Half-sandwich Ruthenium(II)-arene complexes as anticancer agents

Abstract

Metals are rarely considered as promising candidate for pharmaceutical components and it is a common perception that metal compounds are toxic, unstable and generally not well suited for pharmaceutical applications. However, over the past few decades certain particular chemical reactivity of metals, their magnetic and nuclear properties and the structural variety of their compounds, have become important for a possible medical applications. The organ specific uptake of technetium radio-pharmaceuticals and the highly specific nature of the binding of cis-platin to DNA demonstrate the potential of this class of compounds in specific medicinal applications. Although platinum drugs, particularly cis-platin, carboplatin and oxaliplatin, are used worldwide for number of neoplasms and are essential constituents of many anticancer therapies, they have consistent side effects and often become extra sensitive towards resistance mechanisms. These drugs and their associated problems have guided the search for new transition metal based chemical entities to overcome suchlimitations and among many others, ruthenium based compounds have shown remarkable activities and promising development. Two of the ruthenium complexes, KP1019 and NAMI-A are currently undergoing chemical trials and have shown some success in preliminary results. After more than 25 years of discovery of these compounds, during which a number of chemical possibilities have been explored, a series of Ru(II) complexes were developed, named as RAPTA, which represent a new important class of compound to treat cancer. RAPTA complexes of the general formula [Ru(η6-arene)(PTA)X2] show relatively low toxicity in vitro, but in vivo studies revealed excellent inhibition of metastasis growth, in addition to high selectivity and extremely low general toxicity. Although reaction mechanism of RAPTA complexes is still unclear and there is uncertainty on the main molecular target responsible for its anti-tumour and anti-metastatic activity, investigations on the anticancer activity of organometallic Ru(II)-arene compounds have emerged a new era for thelast few decades. Therefore, design of new Ru(II)-arene complexes withpotential targets and analysis of the mode of action within the cell becomes most vital part in the arena of ruthenium based anti-cancer drugs. The primary objectives of the research work reported in this thesis are:  To design and synthesize new ruthenium based anticancer compounds based on a flexible scaffold (RAPTA) onto which various groups of known biological function can get attached.  To develop target specific anticancer drug by attaching biologically active groups with known therapeutic function to the ruthenium centre.  To explore antiproliferative activity of the prepared compounds.  To investigate interaction of the compounds with different biomolecules e.g. DNA, BSA, HSA, amino acids etc.  To investigate possible mechanistic pathway to determine the mode of action of synthesized compounds.