Molecular arene ruthenium cages: new vectors to deliver drugs to cancer cells

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.

Thèse de doctorat : Université de Neuchâtel, 2010