Süss-Fink, Georg

2015, Stíbal, David, Süss-Fink, Georg

Cancer is a major cause of morbidity and mortality in today’s world, affecting populations in all countries and all regions. Although no drug or treatment able to cure cancer in all of its forms and variations was found so far, the clinical advancements of 20^th and 21^st century provided a number of effective drugs for specific types of cancers and had a significant effect on the survival and the quality of life of patients. One of these drugs, the platinum-based complex cisplatin, achieved almost 100% cure rate of testicular cancer, not only saving lives of thousands of patients every year but also overturning a paradigm of medicinal chemistry – it was the first metal-based anticancer drug used in the clinic. The success of cisplatin encouraged the search for new metal-based anticancer agents, which soon expanded to other metals, such as ruthenium. During the last three decades, numerous ruthenium-based compounds with interesting anticancer properties were prepared and thoroughly investigated, two of which (NAMI-A and KP1019) were ultimately introduced into clinical trials, showing the potential of ruthenium complexes in cancer therapy.
The goal of the presented thesis was to investigate the properties of dinuclear arene ruthenium thiolato-bridged complexes and to establish their potential as anticancer drugs. In the first part of the thesis, several monothiolato, dithiolato and trithiolato complexes were synthesized and evaluated for their stability and reactivity with biological substrates. The results were correlated with the in vitro anticancer activity of the three types of complexes and showed the most stable trithiolato complexes to be the most active against ovarian cancer cell lines. Subsequently, the most active trithiolato derivative, diruthenium-1, was thoroughly investigated in vitro and in vivo to establish the mode of action of this complex, showing its promising ability to influence the tumor growth and to prolong the survival of tumor-bearing mice.
In the second part of this thesis, three series of conjugates of the mixed trithiolato complexes were synthesized to demonstrate the potential of the coupling of dinuclear arene ruthenium complexes with biologically active organic molecules. Thus, the thiolato-bridged complexes were coupled with propargyl bromide, the resulting conjugates being available for the 1,3-Huisgen addition with tumor targeting compounds. Conjugates with ibuprofen were synthesized to investigate the effect of the antiinflamatory agent on the activity and selectivity of the resulting complexes towards cancer cells. Finally, conjugates of dinuclear trithiolato arene ruthenium complexes with alkylating agent chlorambucil were synthesized to show the effect of the two different modes of action of the conjugates on their activity in vitro and in vivo.
These results demonstrate the potential of the dinuclear thiolato-bridged arene ruthenium complexes as a versatile platform for the synthesis of anticancer agents with variable biological properties and modes of action.

2010, Gras, Michaël, Süss-Fink, Georg, Deschenaux, Robert

Le but de ce travail de thèse a été de développer dans un premier temps des complexes mononucléaires arène-ruthénium à ligands thiolatopyridine et à ligands chélatants 2-(pyridine-2-yl)thiazaole, puis dans un deuxième temps des complexes dinucléaires arène-ruthénium contenant trois ponts thiophénolato ainsi que des complexes dinucléaires de carbonyle-ruthénium à ponts carboxylato et ligands porphyrines terminaux. Les propriétés biologiques de ces complexes ont été évaluées afin de déterminer le potentiel antitumorale de ces complexes.

Depuis que Rosenberg a découvert l’activité anticancéreuse du cisplatin en 1969, le développement de complexes organométalliques arène-ruthénium a connu un énorme essor dans le but d’évaluer leurs propriétés cytotoxiques. Durant cette thèse, nous avons synthétisé des complexes mononucléaires de type [(arène)Ru(S-C₅H₄NH)₃]²⁺, [(arène)Ru(pyTz)Cl]⁺ et [(arène)Ru(pyTz)(SnCl₃)]⁺ qui possèdent une activité cytotoxique ; toutefois, cette dernière s’est avérée être faible par rapport à celle observée pour les complexes de ruthénium déjà connus. Nous avons également développé des complexes dinucléaires de type [(arène)₂Ru₂(S-p-C₆H₄-OH)₃]⁺ pour lesquels nous avons observé une cytotoxicité plus importante mais les résultats les plus prometteurs ont été obtenu pour les complexes de type [(arène)₂Ru₂(SPh)₃]⁺. Parmi les complexes synthétisés au cours de cette thèse, le plus actif des complexes [(arène)2Ru₂(SPh)₃]⁺ avec arène = C₆H₅R et R = (CH₂)₄­O­C(O)­CH=CH­C₆H₄­p­OCH₃ (25) possède des IC₅₀ de 0,49 μM envers la lignée cellulaire A2780 et de 0,56 μM envers la lignée cellulaire A2780cisR. Au vue de ces résultats, nous avons évalué les propriétés biologiques des complexes [(arène)₂Ru₂(SPh)₃]⁺ dont l’arène n’est pas fonctionnalisé, et ces derniers se sont avérés posséder une cytotoxicité encore plus forte. Enfin, nous avons développé des complexes dinucléaires de ruthénium à ponts carboxylato et ligands porphyrines terminaux afin de les utiliser comme agent photosensibilisant pour la thérapie photodynamique. Toutefois, la phototoxicité des ces derniers n’a pas été évalué en raison de leur faible solubilité.

2010, Mattsson, Johann, Therrien, Bruno, Süss-Fink, Georg

Ever since the discovery of cisplatin by Rosenberg in the 1970’s metal complexes as anti-cancer drugs have become an increasing subject of research. Ruthenium as a substitute for the toxic platinum metal has received a lot of attention recently. Organometallic compounds such as arene ruthenium complexes are very versatile and have proven to be active against cancer cells. In order to exploit their activity this work consisted in incorporating arene ruthenium compounds in large systems for facilitating transport into cancer cells. In a first approach, arene ruthenium compounds were combined with dendritic systems to form metalla-dendrimers: The goal of this being to transport the active ruthenium compounds into cancer cells by large dendrimers. The biological activity was measured which revealed that these complexes are taken up by cells, showing moderate to high cytotoxicity. In a second approach, as arene ruthenium complexes are also interesting supramolecular building blocks, supramolecular rectangles were constructed. The rectangles are tetra-cationic and slightly water soluble. These discrete supramolecular assemblies show moderate to high cytotoxicity depending on the properties of the building blocks used. In a third approach, supramolecular triangular prisms were investigated. The prismatic structures can encapsulate large planar compounds. Studies showed that the encapsulated compound can not escape the prismatic cage unless it breaks. This property can be useful for drug transport, therefore a series of functionalized pyrenyl derivatives were encapsulated in the prism. Even though the prism itself is moderately cytotoxic, the activity was found to increase with some of the encapsulated pyrenyl derivatives. Fluorescent studies were made on the encapsulated 1-(4,6-dichloro-1,3,5-triazin-2-yl)pyrene. The study agrees with the theory that these complexes are taken up by the cell and then, like a Trojan horse, breaks to release the encapsulated species trapped inside.