Despite the appearance in the market of platinum compounds with minor side effects than cisplatin (i.e. carboplatin and oxaliplatin), they did not solve the ineffectiveness on some types of tumors, having the same mechanism of action proposed for cisplatin (DNA platination). For this reason, many research groups have focused their attention on the synthesis and determination of the anticancer properties of compounds with metals different from platinum. Among the most investigated metals there are certainly ruthenium and gold and, only recently, palladium. The latter, despite belonging to the same group of platinum, has some rather different features: •Better water solubility of its complexes. •Structure-activity relationships and mechanisms of action generally different from platinum compounds. However, the fast dissociation pattern of palladium complexes compared to platinum represents a problem since the speciation, which heavily affects the biological activity and the pharmacokinetic properties, could be increased. To remedy this contraindication the most direct option is the introduction of ligands firmly anchored to the metal such as N-Heterocylic Carbenes (NHCs), which are known to give strong s-bonds with most of the transition metals. Moreover, several NHC-palladium complexes have already exhibited an interesting cytotoxic activity in vitro and tumour growth suppression even in vivo. In this PhD thesis, the synthesis and characterization of new palladium compounds stabilized by different types of N-Heterocyclic Carbenes and important organometallic fragments such as h3-allyl-Pd(II), palladacyclopentadienyl and h2-olefin-Pd(0) will be exposed. The reactivity and the importance in many catalytic processes of the fragments reported in Fig. A1 are well known, on the contrary, their biological activity is almost unexplored. Starting from these premises, it was decided to test the synthesized compounds toward different tumor lines, particularly on ovarian carcinoma, and human fibroblasts (healthy cells). From the antiproliferative activity data collected for about one hundred compounds, emerges that, regardless of the nature of the selected carbene ligand, the most active compounds bear the allyl fragment. For these species the evaluation of their activity in vivo and experiments aimed at identify the primary biological target, in order to propose the possible mechanism of action, are planned. A class of compounds generally slightly less active than that containing the allyl residue is represented by the palladacyclopentadienyl complexes and their derivatives. Nevertheless, for some of the synthesized compounds, an excellent antiproliferative and proapoptotic activity has been shown on ovarian cancer cell lines (CisPt sensitive and CisPt resistance), accompanied by a poor activity against normal cells. For the compound 40a a thorough investigation on the main biological target, which was found to be DNA, and on the degree of uptake in tumor cells was also carried out. Due to the high stability imparted by the palladaciclopentadienyl fragment and the chelatig biscarbene ligand, this compound does not undergo substitution reactions when reacted with reduced glutathione (GSH), which is a potential coordinating species present in abundance in the biological environment. It is therefore reasonable to suppose that the interaction with the DNA occurs through non-covalent interactions with the polynucleotide chain. Finally, the class of compounds decidedly less active than those described so far is represented by the Pd (0) derivatives stabilized by olefinic ligands. For these complexes the antiproliferative and proapoptotic activity was evaluated only in ovarian carcinoma lines, observing only in very few cases IC50 values comparable to those of cisplatin.

Palladium organometallic compounds bearing N-Heterocyclic Carbene ligands as promising anticancer agents / Scattolin, Thomas. - (2019 Mar 01).

Palladium organometallic compounds bearing N-Heterocyclic Carbene ligands as promising anticancer agents

SCATTOLIN, THOMAS
2019-03-01

Abstract

Despite the appearance in the market of platinum compounds with minor side effects than cisplatin (i.e. carboplatin and oxaliplatin), they did not solve the ineffectiveness on some types of tumors, having the same mechanism of action proposed for cisplatin (DNA platination). For this reason, many research groups have focused their attention on the synthesis and determination of the anticancer properties of compounds with metals different from platinum. Among the most investigated metals there are certainly ruthenium and gold and, only recently, palladium. The latter, despite belonging to the same group of platinum, has some rather different features: •Better water solubility of its complexes. •Structure-activity relationships and mechanisms of action generally different from platinum compounds. However, the fast dissociation pattern of palladium complexes compared to platinum represents a problem since the speciation, which heavily affects the biological activity and the pharmacokinetic properties, could be increased. To remedy this contraindication the most direct option is the introduction of ligands firmly anchored to the metal such as N-Heterocylic Carbenes (NHCs), which are known to give strong s-bonds with most of the transition metals. Moreover, several NHC-palladium complexes have already exhibited an interesting cytotoxic activity in vitro and tumour growth suppression even in vivo. In this PhD thesis, the synthesis and characterization of new palladium compounds stabilized by different types of N-Heterocyclic Carbenes and important organometallic fragments such as h3-allyl-Pd(II), palladacyclopentadienyl and h2-olefin-Pd(0) will be exposed. The reactivity and the importance in many catalytic processes of the fragments reported in Fig. A1 are well known, on the contrary, their biological activity is almost unexplored. Starting from these premises, it was decided to test the synthesized compounds toward different tumor lines, particularly on ovarian carcinoma, and human fibroblasts (healthy cells). From the antiproliferative activity data collected for about one hundred compounds, emerges that, regardless of the nature of the selected carbene ligand, the most active compounds bear the allyl fragment. For these species the evaluation of their activity in vivo and experiments aimed at identify the primary biological target, in order to propose the possible mechanism of action, are planned. A class of compounds generally slightly less active than that containing the allyl residue is represented by the palladacyclopentadienyl complexes and their derivatives. Nevertheless, for some of the synthesized compounds, an excellent antiproliferative and proapoptotic activity has been shown on ovarian cancer cell lines (CisPt sensitive and CisPt resistance), accompanied by a poor activity against normal cells. For the compound 40a a thorough investigation on the main biological target, which was found to be DNA, and on the degree of uptake in tumor cells was also carried out. Due to the high stability imparted by the palladaciclopentadienyl fragment and the chelatig biscarbene ligand, this compound does not undergo substitution reactions when reacted with reduced glutathione (GSH), which is a potential coordinating species present in abundance in the biological environment. It is therefore reasonable to suppose that the interaction with the DNA occurs through non-covalent interactions with the polynucleotide chain. Finally, the class of compounds decidedly less active than those described so far is represented by the Pd (0) derivatives stabilized by olefinic ligands. For these complexes the antiproliferative and proapoptotic activity was evaluated only in ovarian carcinoma lines, observing only in very few cases IC50 values comparable to those of cisplatin.
1-mar-2019
31
2017/2018
Settore CHIM/03 - Chimica Generale e Inorganica
Università degli Studi di Trieste
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2938813
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