Antitumour gallium(III) and iron(III) complexes with thiosemicarbazones
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2022-02-04 13:07
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ARION, Vladimir, KOWOL, Christian, BERGER, Roland, EICHINGER, Rene, JAKUPEC, Michael, KEPPLER, Bernhard. Antitumour gallium(III) and iron(III) complexes with thiosemicarbazones. In: Physical Methods in Coordination and Supramolecular Chemistry, 27 septembrie - 1 octombrie 2006, Chişinău. Chisinau, Republic of Moldova: 2006, XVII, pp. 13-14. ISBN 978-9975-62-066-6.
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Physical Methods in Coordination and Supramolecular Chemistry
XVII, 2006
Conferința "The XV-th International Conference Physical Methods in Coordination and Supramolecular Chemistry : The XVII-th Reading in memory of Acad. A.Ablov"
Chişinău, Moldova, 27 septembrie - 1 octombrie 2006

Antitumour gallium(III) and iron(III) complexes with thiosemicarbazones


Pag. 13-14

Arion Vladimir, Kowol Christian, Berger Roland, Eichinger Rene, Jakupec Michael, Keppler Bernhard
 
Institute of Inorganic Chemistry, University of Vienna
 
Disponibil în IBN: 4 iunie 2020


Rezumat

Thiosemicarbazones have been explored for their applicability as antitumour agents for half a centure [1]. The enzyme ribonucleotide reductase has been identified as the principal target [2]. In fact, these compounds are the strongest known inhibitors of this enzyme, both in cell-free assays and in intact tumour cells, being several orders of magnitude more effective than hydroxyurea, the first clinically applied ribonucleotide reductase inhibitor. The enzyme that catalyzes the conversion of ribonucleotides to deoxyribonucleotides is produced at the transition from the G1 to the S phase of the cell cycle as a prerequisite for DNA replication and is highly expressed in tumour cells, making it a suitable and well established target for cancer chemotherapy. Inhibitors of this enzyme are classified by their mode of interference with the enzyme’s functions: (i) radical scavengers (e.g. hydroxyurea) that destroy the tyrosyl radical; (ii) chelating molecules (e.g. desferrioxamine) that prevent incorporation of iron into the catalytically active centre (or remove it from the catalytical centre); and (iii) nucleotide or nucleoside analogues (e.g. gemcitabine, cladribine, fludarabine, cytarabine) that interfere with substrate binding. The ribonucleotide reductase-inhibiting activity of thiosemicarbazones has originally been explained by their iron-chelating properties, either by binding of iron from the R2 subunit or by preformation of an iron chelate which then inhibits the enzyme. It was also suggested that preformed iron(III) chelates can be readily reduced in blood or in the presence of thiols to Fe(II) species, which in turn are able to destroy the tyrosyl radical of the enzyme by a one electron reduction in an oxygen-requiring reaction that can be counteracted by an excess of dithiols. Appart from the well-established inhibition of ribonucleotide reductase, additional targets and modes of action have also been proposed [3]. In particular, radical reactions similar to those induced by bleomycin may explain the formation of DNA strand breaks observed with 5-hydroxy2-formylpyridine-thiosemicarbazone (3-AP, triapine) and 1-formylisoquinoline-thiosemicarbazone, suggesting the induction of direct DNA damage that might be reinforced by the inhibitory effects of ribonucleotide reductase. Besides, inhibition of topoisomerase II by a mechanism distinctly different from that of etoposide has been suggested for a variety of 4N-substituted thiosemicarbazones and, in particular, their copper(II) complexes. The rationale for preparing gallium(III) complexes of thiosemicarbazones is based on the fact that gallium(III) also inhibits the activity of ribonucleotide reductase [4] and is endowed with clinically useful antiproliferative properties [5] Due to similarity in ligands binding affinity with iron(III), gallium(III) affects intracellular iron availability, but also interacts directly with ribonucleotide reductase, by competing with iron for its binding site in the R2 subunit of the enzyme. Combining a central metal and a ligand that are directed at the same molecular target in different ways is being pursued as a strategy to produce highly potent ribonucleotide reductase inhibitors expected to benefit from a synergistic action of the two components. Herewith we will report on the synthesis of a number of gallium(III) and iron(III) complexes with five different 4N-substituted thiosemicarbazones, viz., 2-acetylpyridine dimethylthiosemic arbazone, acetylpyrazine dimethylthiosemicarbazone, 2-acetylpyridine N-pyrrolidinylthiosemicar bazone, acetylpyrazine N-pyrrolidinylthiosemicarbazone and acetylpyrazine N-piperidinylthiosem icarbazone allowing the exploration of structure-activity relationships with regard to the role of the central metal (gallium vs. iron), the metal-to-ligand stoichiometry and the impact of structural modifications of the thiosemicarbazone ligand.