A Theoretical Study On The Mechanism Of Free Radical On Pt-based Antitumor Drugs Interaction With Biological Target Molecules

Platinum anticancer drugs have been carried out for nearly 30 years.Cis-config uration Pt-based complexes showed good antitumor activity,such as cisplatin and carboplatin.And trans platinum complexes such as trans-[PtCl2(NH3)2] in NH3 are instead by other ligands such as pyridine,quinoline and imino,having a dramatic change in anticancer activity,and some complexes exist the anticancer activity even more than cisplatin.Despite the success of these complexes in cancer therapy,there are two main disadvantages: severe side effects and internal / acquired resistance.In addition,we can modify the reaction mechanism of initial anticancer drug and improve the anticancer activity by the modern chemical or physical methods except for improving of new drugs.At present,although the anticancer mechanism of platinum drugs reported in a lot,the mechanism is still not clear.Especially the mechanism of the interaction between based platinum anticancer drugs and electrons is still rarely concerned by a density functional theory study.In the third chapter,we study the interaction of electronic and trans-[Pt(P)NH3 Cl2](P = 3-picoline or pyridine)then attacking ribose ring or thymine(T).We can obtain conclusion that one-electron attach trans-[Pt(P)NH3Cl2] and generates a Cl ions and T-shaped trans-[Pt(P)NH3Cl]? neutral radical,and then the combination of trans-[Pt(P)NH3Cl]? with the second electron can form a linear type trans-[Pt(P)NH3]? radical.Our calculations found that trans-[Pt(P)NH3Cl]? binds with purines bases and will be lost high affinity but it might capture hydrogen from ribose((H4'/H5'/C3'–O))or a hydrogen of methyl groups(–CH3–H')on thymine(T)to improve the yield of DNA strand breaks.In summary,the results may have significance that the H4'site on ribose or –CH3–H' site on T might be the most dominant target from the trans-[Pt(P)NH3Cl]?.In the fourth chapter,structures of all species?transition state and activation energy barrier of the interaction of platinum drugs and electronic has been studied.the free radical reaction mechanism of platinum complexes showed that Lu et al.and Kopyra et al are obtained by spectral methods and are very hard to verify our overall theory.For our calculation results can be said that these free radical reactions are no barrier reaction and activation energy is either close to zero or negative.