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Combining 1,3-ditriazolyl-benzene and quinoline to discover a new G-quadruplex interactive small molecule active against cancer stem-like cells

2019-06-04Artigo científico Acesso restrito
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dc.contributor.authorMendes, Maria Eduarda
dc.contributor.authorCadoni, Enrico
dc.contributor.authorCarneiro, Filipa
dc.contributor.authorAfonso, Marta
dc.contributor.authorBrito, Hugo
dc.contributor.authorLavrado, João
dc.contributor.authorSantos, Daniel J. V. A. dos
dc.contributor.authorVítor, Jorge M. B.
dc.contributor.authorNeidle, Stephen
dc.contributor.authorRodrigues, Cecília M. P.
dc.contributor.authorPaulo, Alexandra
dc.date.accessioned2023-08-16T11:45:56Z
dc.date.available2023-08-16T11:45:56Z
dc.date.issued2019-06-04
dc.date.updated2022-10-19T21:50:51Z
dc.description.abstractQuadruplex nucleic acids are promising targets for cancer therapy. In this study we used a fragment-based approach to create new flexible G-quadruplex (G4) DNA-interactive small molecules with good calculated oral drug-like properties, based on quinoline and triazole heterocycles. G4 melting temperature and polymerase chain reaction (PCR)-stop assays showed that two of these compounds are selective G4 ligands, as they were able to induce and stabilize G4s in a dose- and DNA sequence-dependent manner. Molecular docking studies have suggested plausible quadruplex binding to both the Gquartet and groove, with the quinoline module playing the major role. Compounds were screened for cytotoxicity against four cancer cell lines, where 4,4’-(4,4’-(1,3-phenylene)bis(1H1,2,3-triazole-4,1-diyl))bis(1-methylquinolin-1-ium) (1 d) showed the greater activity. Importantly, dose–response curves show that 1 d is cytotoxic in the human colon cancer HT-29 cell line enriched in cancer stem-like cells, a subpopulation of cells implicated in chemoresistance. Overall, this study identified a new small molecule as a promising lead for the development of drugs targeting G4 in cancer stem cells.pt_PT
dc.description.sponsorshipThis work received funding from European Structural & Investment Funds through the COMPETE Program—Programa Operacional de Lisboa under Program grant LISBOA-01-0145-FEDER-016405, and from National Funds through Fundação para a Ciência e Tecnologia (FCT) under Program grant SAICTPAC/0019/2015. J.B.V.′s research group was financed by New England Biolabs, Inc. (USA).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1002/cmdc.201900243pt_PT
dc.identifier.issn1860-7179
dc.identifier.issn1860-7187
dc.identifier.slugcv-prod-625676
dc.identifier.urihttp://hdl.handle.net/10451/58885
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWiley-VCHpt_PT
dc.relationPRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
dc.relation.publisherversionMendes E, Cadoni E, Carneiro F, Afonso MB, Brito H, Lavrado J, et al. Combining 1,3‐ditriazolylbenzene and quinoline to discover a new g‐quadruplex‐interactive small molecule active against cancer stem‐like cells. ChemMedChem [Internet]. 17 de julho de 2019;14(14):1325–8. Disponível em: https://onlinelibrary.wiley.com/doi/10.1002/cmdc.201900243pt_PT
dc.titleCombining 1,3-ditriazolyl-benzene and quinoline to discover a new G-quadruplex interactive small molecule active against cancer stem-like cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberSAICTPAC/0019/2015
oaire.awardTitlePRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/SAICTPAC%2F0019%2F2015/PT
oaire.citation.endPage1328pt_PT
oaire.citation.startPage1325pt_PT
oaire.citation.titleChemMedChempt_PT
oaire.citation.volume14pt_PT
oaire.fundingStream9471 - RIDTI
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project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.cv.cienciaidFF19-99F4-3964 | Jorge Manuel Barreto Vítor
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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