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As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe2 and COTI-NMeCy), and the non-substituted analogue (COTI-NH2) with iron, copper, and zinc ions was characterized in detail. Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe2 as an interesting new drug candidate with improved anticancer activity and resistance profile.<\/jats:p>","DOI":"10.3390\/cancers14184455","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T20:50:45Z","timestamp":1663188645000},"page":"4455","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance"],"prefix":"10.3390","volume":"14","author":[{"given":"Vivien","family":"P\u00f3sa","sequence":"first","affiliation":[{"name":"Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre and MTA-SZTE Lend\u00fclet Functional Metal Complexes Research Group, University of Szeged, D\u00f3m t\u00e9r 7, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5262-1146","authenticated-orcid":false,"given":"Alessia","family":"Stefanelli","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8113-6679","authenticated-orcid":false,"given":"Julia H. Bormio","family":"Nunes","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria"},{"name":"Inorganic Chemistry Department, Institute of Chemistry, University of Campinas\u2014UNICAMP, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8221-1044","authenticated-orcid":false,"given":"Sonja","family":"Hager","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria"},{"name":"Research Cluster \u2018\u2018Translational Cancer Therapy Research\u2019\u2019, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Mathuber","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4770-4681","authenticated-orcid":false,"given":"N\u00f3ra V.","family":"May","sequence":"additional","affiliation":[{"name":"Centre for Structural Science, Research Centre for Natural Sciences, Magyar Tud\u00f3sok K\u00f6r\u00fatja 2, H-1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0014-1658","authenticated-orcid":false,"given":"Walter","family":"Berger","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria"},{"name":"Research Cluster \u2018\u2018Translational Cancer Therapy Research\u2019\u2019, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard K.","family":"Keppler","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria"},{"name":"Research Cluster \u2018\u2018Translational Cancer Therapy Research\u2019\u2019, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8311-1632","authenticated-orcid":false,"given":"Christian R.","family":"Kowol","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria"},{"name":"Research Cluster \u2018\u2018Translational Cancer Therapy Research\u2019\u2019, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8058-8128","authenticated-orcid":false,"given":"\u00c9va A.","family":"Enyedy","sequence":"additional","affiliation":[{"name":"Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre and MTA-SZTE Lend\u00fclet Functional Metal Complexes Research Group, University of Szeged, D\u00f3m t\u00e9r 7, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6401-8646","authenticated-orcid":false,"given":"Petra","family":"Heffeter","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria"},{"name":"Research Cluster \u2018\u2018Translational Cancer Therapy Research\u2019\u2019, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.2174\/092986712800609706","article-title":"Iron chelators for the treatment of cancer","volume":"19","author":"Yu","year":"2012","journal-title":"Curr. 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