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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Main Authors: Pósa Vivien
Stefanelli Alessia
Nunes Julia H. Bormio
Hager Sonja
Mathuber Marlene
May Nóra Veronika
Berger Walter
Keppler Bernhard K.
Kowol Christian R.
Enyedy Éva Anna
Heffeter Petra
Format: Article
Published: 2022
Series:CANCERS 14 No. 18
Subjects:
doi:10.3390/cancers14184455

mtmt:33097691
Online Access:http://publicatio.bibl.u-szeged.hu/25102
Description
Summary: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-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.
Physical Description:Terjedelem: 27 p.-Azonosító: 4455
ISSN:2072-6694