Theoretical Study On The Interaction Of Gold(Ⅰ) Antitumor Drug With Target Molecules

Recently, gold complexes are recognized to be one of the promising non-platinum drugs. Au(I) phosphine compounds have achieved great success in clinical treatment, for instance, the treatment success rate of rheumatoid arthritis has been increased to 70% since the auranofin and its chloro analog Et3 PAuCl used in the treatment of rheumatoid arthritis. Because of the special biological situation, however, Au(I) phosphine compounds more easily bond to other biological molecules including S or Se atom. The researches represent a highly interesting to Au(I) NHC complexes because of the strong σ-donating properties the same as Au(I) phosphine, and the Au–C bond was formed by п-back effect, which was proved to more stable than Au(I) phosphine. In addition, the Au(I) NHC complexes was confirmed to have a different mechanism, hardly targeting DNA. They could selectively inhibit the activty of the enzyme thioredoxin reductase(TrxR) and then induce the apoptosis of the cancer cellula. The reaction mechanism of[(R2Im)2Au]+and(R2Im)AuCl complexes was studied with the DFT at the B3 LYP level in this essay.In chapter 3, we have investigated the reaction of[(R2Im)2Au]+(R=Me, Et, i-P and n-Pr) complexes binding to Cys and Sec. The calculations showed that the reaction of [(R2Im)2Au]+ complexes binding to Sec is more easy than to Cys. In addition, the order of activation energy increased in Cys and Sec systems is Me < Et < i-Pr < n-Pr during the monofunctional substitution reaction. For the bifunctional substitution reaction, the order of activation energy increased in Cys and Sec systems is n-Pr > Et > Me > i-Pr. Furthermore, the affect of the environment is weak to the reaction.To further study the Au(I)-NHC complexes, we also calculated the reaction of hydrolysates of(R2Im)AuCl(R=Me, Et, i-P and n-Pr) complexes binding to Cys and Sec. The results indicated that the reaction of hydrolysates of(R2Im)AuCl complexes binding to Sec was more prefer. There were different order of activation energy in Cys and Sec systems. For the monofunctional substitution reaction, Me group was much more favourable in Cys system but in Sec system the most popular group was Et group. For the bifunctional substitution reaction, the activation energy of i-Pr group was lower than other group. Moreover, the different order of activation energy increased was showed in aqueous solution and protein.