| Summary: | Includes bibliographical references. === The success of cisplatin and its analogues for the treatment of different cancers has had a profound effect on establishing the application of metal complexes in medicine. Lately, increasing drug resistance and the emergence of unwanted side effects to currently available therapies have bred a need for novel pharmacological agents. Thus, the design and study of organometallic complexes as potential chemotherapeutics may potentially identify new drug candidates. Apart from platinum based compounds, platinum-like metals such as ruthenium(II), rhodium(III) and iridium(III), have been identified as biologically relevant metals. The purpose of this study is to synthesize three classes of polynuclear complexes containing metals from the Platinum Group Metal (PGM) series and evaluate each class for pharmacological activity in vitro. Each complex class is based on a different ligand type. New mono- and polynuclear organometallic Platinum Group Metal (PGM) complexes based on three ligand classes have been synthesised and characterised using several analytical and spectroscopic techniques including 1H, 13C and 31P NMR, infrared and UV-vis spectroscopy. The first complex series is based on the thiourea containing ligand, 3,4-dichloroacetophenonethiosemicarbazone, which has demonstrated in vitro pharmacological activity. This ligand was reacted with K2[PtCl4] to afford a tetranuclear cycloplatinated thiosemicarbazone complex (2.2). Reaction of 2.2 with different mono- and diphosphanes yielded two mono- and three dinuclear Pt(II) thiosemicarbazone ligands (2.3-2.7). In all of the complexes (2.2-2.7), the thiosemicarbazone ligands act as a dinegative tridentate [C,N,S] donor to each metal centre. Single crystal X-ray analyses of three of the complexes in this series, including the tetraplatinum derivative, confirmed the structural integrity of these complexes. Reactivity studies of the mononuclear platinum(II) complexes revealed that one complex is able to undergo oxidative addition reactions with different aryl iodide substrates. In vitro pharmacological studies of a selection of these complexes as antiparasitic agents have been carried out against the P. falciparum strains, D10 (cisplatin sensitive) and Dd2 (cisplatin resistant)) and Trichomonas vaginalis T1. Their cytotoxic effects on the A2780 (cisplatin sensitive) and A2780cisR (cisplatin resistant) human ovarian carcinoma cell line has also been determined. All of the complexes demonstrated moderate cytotoxic effects as antiparasitics and antitumor agents. No correlation between the number of platinumthiosemicarbazone moieties and pharmacological activity could be discerned. Instead, the type of ancillary ligand used to prepare each complex may influence the lipophilic nature of each complex thus explaining the trend observed.
|
|---|
