Synthesis, in vitro evaluation and QSAR modelling of potential antitumoral 3,4-dihydropyrimidin-2-(1H)-thiones

Detalhes bibliográficos
Autor(a) principal: Matias, Mariana
Data de Publicação: 2019
Outros Autores: Campos, Gonçalo, Santos, Adriana O., Falcão, Amílcar, Silvestre, Samuel, Alves, Gilberto
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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spelling 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
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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
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