氨基糖衍生物及其稀土配合物的合成和结构表征
|
摘要
本文在计算机辅助设计的指导下，对一类顺丁烯二酸酐衍生物与氨基糖相连的化合物进行了结构改造。
结构改造包括：改变糖环部分保护基，合成了乙酰基保护的、苯甲酰基保护的和苄基保护的2-脱氧-N-葡萄糖酰胺丙烯酸(化合物A、B、C)；改变氢键供体和共轭体系，合成了乙酰基保护的2-脱氧-N-葡萄糖丁烯二酰亚胺、乙酰基保护的2-脱氧-N-葡萄糖酰胺丙酸和2-脱氧-N-葡萄糖酰胺邻苯甲酸；去掉糖环上的保护基，增大糖环极性，合成了2-脱氧-N-葡萄糖酰胺邻苯甲酸；改变糖环与共轭体系的空间位置、改变糖的种类分别合成了1-脱氧-N-葡萄糖酰胺丙烯酸、1-脱氧-N-半乳糖酰胺丙烯酸。其中，化合物A、化合物B、化合物C得到了晶型较好的单晶，有待于晶体结构分析。对上述化合物用红外光谱和核磁共振技术进行了结构确证。用异头效应和邻基参与效应解释了两种中间体：1-溴乙酰糖和1-叠氮乙酰糖的构型。
另外，本文还以抑瘤活性较好的化合物A和化合物B为配体，与三氯化钐、三氯化镨、三氯化钕、三氯化镝合成了三类，共九种稀土金属配合物。通过对稀土元素含量、氯元素含量的滴定，以及红外光谱，核磁共振技术对配合物的结构进行了初步的确证，推测了配合物可能的结构分别是：配合物A系列Ln以三个共价离子键与羧基氧相连，三个NH的N以及二个EtOH的O与Ln形成配位键，形成Ln系元素以八配位结构存在。配合物A系列Ln以三个共价离子键与羧基氧相连，三个NH的N与Ln形成配位键，苯甲酰基保护的糖分散在金属配合物的外围，形成Ln系元素以六配位结构存在。配合物C中Ln以三个共价离子键与羧基氧相连，三个NH的N与Ln形成配位键，形成Ln系元素以六配位结构存在。对含不同保护基的糖配体与稀土金属形成的配合物的性质差异进行了探讨。为进一步研究，利用稀土离子的生物探针作用来研究药物在体内的作用机理，做了必要的准备。
本文所合成的部分化合物以及配合物的活性测试尚在进行当中。配合物单晶
结构测定正在进行中。
Based on the results of computer added drug design, a series of glucosamines with maleic anhydride derivative have been structural modifided and synthesized.
This structural modification are comprised by (1) changing the protected groups of saccharide part to sythesize the compounds 2-amino- glucose linking with 3-formyl-propenoic acid with the deferent hydroxyl protected groups, such as acetyl, benzoyl, benzyl on saccharide; (Compound A, B andC) (2)change hydrogen bond donor and conjugate system in order to sythesizing the compounds 2-deoxyglucose linking with maleic acyl imide with the hydroxyl protected groups, acetyl, on saccharide and 2-amino-glucose linding with 3-formyl-propanic acid with the hydroxyl protected groups, acetyl, on saccharide, 2-amino-glucose linding with 2-formylbenzoic acid; (3)Deprotect those protected groups of saccharide in order to increasing their polarity, sythesize the compound 2-amino-glucose linking with 2-formylbenzoic acid; (4)change the spatial arrangement and the kind of sacchride, sythesize the compounds 1-ammo-glucose, 1-amino-galactose linking with 3-formyl-propenic acid with the hydroxyl protected groups, acetyl, on saccha
ride. Among of these compounds, A, B and C have been fostered their singal crystals which now is being testing their crystal structure. All compounds have been characterized by IR and NMR spectrum. The configuration of 1-bromido-peracetyl-glucose and 1-azido-peracetyl-glucose have been explained by anomeric effect and ortho-groups attached effect.
Moreover, three series of Lantnide-sccharide complexes hve been firstly synthesized by the reaction of Lanthanide tricloride with the compounds d A , B as the ligand at the different ratio. The structure have been characterized by the NMR, IR and elemental aanalysis of metal and chloride. The distinction of the complexes
characters which have been synthesized by the saccharide including different protected groups and Lanthanide, have been discussed. The necessary preparation have been done to learn the mechanism of medicine in vivo by bio-probe effect of rare earth.
Further determination of bioactivities of all comounds are currently researching. The singal crystals now is being fostering and testing their crystal structure.
结构改造包括：改变糖环部分保护基，合成了乙酰基保护的、苯甲酰基保护的和苄基保护的2-脱氧-N-葡萄糖酰胺丙烯酸(化合物A、B、C)；改变氢键供体和共轭体系，合成了乙酰基保护的2-脱氧-N-葡萄糖丁烯二酰亚胺、乙酰基保护的2-脱氧-N-葡萄糖酰胺丙酸和2-脱氧-N-葡萄糖酰胺邻苯甲酸；去掉糖环上的保护基，增大糖环极性，合成了2-脱氧-N-葡萄糖酰胺邻苯甲酸；改变糖环与共轭体系的空间位置、改变糖的种类分别合成了1-脱氧-N-葡萄糖酰胺丙烯酸、1-脱氧-N-半乳糖酰胺丙烯酸。其中，化合物A、化合物B、化合物C得到了晶型较好的单晶，有待于晶体结构分析。对上述化合物用红外光谱和核磁共振技术进行了结构确证。用异头效应和邻基参与效应解释了两种中间体：1-溴乙酰糖和1-叠氮乙酰糖的构型。
另外，本文还以抑瘤活性较好的化合物A和化合物B为配体，与三氯化钐、三氯化镨、三氯化钕、三氯化镝合成了三类，共九种稀土金属配合物。通过对稀土元素含量、氯元素含量的滴定，以及红外光谱，核磁共振技术对配合物的结构进行了初步的确证，推测了配合物可能的结构分别是：配合物A系列Ln以三个共价离子键与羧基氧相连，三个NH的N以及二个EtOH的O与Ln形成配位键，形成Ln系元素以八配位结构存在。配合物A系列Ln以三个共价离子键与羧基氧相连，三个NH的N与Ln形成配位键，苯甲酰基保护的糖分散在金属配合物的外围，形成Ln系元素以六配位结构存在。配合物C中Ln以三个共价离子键与羧基氧相连，三个NH的N与Ln形成配位键，形成Ln系元素以六配位结构存在。对含不同保护基的糖配体与稀土金属形成的配合物的性质差异进行了探讨。为进一步研究，利用稀土离子的生物探针作用来研究药物在体内的作用机理，做了必要的准备。
本文所合成的部分化合物以及配合物的活性测试尚在进行当中。配合物单晶
结构测定正在进行中。
Based on the results of computer added drug design, a series of glucosamines with maleic anhydride derivative have been structural modifided and synthesized.
This structural modification are comprised by (1) changing the protected groups of saccharide part to sythesize the compounds 2-amino- glucose linking with 3-formyl-propenoic acid with the deferent hydroxyl protected groups, such as acetyl, benzoyl, benzyl on saccharide; (Compound A, B andC) (2)change hydrogen bond donor and conjugate system in order to sythesizing the compounds 2-deoxyglucose linking with maleic acyl imide with the hydroxyl protected groups, acetyl, on saccharide and 2-amino-glucose linding with 3-formyl-propanic acid with the hydroxyl protected groups, acetyl, on saccharide, 2-amino-glucose linding with 2-formylbenzoic acid; (3)Deprotect those protected groups of saccharide in order to increasing their polarity, sythesize the compound 2-amino-glucose linking with 2-formylbenzoic acid; (4)change the spatial arrangement and the kind of sacchride, sythesize the compounds 1-ammo-glucose, 1-amino-galactose linking with 3-formyl-propenic acid with the hydroxyl protected groups, acetyl, on saccha
ride. Among of these compounds, A, B and C have been fostered their singal crystals which now is being testing their crystal structure. All compounds have been characterized by IR and NMR spectrum. The configuration of 1-bromido-peracetyl-glucose and 1-azido-peracetyl-glucose have been explained by anomeric effect and ortho-groups attached effect.
Moreover, three series of Lantnide-sccharide complexes hve been firstly synthesized by the reaction of Lanthanide tricloride with the compounds d A , B as the ligand at the different ratio. The structure have been characterized by the NMR, IR and elemental aanalysis of metal and chloride. The distinction of the complexes
characters which have been synthesized by the saccharide including different protected groups and Lanthanide, have been discussed. The necessary preparation have been done to learn the mechanism of medicine in vivo by bio-probe effect of rare earth.
Further determination of bioactivities of all comounds are currently researching. The singal crystals now is being fostering and testing their crystal structure.
引文
[1] Matzuk M M, Kenne J L, Boime I, J. Biol. Chem., 1989, 264(2409).
[2] Baenriger J U, Green E D, in Biology of Carbohydrates Vol. 3, (eds. Ginsburg V, Robbinson P,) John Wiley, 1991, p. l.
[3] Hascall V C, in Biology of Carbohydrates Vol. 1(eds. Ginsburg V, Ribbinson P,)John Wiley, 1981, p.l.
[4] Albershem P, Darvill A, Augur C, Cheong J J, Eberhard S, Hahn M G, Marfa V, Mohnen D, O' Neill M A, Spiro M D, York W S, Acc. Chem. Res., 1992, 25, 77.
[5] Kennedy E P et al., Nature, 1991, 354, 125.
[6] John A J R Soc Med, 1997, 90: 260.
[7] Osman N et al. Proc Natl Acad Sci USA, 1997, 94: 14677.
[8] Kar. et al. J Nephrol Disly Trans Plant, 1997, 6: 509.
[9] 卢睿春等。抗肿瘤活性的研究[J]。海洋科学，1998(3)；63-64。
[10] 周绪斌等。中国生化药物杂志，2000，21(6)：308-310．
[11] 邱蔚然等。核糖在保护心脏功能中的作用[J]。中国生化药物杂志，2000，21(6)：319-321。
[12] 付新梅，江涛等。糖类对先导化合物的化学修饰及其在药学中的应用。中国海洋药物，2001，(2)：54-62。
[13] 世界有色金属，1995(7)：29-30
[14] 孔为，张秀英。稀土元素在医药上的应用，微量元素与健康研究，2000，17(2)：67-69
[15] Jancso N, Jancso-Gabor A. Effect of anticoaglulants on inflammatory tissue reactions Naungn-schmiedebergs Arch exp Path, pharmacol, 1960, 238: 83
[16] 曾正志，吴集贵，邓汝温。稀土化合物的药理学性质，化学通报，1986，(11)：28-31
[17] 曾正志，崔建中，邓汝温。甘草酸稀土配合物的制备及抗炎作用，科学通报(英文版)，1989，34(9)：751
[18] Chen Zhoung-ning, Deng Ru-wen, Wuji-gui. Synthesis, Characterization and anti-inflammatory activity of naproxen complexes with rare earth(Ⅲ), J. Inorg Biochem, 1992, 47(1): 56-81
[19] 马娴贤，吴集贵，邓汝温等。稀土与樟脑磺酸，邻菲啰啉二元及三元配合物及其药敏作用的研究，科学通报，1990，35(1)：38-39
[20] 陈淑英，张新怀，王金玉等。具有生物活性的金属配合物研究(Ⅵ)——对氨基水杨酸稀土配合物的合成、性质、抗结核菌及毒性研究，高等学校化学学报，1988，9(8)：75-763
[21] 宋之刚，戴荣斌，刘颖梅等。茜黄素GG稀土配合物的合成及其抗菌活性的研究，兰州大学学报(自然科学版)，1999，35(1)：111-115
[22] 邓汝温、张仲生。稀土药物和药物性质，稀土，1987，8(3)：36-47
[23] Vincke E, Sucker E. Nd salt of 3-salfoisonicotimic acid as an antith rombotic Klin Wschr, 1950, 28: 74
[24] Deng Ru-Wen, WuJi-gui, Long La-sheng. Lanthaanide complexes of rthyl biscoumocetate and their anticoagulan acticoagulant action. Synth. React Inorg Met Org Chem, 1993, 23(4): 493-500
[25] Deng Ru-wen, Lanthanide complexes of di(4-hedroxycoumariny1-3)acetic acid and their anticoagulant action. Bull Soc Chim Belg, 1992
[26] Wllis KJ. Inorg. Perspect: distribution of calcium in the rat due to chronic, renal failure. Biol Med, 1977, (1): 101-106
[27] 杨正银，王流芳，吴集贵等。某些稀土希夫碱配合物的抗肿瘤活性药理研究，科学通报，199，(9)：813-816
[28] 倪瑾，孟详顺，蔡建明等。Schiff碱稀土金属配合物对辐射导致肿瘤细胞DNA损伤及修复的影响。中华放射医学与防护杂志，2000，20(1)：46-39
[29] Jing H W, Chen B H, Zeng Z Z, et al. Synthesis andantioxidative activity of N-[(benzoylamineno)theiokxomethyl]-glycine complexes weth reare earth metals, J Coord Chem, 1998, 44(1): 16
[30] Ren Yanping, Bai Junfeng, Wang Liufang, et al. Synthesis andantioxidative acticity of N-[(benzoylamineno)theiokxomethyl]-glycine complexes with reare earth metals, J Coord Chem, 1998, 44(1): 16
[31] 邓乐生，董斌，邓汝温等。磺胺噻唑与稀土的西佛碱配合物及其抗氧化作用，兰州大学学报(自然科学版)，1998，34(3)：66-71
[32] 吴集贵，邓汝温，曾正志等。稀土在医药中的应用研究概况，有色金属与稀土应用，1994(1)：19-28
[33] 李永信。氯磺丙脲稀土配合物的急性毒性及其降血糖作用的研究，微量元素与健康研
究1995，12(2)：4-5
[34] 刘晓蕾，陈朝军，王宏宁等。消炎痛稀土(Ce，Sm)盐性质及镇痛、抗炎作用研究，稀土，1997，18(5)：13-16
[35] Drugs of the Future, 1998; 23(8): 924-925
[36] 王则民，我国稀土氨基酸固体配合物的研究进展，稀土，1992，13(3)：39-43
[37] Anindita Mukhopadhyay, Carbohydr, Res. 328(2000) 103
[38] 关怀民，童跃进，稀土，18(1997)20
[39] Fialkov Y. A., Kostromina N. A., Zh. Neorgan. Khim. 4(1959)1507
[40] Kostromina N. A., Ukr. Khim. Zh. 26(1960)3; Chem. Abstr. 54(1960)16252
[41] Sawyer D. T., Ph. D. Thesis, University of California, LosAngeles, Clif.,1956
[42] Clark E. R., Waddams J. A., Nature 180(1957)904
[43] 张树功，倪嘉瓒，无机化学学报，6(1990)422
[44] 扬延民，翁诗甫，高等化学学报，15(1994)646
[45] 吴翌，龙腊生，兰州大学学报(自然科学版)，34(1998)72
[46] 张永安，张英锋，赵慧春，稀土-氨基葡萄糖-咖啡酸配合物的合成与表征，北京师范大学学报(自然科学版)，2000，36(1)：81-84
[47] 江涛，左代妹，一类具有抗肿瘤活性的氨基葡萄糖化合物及其制备方法，中国专利，正在申请中
[48] 潘启超 胥斌 肿瘤药理学与化学治疗学，河南医科大学出版社2000年
[49] Franco Zunino*, Graziella Pratesi, Paola Perego, Role of the sugar moiety in the pharmacological activity of anthracyclines: development of a novel series of disaccharide analogs, Biochemical Pharmacology 61(2001) 933-938
[50] Federico Arcamone, Fabio Animati, Mario Bigioni, Giovanni Capranico, Configurational Requirements of the Sugar Moiety for the Pharmacological Activity of Anthracycline Disaccharides, Biochemical Pharmacology, 57(1999), pp. 1133-1139,.
[51] Tetsuo Shimamoto, Seiichi Imajo, Tadashi Honda, ect. Stucture-activity Relationship Study on N-Glycosyl Moirties Through model Building DNA and Ellipticine N-glycoside Complex, Biorgan. and Med. Chem. Letters, 6(1996) PP1331-1334
[52] 傅佑丽，稀土生物效应机理研究进展，曲阜师范大学学报，2001，27(2)：81-84
[53] Sumaoka J, Yashiro M, Komiyama M, Nucleic Acids Sympser., 1992, 27, 1707-1708
[54] Komiyama M, Yashiro M, Shiba T, J. Fac. Eng. Univ. Tokyo. Ser., 1993, 42(2), 143-154
[55] Komiyama M, Kodama T, Takeda N. J. Biochem., 1994, 115, 809-810
[2] Baenriger J U, Green E D, in Biology of Carbohydrates Vol. 3, (eds. Ginsburg V, Robbinson P,) John Wiley, 1991, p. l.
[3] Hascall V C, in Biology of Carbohydrates Vol. 1(eds. Ginsburg V, Ribbinson P,)John Wiley, 1981, p.l.
[4] Albershem P, Darvill A, Augur C, Cheong J J, Eberhard S, Hahn M G, Marfa V, Mohnen D, O' Neill M A, Spiro M D, York W S, Acc. Chem. Res., 1992, 25, 77.
[5] Kennedy E P et al., Nature, 1991, 354, 125.
[6] John A J R Soc Med, 1997, 90: 260.
[7] Osman N et al. Proc Natl Acad Sci USA, 1997, 94: 14677.
[8] Kar. et al. J Nephrol Disly Trans Plant, 1997, 6: 509.
[9] 卢睿春等。抗肿瘤活性的研究[J]。海洋科学，1998(3)；63-64。
[10] 周绪斌等。中国生化药物杂志，2000，21(6)：308-310．
[11] 邱蔚然等。核糖在保护心脏功能中的作用[J]。中国生化药物杂志，2000，21(6)：319-321。
[12] 付新梅，江涛等。糖类对先导化合物的化学修饰及其在药学中的应用。中国海洋药物，2001，(2)：54-62。
[13] 世界有色金属，1995(7)：29-30
[14] 孔为，张秀英。稀土元素在医药上的应用，微量元素与健康研究，2000，17(2)：67-69
[15] Jancso N, Jancso-Gabor A. Effect of anticoaglulants on inflammatory tissue reactions Naungn-schmiedebergs Arch exp Path, pharmacol, 1960, 238: 83
[16] 曾正志，吴集贵，邓汝温。稀土化合物的药理学性质，化学通报，1986，(11)：28-31
[17] 曾正志，崔建中，邓汝温。甘草酸稀土配合物的制备及抗炎作用，科学通报(英文版)，1989，34(9)：751
[18] Chen Zhoung-ning, Deng Ru-wen, Wuji-gui. Synthesis, Characterization and anti-inflammatory activity of naproxen complexes with rare earth(Ⅲ), J. Inorg Biochem, 1992, 47(1): 56-81
[19] 马娴贤，吴集贵，邓汝温等。稀土与樟脑磺酸，邻菲啰啉二元及三元配合物及其药敏作用的研究，科学通报，1990，35(1)：38-39
[20] 陈淑英，张新怀，王金玉等。具有生物活性的金属配合物研究(Ⅵ)——对氨基水杨酸稀土配合物的合成、性质、抗结核菌及毒性研究，高等学校化学学报，1988，9(8)：75-763
[21] 宋之刚，戴荣斌，刘颖梅等。茜黄素GG稀土配合物的合成及其抗菌活性的研究，兰州大学学报(自然科学版)，1999，35(1)：111-115
[22] 邓汝温、张仲生。稀土药物和药物性质，稀土，1987，8(3)：36-47
[23] Vincke E, Sucker E. Nd salt of 3-salfoisonicotimic acid as an antith rombotic Klin Wschr, 1950, 28: 74
[24] Deng Ru-Wen, WuJi-gui, Long La-sheng. Lanthaanide complexes of rthyl biscoumocetate and their anticoagulan acticoagulant action. Synth. React Inorg Met Org Chem, 1993, 23(4): 493-500
[25] Deng Ru-wen, Lanthanide complexes of di(4-hedroxycoumariny1-3)acetic acid and their anticoagulant action. Bull Soc Chim Belg, 1992
[26] Wllis KJ. Inorg. Perspect: distribution of calcium in the rat due to chronic, renal failure. Biol Med, 1977, (1): 101-106
[27] 杨正银，王流芳，吴集贵等。某些稀土希夫碱配合物的抗肿瘤活性药理研究，科学通报，199，(9)：813-816
[28] 倪瑾，孟详顺，蔡建明等。Schiff碱稀土金属配合物对辐射导致肿瘤细胞DNA损伤及修复的影响。中华放射医学与防护杂志，2000，20(1)：46-39
[29] Jing H W, Chen B H, Zeng Z Z, et al. Synthesis andantioxidative activity of N-[(benzoylamineno)theiokxomethyl]-glycine complexes weth reare earth metals, J Coord Chem, 1998, 44(1): 16
[30] Ren Yanping, Bai Junfeng, Wang Liufang, et al. Synthesis andantioxidative acticity of N-[(benzoylamineno)theiokxomethyl]-glycine complexes with reare earth metals, J Coord Chem, 1998, 44(1): 16
[31] 邓乐生，董斌，邓汝温等。磺胺噻唑与稀土的西佛碱配合物及其抗氧化作用，兰州大学学报(自然科学版)，1998，34(3)：66-71
[32] 吴集贵，邓汝温，曾正志等。稀土在医药中的应用研究概况，有色金属与稀土应用，1994(1)：19-28
[33] 李永信。氯磺丙脲稀土配合物的急性毒性及其降血糖作用的研究，微量元素与健康研
究1995，12(2)：4-5
[34] 刘晓蕾，陈朝军，王宏宁等。消炎痛稀土(Ce，Sm)盐性质及镇痛、抗炎作用研究，稀土，1997，18(5)：13-16
[35] Drugs of the Future, 1998; 23(8): 924-925
[36] 王则民，我国稀土氨基酸固体配合物的研究进展，稀土，1992，13(3)：39-43
[37] Anindita Mukhopadhyay, Carbohydr, Res. 328(2000) 103
[38] 关怀民，童跃进，稀土，18(1997)20
[39] Fialkov Y. A., Kostromina N. A., Zh. Neorgan. Khim. 4(1959)1507
[40] Kostromina N. A., Ukr. Khim. Zh. 26(1960)3; Chem. Abstr. 54(1960)16252
[41] Sawyer D. T., Ph. D. Thesis, University of California, LosAngeles, Clif.,1956
[42] Clark E. R., Waddams J. A., Nature 180(1957)904
[43] 张树功，倪嘉瓒，无机化学学报，6(1990)422
[44] 扬延民，翁诗甫，高等化学学报，15(1994)646
[45] 吴翌，龙腊生，兰州大学学报(自然科学版)，34(1998)72
[46] 张永安，张英锋，赵慧春，稀土-氨基葡萄糖-咖啡酸配合物的合成与表征，北京师范大学学报(自然科学版)，2000，36(1)：81-84
[47] 江涛，左代妹，一类具有抗肿瘤活性的氨基葡萄糖化合物及其制备方法，中国专利，正在申请中
[48] 潘启超 胥斌 肿瘤药理学与化学治疗学，河南医科大学出版社2000年
[49] Franco Zunino*, Graziella Pratesi, Paola Perego, Role of the sugar moiety in the pharmacological activity of anthracyclines: development of a novel series of disaccharide analogs, Biochemical Pharmacology 61(2001) 933-938
[50] Federico Arcamone, Fabio Animati, Mario Bigioni, Giovanni Capranico, Configurational Requirements of the Sugar Moiety for the Pharmacological Activity of Anthracycline Disaccharides, Biochemical Pharmacology, 57(1999), pp. 1133-1139,.
[51] Tetsuo Shimamoto, Seiichi Imajo, Tadashi Honda, ect. Stucture-activity Relationship Study on N-Glycosyl Moirties Through model Building DNA and Ellipticine N-glycoside Complex, Biorgan. and Med. Chem. Letters, 6(1996) PP1331-1334
[52] 傅佑丽，稀土生物效应机理研究进展，曲阜师范大学学报，2001，27(2)：81-84
[53] Sumaoka J, Yashiro M, Komiyama M, Nucleic Acids Sympser., 1992, 27, 1707-1708
[54] Komiyama M, Yashiro M, Shiba T, J. Fac. Eng. Univ. Tokyo. Ser., 1993, 42(2), 143-154
[55] Komiyama M, Kodama T, Takeda N. J. Biochem., 1994, 115, 809-810