青蒿素及其衍生物抗疟活性的密度泛函理论研究
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摘要
为了深入研究青蒿素及其衍生物的抗疟活性和分子结构之间的关系,运用密度泛函理论B3LYP方法,以6-31G*为基组对青蒿素及其衍生物二氢青蒿素、蒿甲醚和青蒿琥酯进行了优化计算.从分子的几何构型、NBO电荷及前线轨道能等方面分析了青蒿素及其衍生物的抗疟活性与结构之间的关系.青蒿素及其衍生物结构中的过氧桥键是其抗疟作用的活性位,O17和O_20带负电荷越多、ΔE_(LUMO-HOMO)越低、E_(HOMO)能级越高,分子的抗疟活性越强.结果表明,4种化合物的抗疟活性顺序为:青蒿素<二氢青蒿素<蒿甲醚<青蒿琥酯,与临床实验结果相吻合.
In order to study the relationship between the structure and antimalarial activity of artemisinin and its derivatives,the density functional theory( DFT) B3 LYP method with 6-31G*as a basis set was used to optimize the structure of artemisinin,dihydroartemisinin,artemether and artesunate. The properties of the artemisinin and its derivatives have been discussed in detail based on their molecular structures,NBO charges and the energies of the frontier molecular orbitals. The results showed that the endoperoxy bridge is likely the most active site and essential for antimalarial activity of artemisinin and its derivatives. The more negative charge of O17 and O_20,the lower enengy of ΔE_( LUMO-HOMO)and the higher energy of E_(HOMO)resulted in the stronger antimalarial activity of the compounds. It was revealed that the antimalarial activity of the compounds goes along with the order: artemisinin
In order to study the relationship between the structure and antimalarial activity of artemisinin and its derivatives,the density functional theory( DFT) B3 LYP method with 6-31G*as a basis set was used to optimize the structure of artemisinin,dihydroartemisinin,artemether and artesunate. The properties of the artemisinin and its derivatives have been discussed in detail based on their molecular structures,NBO charges and the energies of the frontier molecular orbitals. The results showed that the endoperoxy bridge is likely the most active site and essential for antimalarial activity of artemisinin and its derivatives. The more negative charge of O17 and O_20,the lower enengy of ΔE_( LUMO-HOMO)and the higher energy of E_(HOMO)resulted in the stronger antimalarial activity of the compounds. It was revealed that the antimalarial activity of the compounds goes along with the order: artemisinin
引文
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[17]张鑫,杨英杰,吕庆章.4种甘草黄酮类化合物抗氧化活性的密度泛函理论研究[J].计算机与应用化学,2012,29(6):656-660.ZHANG X,YANG Y J,LQ Z.Density functional theory calculations on antioxidation activity of four flavones from radix glycyrrhizae[J].Computers and Applied Chemistry,2012,29(6):656-660.
[18]张鑫,杨英杰,吕庆章.黄芪异黄酮类化合物抗氧化活性的密度泛函理论研究[J].化学研究与应用,2012,24(11):1662-1669.ZHANG X,YANG Y J,LQ Z.Density functional theory calculations on antioxidation activity of the isoflavone compounds from astragalus[J].Chemical Research and Application,2012,24(11):1662-1669.
[19]陈莹,徐抗震,宋纪蓉,等.酚酸抗氧化活性的理论计算[J].食品科学,2011,32(9):36-39.CHEN Y,XU K Z,SONG J R,et al.Theoretical study on antioxidant activity of phenolic acids[J].Food Science,2011,32(9):36-39.
[2]青蒿结构研究协作组.一种新型的倍半萜内酯-青蒿素[J].科学通报,1977,22(3):123.Research Group of Artemisinin Structure.A new kind of half terpene lactones-artemisinin[J].Chinese Science Bulletin,1977,22(3):123.
[3]中国科学院生物物理研究所青蒿素协作组.青蒿素的晶体结构及其绝对构型[J].中国科学,1979,11:1114-1128.Institute of Biophysics,Chinese Academy of Sciences,Artemisinin Group.The crystal structure of artemisinin and its absolute configuration[J].Science China,1979,11:1114-1128.
[4]李英,虞佩琳,陈一心,等.青蒿素衍生物的合成[J].科学通报,1979,24(14):667-669.LI Y,YU P L,CHEN Y X,et al.Synthesis of some derivatives of artemisinin[J].Chinese Science Bulletin,1979,24(14):667-669.
[5]梁洁,李英.青蒿素芳香醚类衍生物的合成[J].中国药物化学杂志,1996,19:22-25.LIANG J,LI Y.Synthesis of the arylether derivatives of artemisinin[J].Chinese Journal of Medicinal Chemistry,1996,19:22-25.
[6]刘旭.青蒿素衍生物的研究[J].药学通报,1980,15(4):183.LIU X.Research of artemisinin derivatives[J].Chinese Pharmaceutical Bulletin,1980,15(4):183.
[7]郭燕,王俊,陈正堂.青蒿素类药物的药理作用新进展[J].中国临床药理学与治疗学,2006,11(6):615-620.GUO Y,WANG J,CHEN Z T.Recent advancement in pharmacological effects of artemisinin and its derivatives[J].Chinese Journal of Clinical Pharmacology and Therapeutics,2006,11(6):615-620.
[8]李琛琛,尹昆,闫歌.抗疟药青蒿素及其衍生物相关药理作用研究进展[J].中国病原生物杂志,2016,11(2):185-187.LI C C,YIN K,YAN G.Advances in research on the pharmacological action of the antimalarial artemisinin and its derivatives[J].Journal of Pathogen Biology,2016,11(2):185-187.
[9]张楠.青蒿素类药物的主要研究进展[J].中国药物评价,2013,30(1):13-16.ZHANG N.Research progress of the artemisinin drugs[J].Chinese Journal of Drug Evaluation,2013,30(1):13-16.
[10]FRISCH M J,TRUCKS G W,SCHLEGEL H B,et al.Gaussian 03[CP].Revision A.01,Wallingford CT:Gaussian,Inc.,2004.
[11]HNYK D,MACHACEK J,ARGUELLO G A,et al.Stucture and conformational properties of bis(trifluoromethyl)peroxydicarbonate,CF3OC(O)O-OC(O)OCF3[J].The Journal of Physical Chemistry A,2003,107(6):847-851.
[12]陈扬,朱世民,陈洪渊.青蒿素类抗疟药研究进展[J].药学学报,1998,33(3):234-239.CHEN Y,ZHU S M,CHEN H Y.The research progress of artemisinin-based antimalarial drugs[J].Acta Pharmaceutica Sinica,1998,33(3):234-239.
[13]BUTLER A R,WU Y L.Artemisinin(qinghaosu):a new type of antimalarial drug[J].Chemical Society Reviews,1992,21(2):85-90.
[14]GOLENSER J,WAKNINE J H,KRUGLIAK M,et al.Current perspectives on the mechanism of action of artemisinins[J].International Journal for Parasitology,2006,36(14):1427-1441.
[15]SHUKLA K L,GUND T M,MESHNICK S R.Molecular modeling studies of the artemisinin(qinghaosu)-hemin interaction:Docking between the antimalarial agent and its putative receptor[J].Journal of Molecular Graphics,1995,13(4):215-222.
[16]程永浩,李晓艳,郑世均.青蒿素及其衍生物的量子化学及构效关系研究[J].计算机与应用化学,2000,17(21):21-22.CHENG Y H,LI X Y,ZHENG S J.Quantum chemistry and structure-activity relationship studies of artemisinin and its derivatives[J].Computers and Applied Chemistry,2000,17(21):21-22.
[17]张鑫,杨英杰,吕庆章.4种甘草黄酮类化合物抗氧化活性的密度泛函理论研究[J].计算机与应用化学,2012,29(6):656-660.ZHANG X,YANG Y J,LQ Z.Density functional theory calculations on antioxidation activity of four flavones from radix glycyrrhizae[J].Computers and Applied Chemistry,2012,29(6):656-660.
[18]张鑫,杨英杰,吕庆章.黄芪异黄酮类化合物抗氧化活性的密度泛函理论研究[J].化学研究与应用,2012,24(11):1662-1669.ZHANG X,YANG Y J,LQ Z.Density functional theory calculations on antioxidation activity of the isoflavone compounds from astragalus[J].Chemical Research and Application,2012,24(11):1662-1669.
[19]陈莹,徐抗震,宋纪蓉,等.酚酸抗氧化活性的理论计算[J].食品科学,2011,32(9):36-39.CHEN Y,XU K Z,SONG J R,et al.Theoretical study on antioxidant activity of phenolic acids[J].Food Science,2011,32(9):36-39.