Theoretical Study On The Substitutions Of Platinum Complexes With Nonplanar Heterocyclic Piperidine Ligands Binding To Biological Targets

Despite its high activity and wide use, cisplatin has some critical drawbacks as ananticancer drug, including severe toxic side effects, inherent and acquired resistance, and limited solubility in aqueous solution. Recent research indicates that the replacement of one (or both) ammine ligand(s) of transplatin by a heterocyclic ligand such as planar pyridine, thiazole or nonplanar piperidine and piperazine greatly enhances the cytotoxicity of such species with respect to their corresponding cis isomers and also to cisplatin. They also have fine antitumor activity even including tumor cells resistant to cisplatin. In this dissertation, the monofunctional substitution reaction of these novel non-planar heterocyclic trans-platinum complexes with DNA purine bases were explored.All species were optimized at B3LYP/(Lan12DZ+6-31g(d,p)) level of theory and frequency calculations were performed on the same level of theory. The obtained transition states were confirmed using the intrinsic reaction coordinate (IRC). And single point energies were calculated at B3LYP/(LanL2DZ+ 6-311++G(2d,2p) level of theory and salvation energies were obtained on the same level of theory using IEF-PCM method.In Chapter 3, the monofunctional binding of trans-[PtCl2NH3(piperidine)] to DNA Purine Bases was explored. Our calculations demonstrate that the barrier heights of chloroaqua are lower than the corresponding values of diaqua for adenine and guanine, in addition, the free energies of activation for guanine in aqueous solution are all smaller than that for adenine, which predicts a preference of 1.9 kcal/mol when trans-[PtCl(H2O)(NH3)(pip)]+ and trans-[Pt(H2O)2(NH3)(pip)]2+ are the active agents.In Chapter 4, the monofunctional binding of trans-[PtCl2(piperidine)2] to DNA Purine Bases was explored. The calculations demonstrate that the barrier heights of chloroaqua are also lower than the corresponding values of diaqua for adenine and guanine, in addition, the free energies of activation for guanine in aqueous solution are all smaller than that for adenine, which predicts a preference of～1.9 and～5.3 kcal/mol when trans-[PtCl(H2O)(pip)2]+and trans-[Pt(H2O)2(pip)2]2+ are the active agents. For reactions trans-Pt-chloroaqua (or diaqua) to cis-monoadduct we obtain the same transition-state structure as from reactions trans-Pt-chloroaqua (or diaqua) to trans-monoadduct, which seems that trans-Pt-chloroaqua (or diaqua) complex can generate trans-or cis-monoadduct via the same transition-state.