A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding
Autor(a) principal: | |
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Data de Publicação: | 2013 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/25675 https://doi.org/10.1039/c3dt50553g |
Resumo: | The pyrimidinones mhcpe, 2-methyl-3H-5-hydroxy-6-carboxy-4-pyrimidinone ethyl ester (mhcpe, 1), 2,3- dimethyl-5-benzyloxy-6-carboxy-4-pyrimidinone ethyl ester (dbcpe, 2) and N-methyl-2,3-dimethyl-5- hydroxy-6-carboxyamido-4-pyrimidinone (N-MeHOPY, 3), are synthesized and their structures determined by single crystal X-ray diffraction. The acid–base properties of 1 are studied by potentiometric and spectrophotometric methods, the pKa values being 1.14 and 6.35. DFT calculations were carried out to determine the most stable structure for each of the H2L+, HL and L− forms (HL = mhcpe) and assign the groups involved in the protonation–deprotonation processes. The mhcpe− ligand forms stable complexes with VIVO2+ in the pH range 2 to 10, and potentiometry, EPR and UV-Vis techniques are used to identify and characterize the VIVO–mhcpe species formed. The results are consistent with the formation of VIVO, (VIVO)L, (VIVO)L2, (VIVO)2L2H−2, (VIVO)L2H−1, (VIVO)2L2H−3, (VIVO)LH−2 species and VIVO-hydrolysis products. Calculations indicate that the global binding ability of mhcpe towards VIVO2+ is similar to that of maltol (Hmaltol = 3-hydroxy-2-methyl-4H-pyran-4-one) and lower than that of 1,2-dimethyl-3-hydroxy-4- pyridinone (Hdhp). The interaction of VIVO-complexes with human plasma proteins (transferrin and albumin) is studied by circular dichroism (CD), EPR and 51V NMR spectroscopy. VIVO–mhcpe–protein ternary complexes are formed in both cases. The binding of VIVO2+ to transferrin (hTF) in the presence of mhcpe involves mainly (VIVO)1(hTF)(mhcpe)1, (VIVO)2(hTF)(mhcpe)1 and (VIVO)2(hTF)(mhcpe)2 species, bound at the FeIII binding sites, and the corresponding conditional formation constants are determined. Under the conditions expected to prevail in human blood serum, CD data indicate that the VIVO–mhcpe complexes mainly bind to hTF; the formation of VIVO–hTF–mhcpe complexes occurs in the presence of FeIII as well, distinct EPR signals being clearly obtained for FeIII–hTF and to VIVO–hTF–mhcpe species. Thus this study indicates that transferrin plays the major role in the transport of VIVO–mhcpe complexes under blood plasma conditions in the form of ternary VIV–ligand–protein complexes. |
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A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein bindingThe pyrimidinones mhcpe, 2-methyl-3H-5-hydroxy-6-carboxy-4-pyrimidinone ethyl ester (mhcpe, 1), 2,3- dimethyl-5-benzyloxy-6-carboxy-4-pyrimidinone ethyl ester (dbcpe, 2) and N-methyl-2,3-dimethyl-5- hydroxy-6-carboxyamido-4-pyrimidinone (N-MeHOPY, 3), are synthesized and their structures determined by single crystal X-ray diffraction. The acid–base properties of 1 are studied by potentiometric and spectrophotometric methods, the pKa values being 1.14 and 6.35. DFT calculations were carried out to determine the most stable structure for each of the H2L+, HL and L− forms (HL = mhcpe) and assign the groups involved in the protonation–deprotonation processes. The mhcpe− ligand forms stable complexes with VIVO2+ in the pH range 2 to 10, and potentiometry, EPR and UV-Vis techniques are used to identify and characterize the VIVO–mhcpe species formed. The results are consistent with the formation of VIVO, (VIVO)L, (VIVO)L2, (VIVO)2L2H−2, (VIVO)L2H−1, (VIVO)2L2H−3, (VIVO)LH−2 species and VIVO-hydrolysis products. Calculations indicate that the global binding ability of mhcpe towards VIVO2+ is similar to that of maltol (Hmaltol = 3-hydroxy-2-methyl-4H-pyran-4-one) and lower than that of 1,2-dimethyl-3-hydroxy-4- pyridinone (Hdhp). The interaction of VIVO-complexes with human plasma proteins (transferrin and albumin) is studied by circular dichroism (CD), EPR and 51V NMR spectroscopy. VIVO–mhcpe–protein ternary complexes are formed in both cases. The binding of VIVO2+ to transferrin (hTF) in the presence of mhcpe involves mainly (VIVO)1(hTF)(mhcpe)1, (VIVO)2(hTF)(mhcpe)1 and (VIVO)2(hTF)(mhcpe)2 species, bound at the FeIII binding sites, and the corresponding conditional formation constants are determined. Under the conditions expected to prevail in human blood serum, CD data indicate that the VIVO–mhcpe complexes mainly bind to hTF; the formation of VIVO–hTF–mhcpe complexes occurs in the presence of FeIII as well, distinct EPR signals being clearly obtained for FeIII–hTF and to VIVO–hTF–mhcpe species. Thus this study indicates that transferrin plays the major role in the transport of VIVO–mhcpe complexes under blood plasma conditions in the form of ternary VIV–ligand–protein complexes.The authors are grateful to the Fundo Europeu para o Desenvolvimento Regional, Fundação para a Ciência e Tecnologia (FCT), the POCI 2010 Programme, the Portuguese NMR Network (IST-UTL Center), PEst-OE/QUI/UI0100/2011, University of A Coruña and the Spanish-Portuguese Bilateral Programme (Acção Integrada E-56/05, Acción integrada HP2004- 0074).The Royal Society of Chemistry2013info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/25675http://hdl.handle.net/10316/25675https://doi.org/10.1039/c3dt50553genghttp://pubs.rsc.org/en/Content/ArticleLanding/2013/DT/c3dt50553g#!divAbstractGonçalves, GiselaTomaz, IsabelCorreia, IsabelVieiros, Luís F.Castro, M. M. C. A.Avecilla, FernandoPalacio, LorenaMaestro, MiguelKiss, TámasJakusch, TámasGarcia, M. Helena V.Pessoa, João Costainfo: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:RCAAP2020-05-25T08:34:18Zoai:estudogeral.uc.pt:10316/25675Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:56:03.069239Repositório 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 |
A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding |
title |
A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding |
spellingShingle |
A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding Gonçalves, Gisela |
title_short |
A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding |
title_full |
A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding |
title_fullStr |
A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding |
title_full_unstemmed |
A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding |
title_sort |
A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding |
author |
Gonçalves, Gisela |
author_facet |
Gonçalves, Gisela Tomaz, Isabel Correia, Isabel Vieiros, Luís F. Castro, M. M. C. A. Avecilla, Fernando Palacio, Lorena Maestro, Miguel Kiss, Támas Jakusch, Támas Garcia, M. Helena V. Pessoa, João Costa |
author_role |
author |
author2 |
Tomaz, Isabel Correia, Isabel Vieiros, Luís F. Castro, M. M. C. A. Avecilla, Fernando Palacio, Lorena Maestro, Miguel Kiss, Támas Jakusch, Támas Garcia, M. Helena V. Pessoa, João Costa |
author2_role |
author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Gonçalves, Gisela Tomaz, Isabel Correia, Isabel Vieiros, Luís F. Castro, M. M. C. A. Avecilla, Fernando Palacio, Lorena Maestro, Miguel Kiss, Támas Jakusch, Támas Garcia, M. Helena V. Pessoa, João Costa |
description |
The pyrimidinones mhcpe, 2-methyl-3H-5-hydroxy-6-carboxy-4-pyrimidinone ethyl ester (mhcpe, 1), 2,3- dimethyl-5-benzyloxy-6-carboxy-4-pyrimidinone ethyl ester (dbcpe, 2) and N-methyl-2,3-dimethyl-5- hydroxy-6-carboxyamido-4-pyrimidinone (N-MeHOPY, 3), are synthesized and their structures determined by single crystal X-ray diffraction. The acid–base properties of 1 are studied by potentiometric and spectrophotometric methods, the pKa values being 1.14 and 6.35. DFT calculations were carried out to determine the most stable structure for each of the H2L+, HL and L− forms (HL = mhcpe) and assign the groups involved in the protonation–deprotonation processes. The mhcpe− ligand forms stable complexes with VIVO2+ in the pH range 2 to 10, and potentiometry, EPR and UV-Vis techniques are used to identify and characterize the VIVO–mhcpe species formed. The results are consistent with the formation of VIVO, (VIVO)L, (VIVO)L2, (VIVO)2L2H−2, (VIVO)L2H−1, (VIVO)2L2H−3, (VIVO)LH−2 species and VIVO-hydrolysis products. Calculations indicate that the global binding ability of mhcpe towards VIVO2+ is similar to that of maltol (Hmaltol = 3-hydroxy-2-methyl-4H-pyran-4-one) and lower than that of 1,2-dimethyl-3-hydroxy-4- pyridinone (Hdhp). The interaction of VIVO-complexes with human plasma proteins (transferrin and albumin) is studied by circular dichroism (CD), EPR and 51V NMR spectroscopy. VIVO–mhcpe–protein ternary complexes are formed in both cases. The binding of VIVO2+ to transferrin (hTF) in the presence of mhcpe involves mainly (VIVO)1(hTF)(mhcpe)1, (VIVO)2(hTF)(mhcpe)1 and (VIVO)2(hTF)(mhcpe)2 species, bound at the FeIII binding sites, and the corresponding conditional formation constants are determined. Under the conditions expected to prevail in human blood serum, CD data indicate that the VIVO–mhcpe complexes mainly bind to hTF; the formation of VIVO–hTF–mhcpe complexes occurs in the presence of FeIII as well, distinct EPR signals being clearly obtained for FeIII–hTF and to VIVO–hTF–mhcpe species. Thus this study indicates that transferrin plays the major role in the transport of VIVO–mhcpe complexes under blood plasma conditions in the form of ternary VIV–ligand–protein complexes. |
publishDate |
2013 |
dc.date.none.fl_str_mv |
2013 |
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/10316/25675 http://hdl.handle.net/10316/25675 https://doi.org/10.1039/c3dt50553g |
url |
http://hdl.handle.net/10316/25675 https://doi.org/10.1039/c3dt50553g |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
http://pubs.rsc.org/en/Content/ArticleLanding/2013/DT/c3dt50553g#!divAbstract |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
The Royal Society of Chemistry |
publisher.none.fl_str_mv |
The Royal Society of Chemistry |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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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 |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
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 |
repository.mail.fl_str_mv |
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1799133846017409024 |