Theoretical Studies On Activity Of The Nucleic Acid Mediated By The Small Molecules

For a long time,the effects on the activity of nucleic acid by H₂O,O₂,and other small molecules as well as Pt metal ion are widely attention of research.A large number of studies have demonstrated that the hydroxy radical is a major intermediate produced when water is exposed to the ionizing radiation.The major pathway is believed to involve hydroxyl addition to theπ-bonds of the nucleobases.The subsequent reactivity of the nucleobases radicals and their repective O2 trapping products has been a topic of considerable interest to understand.Moreover,the anticancer mechanism of cisplatin as one of the most widely used drugs for treating cancer has become the focus of the researchers.However,the reactive species and the reaction mechanis of the cisplatin-DNA complex under the radiation are not clear,yet.This dissertation makes systematic study on the reactivity of the nucleobases radicals and the influence of excess electrons on the cisplatin-DNA complex by using the quantum chemistry methods.It also provides theoretical clues for future study on the reactivity effects of some small molecular with nucleic acid and design the new anticancer drug.The reactivity of thymine peroxy radicals in DNA and their fate are studied using the reliable DFT methods.The most accessible H1’abstraction by the C6-peroxyl once reported experimentally is effectively competitive to the crosslinking reaction between the C6-peroxyl and the C5 or C6 on the 5’-adjacent thymine base.The rare transfer of the O_bH1’group to the C1’radical from the formed hydroperoxide happens with a very strong heat release.Afterwards,the parallel reactions including the H1’and H2’abstractions by the C6-alkoxyl in an inter-nucleotidyl manner lead to direct formation of thymine glycol.After the H1’abstraction by the C6-alkoxyl,the apyrimidinic site can be formed on C1’through effective N1–glycosidic bond rupture.Hence,new radical reaction paths for the formation of DNA oxidationproducts are suggested,which are strongly different from the previously suggested paths with the tetraoxide intermediate.In addition,in the DNA double strand,when the–OH and–OO both directe to the5’-adjacent nucleobase,the path of the thymine C6-peroxyl is similar to the paths in the DNA single strand.However,due to the restriction of coplementary strand,the differeces of the torsion angles between the single and double strand are very huge,which leading to the barriers of the C1’-H1’activation reaction much lower than the barrier in the single strand.When the–OH and–OO both directe to the 3’-adjacent nucleobase,the majority of tandem lesions are derived from hydrogen atom abstraction from the thymine methyl group.Concurrently,the C6-O radical is generated in the 5’-thymine which could further abstracte the H atom to formation the thymine glycol in the 5’-end thymine base.The barriers of this process are higher than the thymine glycol formation barrier in the 3’-end thymine base.Therefore,the formation of the oxidative product-thymine glycol is directional.The RNA oxidation is investigated through usage of the modified RNA model with inclusion of the uracil C6-peroxyl stereoisomers.Our results give the clear evidence that efficiency of the H2’abstraction by the C6-peroxyl is normally lower than those of its corresponding carbon-center radical.The present studies unveil the important correlation of conformation with reactivity of the uracil C6-peroxyl,which control the distribution of the various H-abstraction products.Additionally,efficiency of addition reactions between the C6-peroxyl and the adjacent uracil base is almost equivalent to that of the H2’-abstraction reaction.Reliable DFT calculations were used to gain insights into the effects of excess electrons on the cisplatin–DNA complex.One electron injection is enough to break the two Pt–N7 bonds,which is driven by the rare symmetrical in-plane bending vibration.The dissociated[Pt（NH₃）₂]^+.group from the cisplatin–DNA complex could combine with H₂O,Cl^-in the surroundings to form a reactive species.The stable radical anion which formed by multiple electrons addition,have high efficiency for DNA damage.In the present studies,an alternate role of cisplatin in DNA damage was discovered,which strongly confirmed that the cisplatin–DNA complex is more vulnerable to attack from low-energy electrons.