Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones
Autor(a) principal: | |
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Data de Publicação: | 2019 |
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/10316/101596 https://doi.org/10.1016/j.arabjc.2016.12.007 |
Resumo: | A series of 3,4-dihydropyrimidin-2-(1H)-thiones (1–22) was synthesized through the Biginelli reaction in order to find novel anticancer drug candidates based on the structure of monastrol. The antiproliferative activity of the compounds was screened in several cell lines and the chlorinated compounds expressed considerable cytotoxicity in hepatic and/or colon and MCF-7 breast cancer cell lines. Within these, compound 11 was the most potent and showed strong antiproliferative effects on HepaRG cells (IC50= 0.75 lM). Using cell proliferation data, a quantitative structure-activity relationship (QSAR) analysis was performed employing Bayesian regularized artificial neural networks to relate in silico calculated molecular descriptors and bioactivity of the compounds across the tested cell lines. A statistical valid QSAR model was obtained, allowing the prediction of the relative cell proliferation for hypothetical analogous compounds in the studied cell lines. Additionally, cell cycle distribution analysis showed that another potent chlorinated molecule, compound 15, caused accumulation of cells in G0/G1 phase of the cell cycle in HepaRG and MCF-7 cells, which suggests a distinct mechanism of action relatively to monastrol. Overall, chlorinated monastrol analogues showed potent cytotoxic activity in cancer cells and deserve further investigation to ascertain their potential as candidate anticancer agents. |
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Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thionesCell cycleCytotoxicityDihydropyrimidinthionesMonastrolQSAR studiesA series of 3,4-dihydropyrimidin-2-(1H)-thiones (1–22) was synthesized through the Biginelli reaction in order to find novel anticancer drug candidates based on the structure of monastrol. The antiproliferative activity of the compounds was screened in several cell lines and the chlorinated compounds expressed considerable cytotoxicity in hepatic and/or colon and MCF-7 breast cancer cell lines. Within these, compound 11 was the most potent and showed strong antiproliferative effects on HepaRG cells (IC50= 0.75 lM). Using cell proliferation data, a quantitative structure-activity relationship (QSAR) analysis was performed employing Bayesian regularized artificial neural networks to relate in silico calculated molecular descriptors and bioactivity of the compounds across the tested cell lines. A statistical valid QSAR model was obtained, allowing the prediction of the relative cell proliferation for hypothetical analogous compounds in the studied cell lines. Additionally, cell cycle distribution analysis showed that another potent chlorinated molecule, compound 15, caused accumulation of cells in G0/G1 phase of the cell cycle in HepaRG and MCF-7 cells, which suggests a distinct mechanism of action relatively to monastrol. Overall, chlorinated monastrol analogues showed potent cytotoxic activity in cancer cells and deserve further investigation to ascertain their potential as candidate anticancer agents.2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/101596http://hdl.handle.net/10316/101596https://doi.org/10.1016/j.arabjc.2016.12.007eng18785352Matias, MarianaCampos, GonçaloSantos, Adriana O.Falcão, AmílcarSilvestre, SamuelAlves, Gilbertoinfo: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:RCAAP2022-09-01T20:45:44Zoai:estudogeral.uc.pt:10316/101596Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:18:45.312297Repositório 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, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones |
title |
Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones |
spellingShingle |
Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones Matias, Mariana Cell cycle Cytotoxicity Dihydropyrimidinthiones Monastrol QSAR studies |
title_short |
Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones |
title_full |
Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones |
title_fullStr |
Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones |
title_full_unstemmed |
Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones |
title_sort |
Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones |
author |
Matias, Mariana |
author_facet |
Matias, Mariana Campos, Gonçalo Santos, Adriana O. Falcão, Amílcar Silvestre, Samuel Alves, Gilberto |
author_role |
author |
author2 |
Campos, Gonçalo Santos, Adriana O. Falcão, Amílcar Silvestre, Samuel Alves, Gilberto |
author2_role |
author author author author author |
dc.contributor.author.fl_str_mv |
Matias, Mariana Campos, Gonçalo Santos, Adriana O. Falcão, Amílcar Silvestre, Samuel Alves, Gilberto |
dc.subject.por.fl_str_mv |
Cell cycle Cytotoxicity Dihydropyrimidinthiones Monastrol QSAR studies |
topic |
Cell cycle Cytotoxicity Dihydropyrimidinthiones Monastrol QSAR studies |
description |
A series of 3,4-dihydropyrimidin-2-(1H)-thiones (1–22) was synthesized through the Biginelli reaction in order to find novel anticancer drug candidates based on the structure of monastrol. The antiproliferative activity of the compounds was screened in several cell lines and the chlorinated compounds expressed considerable cytotoxicity in hepatic and/or colon and MCF-7 breast cancer cell lines. Within these, compound 11 was the most potent and showed strong antiproliferative effects on HepaRG cells (IC50= 0.75 lM). Using cell proliferation data, a quantitative structure-activity relationship (QSAR) analysis was performed employing Bayesian regularized artificial neural networks to relate in silico calculated molecular descriptors and bioactivity of the compounds across the tested cell lines. A statistical valid QSAR model was obtained, allowing the prediction of the relative cell proliferation for hypothetical analogous compounds in the studied cell lines. Additionally, cell cycle distribution analysis showed that another potent chlorinated molecule, compound 15, caused accumulation of cells in G0/G1 phase of the cell cycle in HepaRG and MCF-7 cells, which suggests a distinct mechanism of action relatively to monastrol. Overall, chlorinated monastrol analogues showed potent cytotoxic activity in cancer cells and deserve further investigation to ascertain their potential as candidate anticancer agents. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019 |
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/10316/101596 http://hdl.handle.net/10316/101596 https://doi.org/10.1016/j.arabjc.2016.12.007 |
url |
http://hdl.handle.net/10316/101596 https://doi.org/10.1016/j.arabjc.2016.12.007 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
18785352 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
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 |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
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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1799134082204958720 |