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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 cells

2021Journal article Open access
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dc.contributor.authorRodrigues, Juliana M.
dc.contributor.authorCalhelha, Ricardo C.
dc.contributor.authorNogueira, António José M.
dc.contributor.authorFerreira, Isabel C.F.R.
dc.contributor.authorBarros, Lillian
dc.contributor.authorQueiroz, Maria João R.P.
dc.date.accessioned2018-02-19T10:00:00Z
dc.date.accessioned2021-11-30T17:11:09Z
dc.date.available2018-01-19T10:00:00Z
dc.date.available2021-11-30T17:11:09Z
dc.date.issued2021
dc.description.abstractSeveral novel methyl 7-[(hetero)arylamino]thieno[2,3-b]pyrazine-6-carboxylates were synthe-sized by Pd-catalyzed C–N Buchwald–Hartwig cross-coupling of either methyl 7-aminothieno[3,2-b] pyrazine-6-carboxylate with (hetero)arylhalides or 7-bromothieno[2,3-b]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 (GI50 ≤ 11 µM), showed some selectivity either against AGS or CaCo-2 cell lines without toxicity at their GI50 values. The effects of the methoxylated compounds 2b (2-OMeC6 H4 ), 2f and 2g (3,4-or 3,5-diOMeC6 H3, respectively) on the cell cycle profile and induction of apoptosis were further studied in the AGS cell line. Nevertheless, even for the most active (GI50 = 7.8 µM) and selective compound (2g) 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.en_EN
dc.description.sponsorshipThis 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.
dc.description.versioninfo:eu-repo/semantics/publishedVersionen_EN
dc.identifier.citationRodrigues, Juliana M.; Calhelha, Ricardo C.; Nogueira, António; Ferreira, Isabel C.F.R.; Barros, Lillian; Queiroz, Maria João R.P. (2021). 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. ISSN 1420-3049. 26:16, p. 1-14en_EN
dc.identifier.doi10.3390/molecules26164823en_EN
dc.identifier.urihttp://hdl.handle.net/10198/23413
dc.language.isoeng
dc.peerreviewedyesen_EN
dc.relationSynthesis of new potential biological active compounds based on thiophene fused N-heterocycle scaffolds using cross-couplings, C-H activation and intra/intermolecular cyclizations Título antigo: Synthesis of new potential biological active compounds based on thiophene fused N-heterocycle scaffolds using cross-couplings, C-H activation and intramolecular cyclizations
dc.relationChemistry Research Centre of the University of Minho
dc.relationMountain Research Center
dc.subjectAntitumor activityen_EN
dc.subjectApoptosisen_EN
dc.subjectCell cycleen_EN
dc.subjectC–N buchwald–hartwig couplingen_EN
dc.subjectGastric adenocarcinomaen_EN
dc.subjectThieno[2,3-b]pyrazinesen_EN
dc.titleSynthesis 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 cellsen_EN
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleSynthesis of new potential biological active compounds based on thiophene fused N-heterocycle scaffolds using cross-couplings, C-H activation and intra/intermolecular cyclizations Título antigo: Synthesis of new potential biological active compounds based on thiophene fused N-heterocycle scaffolds using cross-couplings, C-H activation and intramolecular cyclizations
oaire.awardTitleChemistry Research Centre of the University of Minho
oaire.awardTitleMountain Research Center
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/POR_NORTE/SFRH%2FBD%2F115844%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FQUI%2F00686%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00690%2F2020/PT
oaire.fundingStreamPOR_NORTE
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameCalhelha
person.familyNameNogueira
person.familyNameFerreira
person.familyNameBarros
person.givenNameRicardo C.
person.givenNameAntónio José M.
person.givenNameIsabel C.F.R.
person.givenNameLillian
person.identifier144781
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person.identifier.orcid0000-0002-6801-4578
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person.identifier.orcid0000-0003-4910-4882
person.identifier.orcid0000-0002-9050-5189
person.identifier.ridJ-2172-2014
person.identifier.ridE-8500-2013
person.identifier.ridJ-3600-2013
person.identifier.scopus-author-id6507978333
person.identifier.scopus-author-id55865568268
person.identifier.scopus-author-id36868826600
person.identifier.scopus-author-id35236343600
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccessen_EN
rcaap.typearticleen_EN
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