Targeting enzymes with oligonuclear ruthenium(II) complexes

Despite tremendous progress in modern medicine in the last century and the successful obliteration of many diseases, there are still many diseases challenging human health, and consequently, there is a need for the development of new drugs. Ruthenium-based complexes have been widely examined for their anti-cancer and anti-microbial properties. Due to their unique properties, the interactions of ruthenium complexes with different biological targets, particularly with nucleic acids (DNA and RNA) have been extensively investigated. However, the protein binding and enzyme inhibition properties of ruthenium complexes are less well explored. This thesis aimed at exploring the enzyme inhibition properties of a class of inert oligonuclear polypyridylruthenium(II) complexes (Rubbn) containing the flexible linking ligand bbn, {where bbn = bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n = 7, 12 and 16)} and particularly in their potential as novel anti-parasitic agents. A series of mono-, di-, tri- and tetra-nuclear complexes have been synthesised and their ability to inhibit acetylcholinesterase enzymes (AChEs) in various parasite extracts was examined. The Rubbn complexes selectively inhibited the acetylcholinesterase (AChE) at sub-micromolar concentrations (IC₅₀ MKP-1 > CDC25B. The results of the study also suggested that the tetra-nuclear complexes have the potential to regulate the amount of phosphatase enzyme (MKP-1) synthesised in live cancer cells. However, the Rubbn complexes were less active (between 60- and 200-fold) against the phosphatase enzymes,compared to parasite AChE. The combined results of the enzyme inhibition studies highlight the selectivity of the Rubbn complexes for parasite AChE. The results of this study demonstrates the significant potential of the oligonuclear polypyridylruthenium(II) complexes as anti-parasitic agents. More importantly, to the best of my knowledge, this is the first investigation on inhibitory properties of Rubbn complexes against parasite AChEs and the information provided in this thesis will advance our knowledge in the understanding of enzyme inhibition properties of ruthenium-based complexes and in developing them as therapeutic agents