Theoretical Study On The Interaction Of Polynuclear Platinum(Ⅱ) Aantitumor Drug With Target Molecules

Recently some studies revealed that BBR3464 is significantly more cytotoxic than cisplatin even in the cisplatin resistant cancer cells. It is now generally agreed that cellular DNA is primary target of platinum drug. Since the concentration of glutathione and cysteine inside the cell is about 10 m M, it is supposed that most of the Pt drug interaction with sulfur-biomolecules before it enter cell nucleus to bind to DNA. However, many details of the mechanism of platinum reaction with biological target leading to antitumor activity still remain not clear.In this paper, we systematically studied the interactions cisplatin and novel polynuclear platinum(Ⅱ)(BBR3005 and BBR3464) hydrolyzed complexes with(glutathione, methionine, cysteine and DNA purine bases) with two different DFT-B3LYP/M06 functional methods and IEF-PCM solvation model.In Chapter 3, we explore the monofunctional substitution reactions betweencisplatin and novel polynuclear platinum(Ⅱ)(BBR3005 and BBR3464) hydrolyzedcomplexes and sulfur-donor biomolecules(cysteine, methionine and glutathione)and purine bases(guanine and adenine) in DNA. The calculations revealed that theanticancer activity of BBR3464 was higher than cisplatin and GSH was morefavorable intracellular targets than Met, Cys and DNA purine bases for BBR3464.What is more, the computed activation energy barrier for substitution reaction ofdiaqua-cisplatin with DNA by B3 LYP functional method is 20.1 kcal/mol(11.2kcal/mol for M06 functional method) for guanine(G)(experimental value = 18.3kcal/mol), which shows that the B3 LYP functional method may be more suitable forplatinum-DNA system.In Chapter 4, we mainly studied that the difunctional substitution reaction of polynuclear platinum(Ⅱ)(BBR3005 and BBR3464) hydrolyzed complexes with sulfur-donor biomolecules(cysteine, methionine and glutathione) and purine bases(guanine and adenine) in DNA based on the results of Chapter 3. According to thecalculations, it was demonstrated that the activity order of all difunctional substitution reactions of BBR3005 was G-GSH > GG > GA in the aqueous solution,and the activation free energies of polynuclear platinum binding to DNA purine bases were still lower than those of cisplatin. In addition, the structure of head to head(HH) convert to the structure of head to tail(HT) and the corresponding activation barriers were close to each other. Our calculation demonstrate that interstrand cross-links of head to tail(HT) are being dominating feature of the reaction of polynuclear platinum(Ⅱ)(BBR3005 and BBR3464) with DNA.