Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance
COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. 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...
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MDPI AG
2022-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/18/4455 |
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| author | Vivien Pósa Alessia Stefanelli Julia H. Bormio Nunes Sonja Hager Marlene Mathuber Nóra V. May Walter Berger Bernhard K. Keppler Christian R. Kowol Éva A. Enyedy Petra Heffeter |
| author_facet | Vivien Pósa Alessia Stefanelli Julia H. Bormio Nunes Sonja Hager Marlene Mathuber Nóra V. May Walter Berger Bernhard K. Keppler Christian R. Kowol Éva A. Enyedy Petra Heffeter |
| author_sort | Vivien Pósa |
| collection | DOAJ |
| description | COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. 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-NMe<sub>2</sub> and COTI-NMeCy), and the non-substituted analogue (COTI-NH<sub>2</sub>) 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-NMe<sub>2</sub> as an interesting new drug candidate with improved anticancer activity and resistance profile. |
| first_indexed | 2024-03-10T00:29:22Z |
| format | Article |
| id | doaj.art-3688b614d8fd4e1899b1ede1b72ed230 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T00:29:22Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3688b614d8fd4e1899b1ede1b72ed2302023-11-23T15:27:35ZengMDPI AGCancers2072-66942022-09-011418445510.3390/cancers14184455Thiosemicarbazone Derivatives Developed to Overcome COTI-2 ResistanceVivien Pósa0Alessia Stefanelli1Julia H. Bormio Nunes2Sonja Hager3Marlene Mathuber4Nóra V. May5Walter Berger6Bernhard K. Keppler7Christian R. Kowol8Éva A. Enyedy9Petra Heffeter10Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre and MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, HungaryCenter for Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, AustriaInstitute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, AustriaCenter for Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, AustriaInstitute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, AustriaCentre for Structural Science, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryCenter for Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, AustriaInstitute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, AustriaInstitute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, AustriaDepartment of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre and MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, HungaryCenter for Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, AustriaCOTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. 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-NMe<sub>2</sub> and COTI-NMeCy), and the non-substituted analogue (COTI-NH<sub>2</sub>) 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-NMe<sub>2</sub> as an interesting new drug candidate with improved anticancer activity and resistance profile.https://www.mdpi.com/2072-6694/14/18/4455thiosemicarbazonesCOTI-2zinccopperironmetal binding |
| spellingShingle | Vivien Pósa Alessia Stefanelli Julia H. Bormio Nunes Sonja Hager Marlene Mathuber Nóra V. May Walter Berger Bernhard K. Keppler Christian R. Kowol Éva A. Enyedy Petra Heffeter Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance Cancers thiosemicarbazones COTI-2 zinc copper iron metal binding |
| title | Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance |
| title_full | Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance |
| title_fullStr | Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance |
| title_full_unstemmed | Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance |
| title_short | Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance |
| title_sort | thiosemicarbazone derivatives developed to overcome coti 2 resistance |
| topic | thiosemicarbazones COTI-2 zinc copper iron metal binding |
| url | https://www.mdpi.com/2072-6694/14/18/4455 |
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