Abstract
New palladium complexes with thiosemicarbazonate ligands derived from pyrene exhibit potent antiproliferative activity against A2780 and cisplatin-resistant A2780Cis human ovarian cancer cells, which is dependent on substituent groups of the thiosemicarbazone ligands. Cellular accumulation and distribution studies confirmed that palladium enters the cell nucleus. DNA and topoisomerase IB studies show that one complex is a potent TopIB inhibitor, with selectivity for cancer versus normal cells.
Highlights
Thiosemicarbazones (TSCs) have been extensively studied due to their ability to chelate several metal ions[1] and to suppress tumor growth by inhibiting ribonucleotide reductase (RR), a key enzyme required for DNA synthesis.[2,3] Another well-known target for some TSCs derivatives is Topoisomerase (Top), responsible for DNA topology regulation during cell division.[4]
The cellular accumulation of the palladium complexes, cisplatin and carboplatin was determined in A2780 cells, in order to correlate with the IC50 values in this cell line
We have described the synthesis and characterization of stable new palladium(II) complexes with thiosemicarbazonate ligands derivatized with pyrene
Summary
Thiosemicarbazones (TSCs) have been extensively studied due to their ability to chelate several metal ions[1] and to suppress tumor growth by inhibiting ribonucleotide reductase (RR), a key enzyme required for DNA synthesis.[2,3] Another well-known target for some TSCs derivatives is Topoisomerase (Top), responsible for DNA topology regulation during cell division.[4]. The intercalating properties of pyrene can be used to inhibit cellular DNA replication.[13,14] thiosemicarbazone ligands containing a pyrene moiety (Chart 1) might be promising to achieve metal complexes with mechanisms of action different from cisplatin, making them potentially active against platinum-resistant cell lines. New palladium complexes derived from pyrene thiosemicarbazones were prepared, and designed to have sufficient stability against hydrolysis in solution together with a ‘non-cisplatin like’ mechanism of action against cancer cells, to overcome the acquired resistance of platinum-based drugs.
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