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These complexes, having pendant nitrogen heterocycles, exhibited increased water\u2010solubility, lower lipophilicity at physiological pH and more negative Cu(II)\/Cu(I) redox potential, when compared with the parental complex. The cytotoxic evaluation performed in a panel of cancer cells lines showed an important effect of the metal complexation, and furthermore correlated well with the cellular uptake of the compounds, which was determined using their <jats:sup>64<\/jats:sup>Cu congeners. The radiolabelling of the complexes also allowed more detailed uptake studies, with the results suggesting an active transport or facilitated diffusion mechanism for the cellular uptake of <jats:sup><jats:bold>64<\/jats:bold><\/jats:sup><jats:bold>CuGTSMpip<\/jats:bold> and <jats:sup><jats:bold>64<\/jats:bold><\/jats:sup><jats:bold>CuGTSMmor<\/jats:bold>, with pendant piperidine and morpholine rings, respectively. Additionally, a comparative study with the corresponding Cu(II) complexes derived from ATSM (diacetyl\u2010bis(N<jats:sup>4<\/jats:sup>\u2010methylthiosemicarbazonato) that we have previously described, demonstrated a clear difference in their lysosomotropic properties in particular for the piperidine derivatives. From this study, <jats:bold>CuGTSMpip<\/jats:bold> emerged as the most promising compound to be further evaluated as an anticancer metallodrug.<\/jats:p>","DOI":"10.1002\/ejic.202100168","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T22:15:36Z","timestamp":1614377736000},"page":"1337-1348","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Anticancer Activity and Mode of Action of Copper(II)\u2010Bis(thiosemicarbazonato) Complexes with Pendant Nitrogen Heterocycles"],"prefix":"10.1002","volume":"2021","author":[{"given":"Elisa","family":"Palma","sequence":"first","affiliation":[{"name":"C2TN Centro de Ci\u00eancias e Tecnologias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"}]},{"given":"Paula","family":"Raposinho","sequence":"additional","affiliation":[{"name":"C2TN Centro de Ci\u00eancias e Tecnologias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"},{"name":"DECN Departamento de Engenharia e Ci\u00eancias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"}]},{"given":"Maria Paula Cabral","family":"Campello","sequence":"additional","affiliation":[{"name":"C2TN Centro de Ci\u00eancias e Tecnologias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"},{"name":"DECN Departamento de Engenharia e Ci\u00eancias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"}]},{"given":"Dulce","family":"Belo","sequence":"additional","affiliation":[{"name":"C2TN Centro de Ci\u00eancias e Tecnologias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"},{"name":"DECN Departamento de Engenharia e Ci\u00eancias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"}]},{"given":"Joana F.","family":"Guerreiro","sequence":"additional","affiliation":[{"name":"C2TN Centro de Ci\u00eancias e Tecnologias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"}]},{"given":"V\u00edtor","family":"Alves","sequence":"additional","affiliation":[{"name":"CIBIT\/ICNAS Instituto de Ci\u00eancias Nucleares Aplicadas \u00e0 Sa\u00fade Universidade de Coimbra  Coimbra Portugal"}]},{"given":"Alexandra","family":"Fonseca","sequence":"additional","affiliation":[{"name":"CIBIT\/ICNAS Instituto de Ci\u00eancias Nucleares Aplicadas \u00e0 Sa\u00fade Universidade de Coimbra  Coimbra Portugal"}]},{"given":"Antero J.","family":"Abrunhosa","sequence":"additional","affiliation":[{"name":"CIBIT\/ICNAS Instituto de Ci\u00eancias Nucleares Aplicadas \u00e0 Sa\u00fade Universidade de Coimbra  Coimbra Portugal"}]},{"given":"Ant\u00f3nio","family":"Paulo","sequence":"additional","affiliation":[{"name":"C2TN Centro de Ci\u00eancias e Tecnologias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"},{"name":"DECN Departamento de Engenharia e Ci\u00eancias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0646-1687","authenticated-orcid":false,"given":"Filipa","family":"Mendes","sequence":"additional","affiliation":[{"name":"C2TN Centro de Ci\u00eancias e Tecnologias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"},{"name":"DECN Departamento de Engenharia e Ci\u00eancias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa  Estrada Nacional 10 2695-066 Bobadela LRS Portugal"}]}],"member":"311","published-online":{"date-parts":[[2021,3,18]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"\u00a0"},{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr400135x"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.2174\/1871520616666160310142012"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00238"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1039\/C6MT00105J"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/tcr.201500292"},{"key":"e_1_2_7_7_1","unstructured":"\u00a0"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-003-1130-4"},{"key":"e_1_2_7_9_2","first-page":"193","volume":"53","author":"Holland J. 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