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Targeting DNA G4 structures has emerged as a promising anticancer therapy, highlighting the need for new G4 ligands with reduced number of cationic groups to ensure lower toxicity. Herein, the synthesis of mono\u2010 and di\u2010substituted 5\u2010amino\u201011H\u2010indolo[3,2\u2010<jats:italic>c<\/jats:italic>]isoquinolines is reported. Fluorescence spectroscopy studies indicate that substitution in position 11 dictates the preference of binding to different G4. Compound <jats:bold>10<\/jats:bold>, which features an ethylpyrrolidine side chain, demonstrates a binding preference by one order of magnitude for parallel c\u2010MYCG4 (<jats:italic>K<\/jats:italic><jats:sub>b<\/jats:sub>\u2009=\u200910<jats:sup>7<\/jats:sup>\u2009<jats:sc>m<\/jats:sc><jats:sup>\u22121<\/jats:sup>), over parallel k\u2010RASG4 (<jats:italic>K<\/jats:italic><jats:sub>b<\/jats:sub>\u2009=\u200910<jats:sup>6<\/jats:sup>\u2009<jats:sc>m<\/jats:sc><jats:sup>\u22121<\/jats:sup>), and hybrid TeloG4 and dsDNA (<jats:italic>K<\/jats:italic><jats:sub>b<\/jats:sub>\u2009=\u200910<jats:sup>5<\/jats:sup>\u2009<jats:sc>m<\/jats:sc><jats:sup>\u22121<\/jats:sup>). Molecular docking studies reveal that <jats:bold>10<\/jats:bold> can bind not only to the flat G\u2010quartets but also to bridge between two loops of c\u2010MYCG4 through hydrogen bonds, which may explain its capacity to discriminate between G4. Moreover, <jats:bold>10<\/jats:bold> drastically reduces the cell viability of breast cancer cells at a concentration of 10\u2009\u03bc<jats:sc>m<\/jats:sc>. Overall, herein, the discovery of a new potent and selective G4 ligand, with reduced number of side chains and with antiproliferative activity in cancer cells, is reported, which deserves to be further investigated.<\/jats:p>","DOI":"10.1002\/cmdc.202401019","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T07:51:41Z","timestamp":1742975501000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploiting the 5\u2010Amino\u201011H\u2010Indolo[3,2\u2010c]isoquinoline Core to Achieve Better G\u2010Quadruplex Ligands for Cancer Therapy"],"prefix":"10.1002","volume":"20","author":[{"given":"Israa M.","family":"Aljnadi","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy Research Institute for Medicines (iMed.Ulisboa) Universidade de Lisboa  1649\u2010003 Lisbon Portugal"},{"name":"BioISI \u2010 Biosystems and Integrative Sciences Institute Faculty of Sciences Universidade de Lisboa  Campo Grande, C8 building 1749\u2010016 Lisboa Portugal"}]},{"given":"Barbara","family":"Bahls","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Research Institute for Medicines (iMed.Ulisboa) Universidade de Lisboa  1649\u2010003 Lisbon Portugal"},{"name":"BioISI \u2010 Biosystems and Integrative Sciences Institute Faculty of Sciences Universidade de Lisboa  Campo Grande, C8 building 1749\u2010016 Lisboa Portugal"}]},{"given":"No\u00e9lia","family":"Duarte","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Research Institute for Medicines (iMed.Ulisboa) Universidade de Lisboa  1649\u2010003 Lisbon Portugal"}]},{"given":"Bruno L.","family":"Victor","sequence":"additional","affiliation":[{"name":"BioISI \u2010 Biosystems and Integrative Sciences Institute Faculty of Sciences Universidade de Lisboa  Campo Grande, C8 building 1749\u2010016 Lisboa Portugal"},{"name":"Accelbio: Collaborative Laboratory to Foster Translation and Drug Discovery  3030\u2010197 Cantanhede Portugal"}]},{"given":"Eduarda","family":"Mendes","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Research Institute for Medicines (iMed.Ulisboa) Universidade de Lisboa  1649\u2010003 Lisbon Portugal"}]},{"given":"Sergio P.","family":"Cam\u00f5es","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Research Institute for Medicines (iMed.Ulisboa) Universidade de Lisboa  1649\u2010003 Lisbon Portugal"}]},{"given":"Joana P.","family":"Miranda","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Research Institute for Medicines (iMed.Ulisboa) Universidade de Lisboa  1649\u2010003 Lisbon Portugal"}]},{"given":"Ermelinda","family":"Ma\u00e7\u00f4as","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural (CQE) and Instiute of Molecular Sciences (IMS) Departamento de Qu\u00edmica Instituto Superior T\u00e9cnico Universidade de Lisboa  Av. Rovisco Pais 1049\u2010001 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  1649\u2010003 Lisbon Portugal"}]}],"member":"311","published-online":{"date-parts":[[2025,4,10]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl655"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja501500c"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpls.2017.01163"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz179"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki553"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3295"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2021.09.004"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3662"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/10409238.2022.2121803"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trechm.2019.07.002"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.0c00431"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab187"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab609"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24198-2"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph15030300"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11030969"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2024.122481"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chempr.2018.02.014"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2022.128862"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.armc.2024.09.005"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules29153653"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2015.08.006"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep09696"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41929-021-00652-8"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2006.01.129"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo010643c"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/128_2012_347"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2020.11.013"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cptc.202400241"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1039\/b604686j"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac090"},{"key":"e_1_2_7_33_1","unstructured":"A.Margarida Duarte e Silva S\u00edntese de Compostos Ind\u00f3licos Ativadores DA P53 MSc Thesis University of Lisbon \u2010 Faculty of Pharmacy2020."},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21334"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21600"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph15030368"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202401019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T10:20:13Z","timestamp":1760264413000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202401019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,10]]},"references-count":35,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,6,2]]}},"alternative-id":["10.1002\/cmdc.202401019"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202401019","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,10]]},"assertion":[{"value":"2024-12-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202401019"}}