|Abstract: ||Cisplatin is one of the most active drugs in anticancer therapy, and it is currently used
for the treatment of a wide range of cancers, in particular advanced ones. After its
introduction in clinical therapy, the research in this field has focused on the preparation
of new metal complexes with increased activity and lower side-effects. Besides, the use
of drug combinations with synergistic effect, i.e. an effect greater than the sum of the
effects of the single drugs, has been introduced. This thesis is focused on the preparation
of Cu(II) and Pt(II) complexes and on the study of their cytotoxic properties, alone or in
combination with cisplatin.
Cu(II) complexes with 1,10-phenantroline (phen), 1,10-phenantrolin-5,6-dione and 1,10-
phenantrolin-5,6-diol, with 1:1 or 1:2 metal:ligand stoichiometry, have been synthesized.
In addition, mixed Cu(II) complexes with phen and thiophene derivatives of general
formula [Cu(phen)2(T)](ClO4)2 (T=1-methylthio-thiophene-2-carboxylic acid, 2-
methylthio-thiophene-1-carboxylic acid, 2-thiophenecarboxamide, 2-
thiophenecarboxylate) have been prepared. A family of Pt(II) complexes of general
formula [Pt(P)(D)2](ClO4)2, being P a derivative of phen and D a derivative of
imidazolidin-2-thione, has been synthesized.
In order to find the species present in solution in conditions similar to the physiological
ones (37 °C and NaCl 0.1 M), the formation constants of the complexes have been
determined through potentiometric titrations. The dipole moments of the platinum
complexes have been determined through quantum mechanical calculations.
The in vitro cytotoxic activity of ligands and metal complexes has been evaluated against
a panel of human tumour cell lines, and it has been correlated to their structures.
Finally, a new method, based on experimental design and artificial neural networks, has
been proposed for the evaluation of the synergy in mixtures of two or more drugs.
Exploiting this method, the cytotoxic activity of mixture of cisplatin and three Cu(II)
complexes ([Cu(phen)(H2O)2(ClO4)2], [Cu(phen)2(H2O)](ClO4)2 e
[Cu(phen)2(imidazolidin-2-thione)](ClO4)2) has been studied, and the combination with
higher synergistic effect have been identified.|