{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T20:43:26Z","timestamp":1773434606697,"version":"3.50.1"},"reference-count":94,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SAICTPAC\/0019\/2015, UIDP\/04138\/2020 of iMed, UIDB\/00709\/2020 of CICS, PTDC\/BIA-BFS\/28419\/2017, strategic project UIDB\/04046\/2020-UIDP\/04046\/2020 (BioISI)"],"award-info":[{"award-number":["SAICTPAC\/0019\/2015, UIDP\/04138\/2020 of iMed, UIDB\/00709\/2020 of CICS, PTDC\/BIA-BFS\/28419\/2017, strategic project UIDB\/04046\/2020-UIDP\/04046\/2020 (BioISI)"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Structural &amp; Investment Funds","award":["SAICTPAC\/0019\/2015"],"award-info":[{"award-number":["SAICTPAC\/0019\/2015"]}]},{"name":"COMPETE Program","award":["LISBOA-01-0145-FEDER-016405"],"award-info":[{"award-number":["LISBOA-01-0145-FEDER-016405"]}]},{"name":"Fundo Social Europeu e Programa Operacional Potencial Humano","award":["IF\/00959\/2015"],"award-info":[{"award-number":["IF\/00959\/2015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>G-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\u2013activity 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\u2019 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.<\/jats:p>","DOI":"10.3390\/ph14070669","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T22:25:31Z","timestamp":1626215131000},"page":"669","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["New (Iso)quinolinyl-pyridine-2,6-dicarboxamide G-Quadruplex Stabilizers. A Structure-Activity Relationship Study"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5585-7579","authenticated-orcid":false,"given":"Enrico","family":"Cadoni","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4118-2800","authenticated-orcid":false,"given":"Pedro R.","family":"Magalh\u00e3es","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal"}]},{"given":"Rita M.","family":"Em\u00eddio","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal"}]},{"given":"Eduarda","family":"Mendes","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6486-3444","authenticated-orcid":false,"given":"Jorge","family":"V\u00edtor","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology and Health Technologies, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3035-4881","authenticated-orcid":false,"given":"Josu\u00e9","family":"Carvalho","sequence":"additional","affiliation":[{"name":"CICS-UBI-Centro de Investiga\u00e7\u00e3o em Ci\u00eancias da Sa\u00fade, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6630-1242","authenticated-orcid":false,"given":"Carla","family":"Cruz","sequence":"additional","affiliation":[{"name":"CICS-UBI-Centro de Investiga\u00e7\u00e3o em Ci\u00eancias da Sa\u00fade, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6472-5700","authenticated-orcid":false,"given":"Bruno L.","family":"Victor","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1433-5402","authenticated-orcid":false,"given":"Alexandra","family":"Paulo","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. 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