Anticancer Activity and Mode of Action of Copper(II)‐Bis(thiosemicarbazonato) Complexes with Pendant Nitrogen Heterocycles. Issue 14 (18th March 2021)

• Record Type: Journal Article
• Authors: Palma, Elisa; Raposinho, Paula; Campello, Maria Paula Cabral; Belo, Dulce; Guerreiro, Joana F.; Alves, Vítor; Fonseca, Alexandra; Abrunhosa, Antero J.; Paulo, António; Mendes, Filipa
• Is Part Of: European journal of inorganic chemistry. Issue 14(2021)
• Page Start: 1337
• Page End: 1348
• Publication Date: 2021-03-18
• Subjects: Antitumor agents -- Bis(thiosemicarbazone)s -- Cellular studies -- Copper -- Metallodrugs; Chemistry, Inorganic -- Periodicals; Organometallic chemistry -- Periodicals; Bioinorganic chemistry -- Periodicals; Solid state chemistry -- Periodicals; 546
• DOI: 10.1002/ejic.202100168
• Languages: English
• ISSNs: 1434-1948

Abstract

Abstract: Exploring the potential of bis(thiosemicarbazones) (BTSC), a new family of BTSC ligands derived from GTSM (glyoxal‐bis(N4‐methylthiosemicarbazonato) and respective Cu II BTSC complexes were synthesized. These complexes, having pendant nitrogen heterocycles, exhibited increased water‐solubility, 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 64 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 64 CuGTSMpip and 64 CuGTSMmor, with pendant piperidine and morpholine rings, respectively. Additionally, a comparative study with the corresponding Cu(II) complexes derived from ATSM (diacetyl‐bis(N 4 ‐methylthiosemicarbazonato) that we have previously described, demonstrated a clear difference in their lysosomotropic properties in particular for the piperidine derivatives. From this study, CuGTSMpip emerged as the most promising compound to be further evaluated as an anticancer metallodrug. Abstract : A new family of copper(II) bis(thiosemicarbazonato) complexes with pendant nitrogen heterocycles was synthesized using non‐radioactive copper ( nat Cu) and 64 Cu. The physico‐chemical and biologic behavior of the complexes was evaluated, leading to the most promising complex CuGTSMpip with IC50 values spanning from 0.05 to 0.29 μM, in the tested cancer cell lines.