Abstract ................................................................................................. 127 7.1 Introduction .................................................................................. 128 7.2 Computational Details ................................................................. 129 7.3 Results and Discussion ................................................................ 133 7.4 Acknowledgments ....................................................................... 142 Keywords .............................................................................................. 142 References ............................................................................................. 143

ABSTRACT

Despite many years of intense research, the mechanisms underlying cisplatin (cis-Pt(NH3)2Cl2, cDDP) anticancer activity, toxic side effects, and natural/acquired tumor resistance are still quite elusive. Understanding the cellular, molecular, and submolecular aspects of the drug action while of utmost relevance remain a challenge for researchers. There are some key

points unanimously accepted, such as nuclear DNA being the main biological target and activation step being a hydrolysis reaction of a chloride ligand. A balance between kinetic liability and thermodynamic stability of the metal-ligand bonds has been pointed as a determining issue of cDDP biological activity.