Theoretical Study Of The Anti-tumor Activity Pattern Of Pt(Ⅳ) Compounds Containing Chlorine Leaving Groups

Tetravalent platinum[Pt（Ⅳ）]compounds containing chlorine leaving groups are easily reduced and exert good anticancer activity.However,theoretical studies of these compounds are rarely reported.Therefore,it is necessary to investigate the physicochemical properties and mechanism of action of such compounds through theoretical calculations.This thesis first investigated the theoretical calculation of tetravalent platinum compounds with different substituents containing chlorine leaving groups.Then comparing the anti-tumor activity of tetravalent platinum compounds with different substituents by analyzing the substituent effect.Establishing the transition state model for the reaction with biomolecules to complete the theoretical study of the anti-tumor activity of these compounds.The main study is divided into the following three parts:The first part is the screening of calculation methods for Pt（Ⅳ）compounds containing chlorine leaving groups.There is no very systematic calculation method for tetravalent platinum compounds containing chlorine leaving groups by reviewing and analyzing the literature.Therefore,the first Pt（Ⅳ）compound to enter clinical trials,omaplatin,was selected for the study.Multiple geometric optimization calculation methods and calculation basis sets,frequency calculation methods and calculation basis sets for this compound were compared and selected by using the powerful quantum chemical calculation software Gaussian 16.The geometric optimization reveals the smallest error between the combination of the LSDA/SDD or CEP-121G calculation method and the base group and the experimental data.The results of the frequency calculations show that the combination of LSDA/SDD provides the best fit to the experimental values.The second part is the analysis of the substituent effect of Pt（Ⅳ）compounds containing chlorine leaving groups.The substituent effects of tetravalent platinum compounds that have a similar structure to omaplatin were investigated.The physicochemical properties and vibrational spectra of Pt（bipy）Cl₄ and Pt（en）Cl₄were calculated for the first time.Next,the three compounds were analyzed for their HOMO-LUMO energy gap,flexibility,hardness,natural atomic charge,electrostatic potential,electrostatic polar point,orbital delocalization properties and properties such as toxicity carried by the compounds and the dose required to treat cancer.The results show that Pt（bipy）Cl₄ is the most easily reduced and possesses superior physicochemical properties and drug-forming potential than omaplatin.This result suggests that Pt（bipy）Cl₄ can be investigated as a new antitumor drug and provides a theoretical basis for the development of subsequent drugs in the future.The third part is the reaction mechanism of Pt（Ⅳ）compounds containing chlorine leaving groups.In order to verify whether the rate of reaction of tetravalent platinum compounds containing chlorine leaving groups with biomolecules is related to anticancer activity,we constructed transition state models for the reaction of three tetravalent platinum compounds with L-cysteine.By analyzing the changes of bond lengths and bond angles of different intermediates during the reaction and performing IRC verification to construct a reasonable transition state structure,the reaction mechanism can be further investigated.We also analyzed the relationship between reaction rate and anticancer activity by comparing the changes in Gibbs free energy and reaction enthalpy before and after the reaction.Three parts were studied in this study,including computational analysis and screening of Pt（Ⅳ）compounds containing chlorine substituents,substituent effect analysis and transition state model construction.The calculations include the selection of the best Pt（Ⅳ）compounds containing chlorine substituents,the effect of different types of substituents on the reduction and anticancer effect of the compounds and the reaction mechanism of three Pt（Ⅳ）compounds with biomolecules.Our work lays the theoretical foundation for the further development of new antitumor drugs containing the chlorine leaving group Pt（Ⅳ）.