The thesis project is devoted to the __search of antineoplastic ruthenium/platinum/copper complexes containing also intercalator ligands; such intercalators may show efficient DNA-cleaving and DNA... Show moreThe thesis project is devoted to the __search of antineoplastic ruthenium/platinum/copper complexes containing also intercalator ligands; such intercalators may show efficient DNA-cleaving and DNA-binding properties__. The studies have been carried out using a variety of techniques. Study of the in vitro cytotoxicity against human tumour cell lines along with cellular uptake has been the pivotal point of this research. Synthetic methodologies of the new complexes have been designed to establish structure-activity relation in several series of related complexes. Platinum complexes of derivatized-phenanthroline, pyridine and pyrimidine, have been synthesized and studied in detail for their biological activity. These complexes are different in structure and in overall charges, and were studied to elucidate the effects on the activity profile. A self-activating copper-complex formed from a unique amino-phenol ligand (Hpyramol) inspired the synthesis of platinum and ruthenium analogues. Biological studies including cellular uptake, conformational changes (CD and UV) and DNA cleavage have been performed to interpret the changes in activity profile upon various metal additions. Ruthenium complexes are known as suitable candidates for anticancer (specially as antimetastatic drugs) agents. A group of ruthenium(III) complexes has been studied for their anticancer activity and their DNA-binding properties. The extensive area of homo- or heterometallic dinuclear compounds opens up an interesting challenge towards the synthesis of complexes. The studies of different combinations viz., Ru-Ru, Cu-Cu and Pt-Pt, have been performed to design new series of anticancer complexes. Show less
The design of novel anticancer agents is one of the most active fields in Medicinal Chemistry, as the number of effective drugs for treatment of cancer is still very limited. This demand for new... Show moreThe design of novel anticancer agents is one of the most active fields in Medicinal Chemistry, as the number of effective drugs for treatment of cancer is still very limited. This demand for new drugs is even higher, considering the high cancer-prevalence rate in our society. The therapeutic application of metal complexes is an under-developed area of research and basic principles in the development of metallopharmaceuticals are lacking, or at least just recently being discovered. Metal-containing agents may offer unique therapeutic opportunities. However, significant obstacles, including potential metal accumulations and toxicities, require further research before a promising metal compound may be introduced in the clinic. In particular several ruthenium and gold coordination compounds have shown promising application as anticancer agents. In these terms, this thesis project, performed in the Coordination and Bioinorganic Chemistry group in the Leiden Institute of Chemistry, comprises the design, synthesis, detailed characterization (i.e. elemental analysis, UV-Vis spectroscopy, IR, far-IR, NMR, mass spectroscopy and X-ray single-crystal structure determination) and also the biological evaluation of novel gold compounds and ruthenium compounds. The promising cytotoxic activity developed for several of these compounds and the findings from this research are providing a better understanding of chemistry of Ru(III) and Ru(II) and Au(III) coordination compounds and their structure-activity relationships and may lead to the development of improved ruthenium and gold-chemotherapeutic drugs. Show less
Cancer is a leading cause of death worldwide. Nowadays, the treatment of cancer by chemotherapy can consist of a combination of antitumor drugs. Nevertheless, chemotherapy is accompanied by serious... Show moreCancer is a leading cause of death worldwide. Nowadays, the treatment of cancer by chemotherapy can consist of a combination of antitumor drugs. Nevertheless, chemotherapy is accompanied by serious side effects and intrinsic and acquired resistance to the drugs. This thesis describes the design and synthesis of novel potential antitumor drugs that combine two different mechanisms of action. One of the two active units is derived from cisplatin, which cured Lance Armstrong?s testicular cancer. This platinum compound is known to induce a distortion of the DNA helix upon binding, resulting in the death of the cancer cells. The second active moiety is based on Cu(3-Clip-Phen), which is a highly active nuclease agent. In other words, the platinum moiety act as an antitumor drug and as an anchor to DNA, while the copper unit cleaves the DNA strand in the close proximity of the platinum-DNA adducts. The two active units have been covalently coupled with a (in)flexible bridge aiming at a synergistic action of the two drugs. The cleaving activity of some of the complexes is higher compared to Cu(3-Clip-Phen). Moreover, three of the new complexes have been found to show equivalent or higher cytotoxicities compared to cisplatin or Cu(3-Clip-Phen). Show less
