Integrate approach to the study of chelating agents for the effects of toxic metal ions

Metals are an integral part of many structural and functional components in the body, and the interest on their role in physiological processes, environment and medicine is increasing. Many metal complex are used as metal drugs such as cis-platin for cancer treatment, paramagnetic metal complex as contrast agents for magnetic resonance imaging (MRI); many metal are toxic and metal toxicity may occur due to essential metal overload or exposure to heavy metals from various sources interfering with functions of various organ systems like the central nervous system (CNS), the haematopoietic system, liver, kidneys, etc. New therapeutic strategies, such as chelation therapy, have been developed based on restoring the normal healthy physiology of the body either by direct administration of essential metals, or by chelating out excess or toxic metals, or using them as carriers for targeted drug delivery, or for tagging biomolecules for diagnostics. Thermodynamic studies in the characterization of ligands of biomedical interest are crucial in the design of a new drugs. This thesis is focused on the studies of new molecules that have long been recognized as privileged chelating structures for the design of metal chelating drugs, especially towards hard metal ions, in view of their involvement in metal overload disorders. The approach has been multi-variated, from the chemistry to the biochemistry and biology, which has been possible due to the time spent in others research groups and to the other ones that used to collaborate with us. Because of my stay (research master thesis) in organic chemistry group at Instituto Superior Tecnico of Lisbon guided by Prof. M. Amelia Santos, three hydroxypyridinones ligands have been synthetized, whose biodistribution studies performed at Centro de Ciencias e Tecnologias Nucleares (C2TN) of Lisbon as well. In the Research Group of Chemistry and Stereochemistry of Peptides and Protein headed by Prof. Zbigniew Szewczuk at the University of Wroclaw new strategies of synthesis have been developed involving mimosine peptides derivatives. As opposite to hydroxypyridinones, whose solution equilibria studies have been possible, peptides have been mainly characterized by DFT and biological ones in collaboration with the University of San Sebastian and Cagliari. In the end, three months of my last year of PhD have been spent in the Medicinal Inorganic Chemistry group at the University of British Columbia (Vancouver) under supervision of Prof. Chris Orvig working on solution studies of radiometal complexes of bisphosphonate-picolinic acid derivatives. It needs to be tightened up with regard to PhD that it has industrial characterization under that a collaboration with industry is scheduled. At Innovative Materials I could learn about biology field and how to work with cells, particularly our idea was to test hydroxypyrones ligands on proliferation and differentiation of stamina cells. The study is still uncompleted and results about are not shown in the following chapters This thesis is divided in three chapters: • Chapter 1 – An overview of chelation It describes general aspects of chelation therapy, the rule of metal ions in human body and in human diseases. • Chapter 2 – Ligands It describes structural and chemical properties of a families of ligands studied and shows NTA(PrHP)3, KC18, KC21, SC and six mimosine-peptides derivatives under focus of this thesis. • Chapter 3 – Experimental methods It describes experimental procedures and techniques applied for thesis’s studies.