Synthesis of novel methyl 7-[(hetero)arylamino]thieno[2,3-b] pyrazine-6-carboxylates and antitumor activity evaluation: effects in human tumor cells growth, cell cycle analysis, apoptosis and toxicity in non-tumor cells
Autor(a) principal: | |
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Data de Publicação: | 2021 |
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/1822/74633 |
Resumo: | Several novel methyl 7-[(hetero)arylamino]thieno[2,3-<i>b</i>]pyrazine-6-carboxylates were synthesized by Pd-catalyzed C–N Buchwald–Hartwig cross-coupling of either methyl 7-aminothieno[3,2-<i>b</i>]pyrazine-6-carboxylate with (hetero)arylhalides or 7-bromothieno[2,3-<i>b</i>]pyrazine-6-carboxylate with (hetero)arylamines in good-to-excellent yields (50% quantitative yield), using different reaction conditions, namely ligands and solvents, due to the different electronic character of the substrates. The antitumoral potential of these compounds was evaluated in four human tumor cell lines: gastric adenocarcinoma (AGS), colorectal adenocarcinoma (CaCo-2), breast carcinoma (MCF7), and non-small-cell lung carcinoma (NCI-H460) using the SRB assay, and it was possible to establish some structure–activity relationships. Furthermore, they did not show relevant toxicity against a non-tumor cell line culture from the African green monkey kidney (Vero). The most promising compounds (GI<sub>50</sub> ≤ 11 µM), showed some selectivity either against AGS or CaCo-2 cell lines without toxicity at their GI<sub>50</sub> values. The effects of the methoxylated compounds <b>2b</b> (2-OMeC<sub>6</sub>H<sub>4</sub>), <b>2f</b> and <b>2g</b> (3,4- or 3,5-diOMeC<sub>6</sub>H<sub>3</sub>, respectively) on the cell cycle profile and induction of apoptosis were further studied in the AGS cell line. Nevertheless, even for the most active (GI<sub>50</sub> = 7.8 µM) and selective compound (<b>2g</b>) against this cell line, it was observed that a huge number of dead cells gave rise to an atypical distribution on the cell cycle profile and that these cells were not apoptotic, which points to a different mechanism of action for the AGS cell growth inhibition. |
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Synthesis of novel methyl 7-[(hetero)arylamino]thieno[2,3-b] pyrazine-6-carboxylates and antitumor activity evaluation: effects in human tumor cells growth, cell cycle analysis, apoptosis and toxicity in non-tumor cellsC–N Buchwald–Hartwig couplingThieno[2,3-b]pyrazinesAntitumor activityGastric adenocarcinomaCell cycleApoptosisthieno[23-b]pyrazinesScience & TechnologySeveral novel methyl 7-[(hetero)arylamino]thieno[2,3-<i>b</i>]pyrazine-6-carboxylates were synthesized by Pd-catalyzed C–N Buchwald–Hartwig cross-coupling of either methyl 7-aminothieno[3,2-<i>b</i>]pyrazine-6-carboxylate with (hetero)arylhalides or 7-bromothieno[2,3-<i>b</i>]pyrazine-6-carboxylate with (hetero)arylamines in good-to-excellent yields (50% quantitative yield), using different reaction conditions, namely ligands and solvents, due to the different electronic character of the substrates. The antitumoral potential of these compounds was evaluated in four human tumor cell lines: gastric adenocarcinoma (AGS), colorectal adenocarcinoma (CaCo-2), breast carcinoma (MCF7), and non-small-cell lung carcinoma (NCI-H460) using the SRB assay, and it was possible to establish some structure–activity relationships. Furthermore, they did not show relevant toxicity against a non-tumor cell line culture from the African green monkey kidney (Vero). The most promising compounds (GI<sub>50</sub> ≤ 11 µM), showed some selectivity either against AGS or CaCo-2 cell lines without toxicity at their GI<sub>50</sub> values. The effects of the methoxylated compounds <b>2b</b> (2-OMeC<sub>6</sub>H<sub>4</sub>), <b>2f</b> and <b>2g</b> (3,4- or 3,5-diOMeC<sub>6</sub>H<sub>3</sub>, respectively) on the cell cycle profile and induction of apoptosis were further studied in the AGS cell line. Nevertheless, even for the most active (GI<sub>50</sub> = 7.8 µM) and selective compound (<b>2g</b>) against this cell line, it was observed that a huge number of dead cells gave rise to an atypical distribution on the cell cycle profile and that these cells were not apoptotic, which points to a different mechanism of action for the AGS cell growth inhibition.This research was funded by Fundação para a Ciência e Tecnologia (FCT)—Portugal, which financially supports CQUM (UID/QUI/686/2019), and also financed by the European Regional Develop- ment Fund (ERDF), COMPETE2020 and Portugal2020, and the PTNMR network also supported by Portugal2020. J.M.R. PhD grant (SFRH/BD/115844/2016) was financed by FCT, ESF (European Social Fund—North Portugal Regional Operational Program) and HCOP (Human Capital Operational Program). The authors are grateful to FCT, Portugal, for financial support through national funds FCT/MCTES to the CIMO (UIDB/00690/2020). L.B. and R.C.C. thank the national funding by FCT, Portugal, through the institutional scientific employment program-contract for their contracts.Multidisciplinary Digital Publishing Institute (MDPI)Universidade do MinhoRodrigues, Juliana M.Calhelha, Ricardo C.Nogueira, AntónioFerreira, Isabel C. F. R.Barros, LillianQueiroz, Maria João R. P.2021-08-102021-08-10T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/74633engRodrigues, J.M.; Calhelha, R.C.; Nogueira, A.; Ferreira, I.C.F.R.; Barros, L.; Queiroz, M.-J.R.P. Synthesis of Novel Methyl 7-[(Hetero)arylamino]thieno[2,3-b]pyrazine-6-carboxylates and Antitumor Activity Evaluation: Effects in Human Tumor Cells Growth, Cell Cycle Analysis, Apoptosis and Toxicity in Non-Tumor Cells. Molecules 2021, 26, 4823. https://doi.org/10.3390/molecules261648231420-304910.3390/molecules2616482334443411https://www.mdpi.com/1420-3049/26/16/4823info: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:RCAAP2023-07-21T12:52:19Zoai:repositorium.sdum.uminho.pt:1822/74633Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:51:23.870015Repositório 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 of novel methyl 7-[(hetero)arylamino]thieno[2,3-b] pyrazine-6-carboxylates and antitumor activity evaluation: effects in human tumor cells growth, cell cycle analysis, apoptosis and toxicity in non-tumor cells |
title |
Synthesis of novel methyl 7-[(hetero)arylamino]thieno[2,3-b] pyrazine-6-carboxylates and antitumor activity evaluation: effects in human tumor cells growth, cell cycle analysis, apoptosis and toxicity in non-tumor cells |
spellingShingle |
Synthesis of novel methyl 7-[(hetero)arylamino]thieno[2,3-b] pyrazine-6-carboxylates and antitumor activity evaluation: effects in human tumor cells growth, cell cycle analysis, apoptosis and toxicity in non-tumor cells Rodrigues, Juliana M. C–N Buchwald–Hartwig coupling Thieno[2,3-b]pyrazines Antitumor activity Gastric adenocarcinoma Cell cycle Apoptosis thieno[2 3-b]pyrazines Science & Technology |
title_short |
Synthesis of novel methyl 7-[(hetero)arylamino]thieno[2,3-b] pyrazine-6-carboxylates and antitumor activity evaluation: effects in human tumor cells growth, cell cycle analysis, apoptosis and toxicity in non-tumor cells |
title_full |
Synthesis of novel methyl 7-[(hetero)arylamino]thieno[2,3-b] pyrazine-6-carboxylates and antitumor activity evaluation: effects in human tumor cells growth, cell cycle analysis, apoptosis and toxicity in non-tumor cells |
title_fullStr |
Synthesis of novel methyl 7-[(hetero)arylamino]thieno[2,3-b] pyrazine-6-carboxylates and antitumor activity evaluation: effects in human tumor cells growth, cell cycle analysis, apoptosis and toxicity in non-tumor cells |
title_full_unstemmed |
Synthesis of novel methyl 7-[(hetero)arylamino]thieno[2,3-b] pyrazine-6-carboxylates and antitumor activity evaluation: effects in human tumor cells growth, cell cycle analysis, apoptosis and toxicity in non-tumor cells |
title_sort |
Synthesis of novel methyl 7-[(hetero)arylamino]thieno[2,3-b] pyrazine-6-carboxylates and antitumor activity evaluation: effects in human tumor cells growth, cell cycle analysis, apoptosis and toxicity in non-tumor cells |
author |
Rodrigues, Juliana M. |
author_facet |
Rodrigues, Juliana M. Calhelha, Ricardo C. Nogueira, António Ferreira, Isabel C. F. R. Barros, Lillian Queiroz, Maria João R. P. |
author_role |
author |
author2 |
Calhelha, Ricardo C. Nogueira, António Ferreira, Isabel C. F. R. Barros, Lillian Queiroz, Maria João R. P. |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Rodrigues, Juliana M. Calhelha, Ricardo C. Nogueira, António Ferreira, Isabel C. F. R. Barros, Lillian Queiroz, Maria João R. P. |
dc.subject.por.fl_str_mv |
C–N Buchwald–Hartwig coupling Thieno[2,3-b]pyrazines Antitumor activity Gastric adenocarcinoma Cell cycle Apoptosis thieno[2 3-b]pyrazines Science & Technology |
topic |
C–N Buchwald–Hartwig coupling Thieno[2,3-b]pyrazines Antitumor activity Gastric adenocarcinoma Cell cycle Apoptosis thieno[2 3-b]pyrazines Science & Technology |
description |
Several novel methyl 7-[(hetero)arylamino]thieno[2,3-<i>b</i>]pyrazine-6-carboxylates were synthesized by Pd-catalyzed C–N Buchwald–Hartwig cross-coupling of either methyl 7-aminothieno[3,2-<i>b</i>]pyrazine-6-carboxylate with (hetero)arylhalides or 7-bromothieno[2,3-<i>b</i>]pyrazine-6-carboxylate with (hetero)arylamines in good-to-excellent yields (50% quantitative yield), using different reaction conditions, namely ligands and solvents, due to the different electronic character of the substrates. The antitumoral potential of these compounds was evaluated in four human tumor cell lines: gastric adenocarcinoma (AGS), colorectal adenocarcinoma (CaCo-2), breast carcinoma (MCF7), and non-small-cell lung carcinoma (NCI-H460) using the SRB assay, and it was possible to establish some structure–activity relationships. Furthermore, they did not show relevant toxicity against a non-tumor cell line culture from the African green monkey kidney (Vero). The most promising compounds (GI<sub>50</sub> ≤ 11 µM), showed some selectivity either against AGS or CaCo-2 cell lines without toxicity at their GI<sub>50</sub> values. The effects of the methoxylated compounds <b>2b</b> (2-OMeC<sub>6</sub>H<sub>4</sub>), <b>2f</b> and <b>2g</b> (3,4- or 3,5-diOMeC<sub>6</sub>H<sub>3</sub>, respectively) on the cell cycle profile and induction of apoptosis were further studied in the AGS cell line. Nevertheless, even for the most active (GI<sub>50</sub> = 7.8 µM) and selective compound (<b>2g</b>) against this cell line, it was observed that a huge number of dead cells gave rise to an atypical distribution on the cell cycle profile and that these cells were not apoptotic, which points to a different mechanism of action for the AGS cell growth inhibition. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-08-10 2021-08-10T00:00:00Z |
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/1822/74633 |
url |
http://hdl.handle.net/1822/74633 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Rodrigues, J.M.; Calhelha, R.C.; Nogueira, A.; Ferreira, I.C.F.R.; Barros, L.; Queiroz, M.-J.R.P. Synthesis of Novel Methyl 7-[(Hetero)arylamino]thieno[2,3-b]pyrazine-6-carboxylates and Antitumor Activity Evaluation: Effects in Human Tumor Cells Growth, Cell Cycle Analysis, Apoptosis and Toxicity in Non-Tumor Cells. Molecules 2021, 26, 4823. https://doi.org/10.3390/molecules26164823 1420-3049 10.3390/molecules26164823 34443411 https://www.mdpi.com/1420-3049/26/16/4823 |
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 |
Multidisciplinary Digital Publishing Institute (MDPI) |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
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 |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
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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1799133102102020096 |