C., Abreu, R. M. V., . . . Queiroz, M. J. R. P. (2015). Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors. Bioorganic and Medicinal Chemistry, 23(19), 6497-6509. doi: 10.1016/j.bmc.2015.08.010 0968-0896 10.1016/j.bmc.2015.08.010 26344591 http://dx.doi.org/10.1016/j.bmc.2015.08.010 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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