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《Computers and Applied Chemistry》 2011-02
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Theoretical study on the degradation mechanism of lamivudine

Wang Xuejie and You Jinzong (School of Science and Technology,Zhejiang International Studies University,Hangzhou,310012,Zhejiang,China)  
Lamivudine(LMVD) is an important inhibitor for HIV.For a better understanding the degradation mechanism of LMVD and validating the experiments of Bedse G et al.Based on the quantum chemical software named GAMESS,we studied the electronic structures of LMVD and intermediates during the hydrolysis,oxidation,and MS~n processes.Using the Hartree-Fock method at the level 3-21G,the conformations,atomic net charges,bond orders,dipole moments and potential energies of these compounds in the neutral,acidic,alkaline and oxidative conditions were obtained.Then,the degradation mechanisms of LMVD under the various conditions and the fragmentation mechanisms of MS" were derived.The results indicated that LMVD remained stable in neutral,while it showed instability in acidic and alkali solutions.The degradation pathways of LMVD were similar in acidic and alkali solutions.There were two kind hydrolytic mechanisms.One pathway was that the nucleophilic reaction occurred at C6 site,the C6-N7 bond to be cleaved,and the degradation productⅤto be brought,then the second nucleophilic reaction occurred at C8 site,the N3-C8 bond to be cleaved,and the productⅡto be brought;other pathway was that the nucleophilic reaction occurred at C8 site,the N3-C8 bond to be cleaved,and the degradation productⅠto be brought.In alkali condition,the hydroxyl group had stronger nucleophilicity,the atomic net charges and bond orders were favorable to the nucleophilic reaction,so that,the rate of hydrolysis was faster than in acidic condition.In the H_2O_2 solution, LMVD could be oxidated,but the oxidative productsⅢandⅣwere difficult to be hydrolyzed due to their more stable than LMVD.The bond cleavage of MS occurred primarily at the weakest bonds.The outcomes of our investigation were highly consistent with the results of Bedse G et al.It indicated that it was easy and convenient to presume and explain the degradation mechanism and MS pathways of drugs by using of GAMESS quantum chemical software.
【Key Words】: lamivudine(LMVD) quantum chemistry hydrolysis mechanism
【Fund】: 浙江省重点科研项目(2006C21092)
【CateGory Index】: R91
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