Theoretical Study On The Mechanism Of Antitumor Drugs Iminoether Pt(II) Complexes Interaction With Biological Target Molecules

As metal anticancer compounds, the trans iminoether-containing platinum complexes have been investigated widely in recent years. In the past, people used to think that the trans metal complexes is inactive. However, it is proved that many trans platinum complexes also have very strong anticancer activity,such as trans-[Pt Cl2{E–HN=C(OMe)Me}2](trans-EE), trans-[Pt Cl2{E–HN=C(OMe)Me}-(NH3)](trans-E), trans-[Pt Cl2{Z–HN=C(OMe)-Me}(NH3)](trans-Z). These trans complexes have a certain degree of anticancer activity, and the trans-EE has the highest activity among them, which is commensurate with that of cisplatin. Also, it shows that trans iminoether platinum complexes are a kind of potential anticancer drugs, it will be possibly applied to clinic in the future. This paper makes a detailedly theoretical study on the mechanism of trans-EE, trans-E and trans-Z reaction with biological targets.Although the Pt-based compounds have been studied for many years, the true reaction details and mechanisms of them are still elusive. Therefore, studying the reaction mechanism of platinum-based anticancer drugs has great significance for the research and development of low toxicity of new platinum-based anticancer drugs.Generally, hydrolysis is a key step in drug activation before the drugs reaching to biological molecules. In the third chapter of this paper, we make a in-depth and detailed investigation on the molecule-ion mechanism. The results show that whether in the monofunctional or in the bifunctional substitution, the barriers of the guanine substitution is lower than that of adenine substitution. In the bifunctional substitution reaction, the substitution barriers of S-containing amino acid residues Cys and Met are lower than that of N-containing amino acid residues His and Lys. These results reveal that the S-containing protein and guanine is probably the main targets for the iminoethers platinum compounds. The activation energy of reaction of trans-EE with targets molecules is lowest, which confirmed the correctness of the experiments. In the fourth chapter, we have carried out the exploration to the free radical reactionmechanism of three kinds of anti-iminoether Pt complexes. It is found that the activation energy of reaction of trans iminoether Pt complexes with electrons tends to0. It is very easy for them to rapidly generate free radicals after capturing electrons.These radicals can attack the glucoside of DNA backbones, and lead to the rupture of DNA strands. Calculations show that the active free radicals may attack on C4’ and C5’ site of DNA backbone and the methyl group of thymine, and it is difficult for them to combine with purine bases.