Theoretical Study On The Action Mechanism Of Tumor Active Ru Complexes Binding To Target Molecule

We investigated the interaction mechanism of the anticancer ruthenium complexes binding to their intracellular targets by using DFT theoretically.Ru(Ⅱ)-azpy complexes have been testified to possess desirable anticancer properties. Amongst, the a isomer exhibited the highest cytotoxicity. Based on these, we designated a-[Ru(azpy)2Cl2] as the primary reactant to bind to the target molecule. However, an issue that DNA or protein, which is the preferential attacking target for Ru complexes also exist. Therefore, we calculated the activation free energy for the binding reactions of a-[Ru(azpy)2Cl2] with Guanine, Adenine, Histidine and Methionine, respectively. Finally, the calculated results demonstrated that the hydrolyzed a-[Ru(azpy)2Cl2] may make a easier way to bind to the active sites of amino acids on the surface of proteins in vivo.A series of organometallic ruthenium (RAPTA) compounds with anη6-arene ligand, 1,3,5-triaza-7-phosphaadamantane (pta) ligand and, two labile chloride ligands were showed to cause DNA damage in a solid tumor purposely. It is speculated that the discrepancies in pH value between tumor tissue and healthy tissue is the essential factor for this complex to exert its cytotoxicity, and it is considered to have important relationship with the pta ligand. As the pta ligand can serve as H-bond acceptor, it is deemed that this complex can be activated via protonation of the pta ligand. Hence, we designed reaction processes for protonated and non-protonated complexes, and then we calculated the activation free energy for binding reactions. By comparing the activation free energies for the reactions of the two complexes, it could conclude that the protonation of pta ligand may have nothing with the selectively DNA damage action mode. Besides, generally speaking, this complex probably tends to bind to cysteine other than DNA bases.This thesis provides a deep insight into the action mechanism for ruthenium complexes binding to their intracellular target, which could be good reference for further drug design.