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New (Iso)quinolinyl-pyridine-2,6-dicarboxamide G-Quadruplex Stabilizers. A Structure-Activity Relationship Study

2021-07-13Journal article Open access
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dc.contributor.authorCadoni, Enrico
dc.contributor.authorMagalhães, Pedro R.
dc.contributor.authorEmídio, Rita M.
dc.contributor.authorMendes, Maria Eduarda
dc.contributor.authorVítor, Jorge M. B.
dc.contributor.authorCarvalho, Josué
dc.contributor.authorCruz, Carla
dc.contributor.authorVictor, Bruno L.
dc.contributor.authorPaulo, Alexandra
dc.date.accessioned2023-08-14T12:37:48Z
dc.date.available2023-08-14T12:37:48Z
dc.date.issued2021-07-13
dc.date.updated2022-10-19T21:34:05Z
dc.description.abstractG-quadruplex (G4)-interactive small molecules have a wide range of potential applications, not only as drugs, but also as sensors of quadruplex structures. The purpose of this work is the synthesis of analogues of the bis-methylquinolinium-pyridine-2,6-dicarboxamide G4 ligand 360A, to identify relevant structure–activity relationships to apply to the design of other G4-interactive small molecules bearing bis-quinoline or bis-isoquinoline moieties. Thermal denaturation experiments revealed that non-methylated derivatives with a relative 1,4 position between the amide linker and the nitrogen of the quinoline ring are moderate G4 stabilizers, with a preference for the hybrid h-Telo G4, a 21-nt sequence present in human telomeres. Insertion of a positive charge upon methylation of quinoline/isoquinoline nitrogen increases compounds’ ability to selectively stabilize G4s compared to duplex DNA, with a preference for parallel structures. Among these, compounds having a relative 1,3-position between the charged methylquinolinium/isoquinolinium nitrogen and the amide linker are the best G4 stabilizers. More interestingly, these ligands showed different capacities to selectively block DNA polymerization in a PCR-stop assay and to induce G4 conformation switches of hybrid h-Telo G4. Molecular dynamic simulations with the parallel G4 formed by a 21-nt sequence present in k-RAS gene promoter, showed that the relative spatial orientation of the two methylated quinoline/isoquinoline rings determines the ligands mode and strength of binding to G4s.pt_PT
dc.description.sponsorshipThis research was funded by European Structural & Investment Funds through the COMPETE Program—Programa Operacional de Lisboa under Program grant LISBOA-01-0145-FEDER-016405, and from Fundação para a Ciência e Tecnologia (FCT, Portugal), project grant SAICTPAC/0019/2015, UIDP/04138/2020 of iMed, UIDB/00709/2020 of CICS, PTDC/BIA-BFS/28419/2017, strategic project UIDB/04046/2020 (BioISI) and project ref. IF/00959/2015 funded by Fundo Social Europeu e Programa Operacional Potencial Humano. J.V.’s research group was financed by New England Biolabs, Inc. (Ipswich, MA, USA).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCadoni E, Magalhães PR, Emídio RM, Mendes E, Vítor J, Carvalho J, et al. New (Iso)quinolinyl-pyridine-2,6-dicarboxamide G-Quadruplex Stabilizers. A Structure-Activity Relationship Study. Pharmaceuticals [Internet]. 2021 Jul 13;14(7):669. Available from: http://dx.doi.org/10.3390/ph14070669pt_PT
dc.identifier.doi10.3390/ph14070669pt_PT
dc.identifier.slugcv-prod-2558469
dc.identifier.urihttp://hdl.handle.net/10451/58868
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationLISBOA-01-0145-FEDER-016405pt_PT
dc.relationPRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
dc.relationResearch Institute for Medicines
dc.relationHealth Sciences Research Centre
dc.relationBiosystems and Integrative Sciences Institute
dc.relationNucleolin targeting by G-quadruplex aptamers for cervical cancer therapy
dc.relation.publisherversionhttps://www.mdpi.com/1424-8247/14/7/669pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectQuinolinept_PT
dc.subjectIsoquinolinept_PT
dc.subjectG-quadruplex ligandspt_PT
dc.subjectk-RASpt_PT
dc.subjectc-MYCpt_PT
dc.subjectTelomerept_PT
dc.subjectSARpt_PT
dc.subjectpyridine-dicarboxamidept_PT
dc.subjectMolecular dynamicspt_PT
dc.titleNew (Iso)quinolinyl-pyridine-2,6-dicarboxamide G-Quadruplex Stabilizers. A Structure-Activity Relationship Studypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitlePRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleHealth Sciences Research Centre
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardTitleNucleolin targeting by G-quadruplex aptamers for cervical cancer therapy
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/SAICTPAC%2F0019%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
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oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04046%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00959%2F2015%2FCP1300%2FCT0002/PT
oaire.citation.issue7pt_PT
oaire.citation.startPage669pt_PT
oaire.citation.titlePharmaceuticalspt_PT
oaire.citation.volume14pt_PT
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rcaap.cv.cienciaidFF19-99F4-3964 | Jorge Manuel Barreto Vítor
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