Theoretical Studies On The Hydrolysis Mechanism Of Phosphodiesterase And The Glucosidation Mechanism Of Halophenyl-pyridazinone

As the only metabolizing enzyme for the degradation of second messenger cAMP and cGMP, phosphodiesterase has been the clinical target of various human diseases. But the hydrolysis procedure of PDE is still unclear. To investigate the mechanism of PDE catalysis, three types of PDE, PDE4d, PDE5a and PDE10a were selected and studied by molecular dynamics (MD) simulation and quantum mechanics (QM) calculation methods. MD Simulation results indicated that, different PDEs share a similar hydrolysis area in the active sites, the phosphate parts of cyclic nucleotides take the same orientation and are partly surrounded by water molecules. Based on statistical data from MD simulation, the QM calculation models were built. The calculation results indicated that in aqueous solution, the hydroxide ion that attacks the phosphor atom of the cyclic nucleotide as a nucleophile, may either bridge or migrate between the two metal ions in the active site. To help the ring-open reaction, it is the water molecule that provides proton to the 03'atom of cyclic nucleotide as a donor, and generates another hydroxide ion complex with the metal ion. The relative computational results were accepted by Journal of Theoretical and Computational Chemistry on 28th, Oct.2011.The derivates of pyridazinone which have a great many of pharmacy usages, not only act as inhibitors against PDEs, but also works as anticonvulsant, antiviral, antitumor, plants growing regulating etc. The glucosidation is an efficient method for synthesis of new medicines and improvement of present medicines. In experiments, there were some problems with controlling the products when pyridazinone glucosidation were synthesized. The glucosidation of 6-(4-halophenyl)-3(2H)-pyridazinone engenders two isomers, O-glucoside and N-glucoside. In order to find appropriate methods to obtain different glucosides, density functional theory (DFT) calculation at B3 LYP/6-31 G(d) level was employed to explore the mechanisms of two processes including Koenigs- Knorr reaction and phase-transfer-catalysis reaction (PTC Reaction) of 6-(4-halophenyl)-3(2H)-Pyridazinone glucosidation. The calculation results reveal that both processes are Sn2 reaction, in which O-glucosides are kinetic products and N-glucosides are thermodynamic products. That O-glucosides were main products in Koenigs-Knorr Reaction is due to the assistance of sliver ions, which bond to 2-N of pyridazinone and prevent the transforming from O-glucosides to N-glucosides. According to the results, employment of solvents with lower boiling point in Koenigs-Knorr Reaction should be better way to obtain O-glucosides. The relevant report has been published in Computational and Theoretical Chemistry, (2011) 963, 119-124.5-fluorouracil (5-FU) and derivates are clinic antineoplastic medicines. The glucosidation of 5-FU or its derivates may improve the drugeffect and decrease the side effect. In this paper, the glucosidation mechanisms of 2-phenoxyl-5-fluorouracil and 2-thiophenyl-5-fluorouracil were studied. The synthesis of glucosidations in experiments was performed by two methods, phase-transfer catalysis (PTC) method and Koenigs-Knorr reaction. The results indicate that both methods are follow Sn2 mechanism. In PTC method the N-glucosidation products have lower energy barriers, which agree with the experimental results. And the Ag ion in Koenigs-Knorr reaction help to produce O-glucosidaton products by occupying 1-N position.