含硫席夫碱和缩氨硫脲类化合物的合成及抗肿瘤活性研究
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摘要
研究发现一些含硫席夫碱和缩氨硫脲类化合物具有一定的抗癌活性。
本文研究的目的是为了进一步研究这些化合物的构效关系，期望通过引入不同的芳香基团合成一系列化合物。
本文合成了十三个肼基二硫代甲酸甲酯的席夫碱(Ⅱ)；两个N-单取代哌嗪；一个N-双取代哌嗪；五个缩氨硫脲类化合物(Ⅲ)。通过红外光谱、核磁共振和质谱确证了它们的结构；通过X射线测定了其中两个化合物的结构，并初步测试了它们的体外抗肿瘤活性。
体外对小鼠白血病细胞P-388和人肺腺癌细胞A-549进行了抗肿瘤活性测定，初步的药理实验结果表明：化合物J20、J21、J22、J24、J25、J40、J600、J604、J605、J705和J706十一个化合物具有明显的抗癌活性。
According to the studies on them, it was found that somesulphur-containing Schiff bases(Ⅱ) and thiosemicarbazones(Ⅲ) possessdefinite anticancer activity.
The aim in this dissertation is that, for researching the structure-act-ivity relationship of them further, and looking forward to gaining profou-nd acquaintanceship, and screening out some good anticancer druggeryfinally, which have higher activity and lower toxicity, a series of derive-atives of Schiff bases and thiosemicarbazones were synthesized.
Respectively, thirteen of compounds(Ⅱ) were synthesized, whichstructures were confirmed, and which anticancer activity have also beeninvestigated in vitro; two of N-substituted piperazine; five compounds(Ⅲ)which structures were confirmed, and which anticancer activity have alsobeen investigated in vitro.
The antitumor activity against mouse Leukemia P-388, man cancer ofthe lung A-549 for the compounds has been tested. The results show thatthe compounds J20、J21、J22、J24、J25、J40、J600、J604、J605、J705and J706 have excellent anticancer activity to inhabit P-388 and A-549.
本文研究的目的是为了进一步研究这些化合物的构效关系，期望通过引入不同的芳香基团合成一系列化合物。
本文合成了十三个肼基二硫代甲酸甲酯的席夫碱(Ⅱ)；两个N-单取代哌嗪；一个N-双取代哌嗪；五个缩氨硫脲类化合物(Ⅲ)。通过红外光谱、核磁共振和质谱确证了它们的结构；通过X射线测定了其中两个化合物的结构，并初步测试了它们的体外抗肿瘤活性。
体外对小鼠白血病细胞P-388和人肺腺癌细胞A-549进行了抗肿瘤活性测定，初步的药理实验结果表明：化合物J20、J21、J22、J24、J25、J40、J600、J604、J605、J705和J706十一个化合物具有明显的抗癌活性。
According to the studies on them, it was found that somesulphur-containing Schiff bases(Ⅱ) and thiosemicarbazones(Ⅲ) possessdefinite anticancer activity.
The aim in this dissertation is that, for researching the structure-act-ivity relationship of them further, and looking forward to gaining profou-nd acquaintanceship, and screening out some good anticancer druggeryfinally, which have higher activity and lower toxicity, a series of derive-atives of Schiff bases and thiosemicarbazones were synthesized.
Respectively, thirteen of compounds(Ⅱ) were synthesized, whichstructures were confirmed, and which anticancer activity have also beeninvestigated in vitro; two of N-substituted piperazine; five compounds(Ⅲ)which structures were confirmed, and which anticancer activity have alsobeen investigated in vitro.
The antitumor activity against mouse Leukemia P-388, man cancer ofthe lung A-549 for the compounds has been tested. The results show thatthe compounds J20、J21、J22、J24、J25、J40、J600、J604、J605、J705and J706 have excellent anticancer activity to inhabit P-388 and A-549.
引文
[1] 陈晓光．肿瘤化学预防药物研究进展．第七届全国肿瘤药理与化疗术会．14-18
[2] 胡育新．21世纪的癌症诊疗技术前进论坛．2000，6：29-30
[3] 程广源．适形放疗是21世纪放射肿瘤学的发展方向．立体定向和功能性神经外科杂志．2003，16(4)：240-244
[4] 潘启超，胥彬．肿瘤药理学与化学治疗学．郑州：河南医科大学出版社，2000，1-9
[5] 李薇，梁春利．抗肿瘤药物研究进展．现代中医药．2004，3：64-65
[6] 丁健．抗肿瘤药物的研究进展与发展策略．江西医学院学报．2001，41(2)：33-39
[7] Mosmann T. Rapid Colorimetric Assay for cellular Growth and Survival; Applecation to Proliferation and Cytotoxcity Assays. J Immunol Methods 1983,65:55
[8] Scudiero-DA,. Evaluation of Soluble terragoliam formagan for cell growth and drug seusitivity in calture using human and tumorcell lines. Caneer-Res 1988, 48(17): 4827-4833
[9] Carmichael-J,. Chemosensitivity testing of human lung cancer cell liner using the MTT assay. Br J cancer. 1988,57(6):540
[10] Pieters, R. Relation of cellular drug resistance to loug-tem clinical outcome in childhood acate lymphoblastic leuraemia. Lancef, 1991,388(8764):399-403
[11] Ohyama S. Chemoseusitivity test for gastriccancer by in vitro MTT assay Gran to Kagaku Ryoho 1991, 18(10): 1593-7
[12] 席易人等．急性白血病化疗药物体外敏感性MTT法的研究．中华血液．1990，11(3)：116
[13] 王青素等．SRB显色法用于抗癌药物敏感性试验的研究．科技通报．2000，16(2)：104-107
[14] 杨高文，夏小平，涂欢等．Schiff碱、咪唑金属配合物合成及抗癌活性的荧光筛选研究[J]．化学研究与应用．1995，7(1)：4l-45
[15] Praveen K, Sharma, Ram N Handa,. Synthesis and Characterization of Some Transition Metal Complexes o fN-(2-Hydroxy-1-Naphthylidene) Amino Acids. Synth. React [J]. Inorg Met Org Chem, 1996,26(7):1219-1230
[16] A.Angoso,J.M.Martin-Llorente,J.L.Manzano,. Preparation and Study of amino acid (DL-leucine, L-isoleucine,L-histidine) Schiff bases with ethyl-α-ketocy- clopentyl carboxylate and the corresponding Copper(Ⅱ)Complexes[J]. Inorganic Chimica Acta,1992, 195(1):45-49
[17] 王积涛，许育明，杨晓萍等．含氨基酸．Schiff碱-金属手性配合物的合成及翼相关反应的进展[J]．有机化学，1995，15：449-460
[18] Virinder So Parmar, Amarjit Singh,Kirpal S.Bisht,.SchiffBase of Amino Acid Esters as New Substrates for the Enantioselective Enzymatic Hydrolysis and Accompanied Asymmetric Transformations in Aqueous Organic Solvents[J]. J Org Chem, 1996,61:1223-1227
[19] L.E. Khoo,J.P.Charland,E.J.Gabe,.Synthesis and Structural Studies for a series of Aromatic Schiff Bases Complexes with Tdphenyltin Chloride and Triphenyltin Isothiocyanate[J]. Inorganica Chimina Acta, 1987,128:139-145
[20] Hodnett EM, dunn DJ.Strucreantitumor or acivity correlation of some Schiff base[J]. J Med Chem, 1970, 13(4):768-770
[21] Desai S B,Desai p b, Desai k b.Synthesis of some schiff bases thiazolidinones and azetidinones form 2,6-diaminobozol-[1,2-d:4,5-d]bisthiazole and their anticancer activities [J].Hetercyl Commun,2001,7(1):83-90
[22] 吴自慎，严振寰．钴、镍、铜、锌对(α-羟基乙基)水杨醛亚胺螯合物的合成及其抗癌活性的初步试验[J]．无机化学，1986，1：108-112
[23] 冯英，刘义．D-氨基葡萄糖Schiff碱及其金属配体的抗菌活性[J]．物理化学学报，1996，8：747
[24] 郭应臣，陈欣，卓立宏．水杨酰肼席夫碱的合成、表征、抑菌活性[J]．化学应用与研究，2004，16(4)：580-583
[25] 常光萍，田江红等．第三届全国配位化学会议论文摘要集[C]，1997，B：103
[26] 汪焱钢，叶文法．氨基苯氧乙酸度夫碱的合成和激素活性的研究[J]．武汉大学学报，1996，42(2)：191-194
[27] 袭著革，李官贤，张华山等，2，4-二硝基苯腙的色谱分离分析条件的研究[J]．中国环境检测1998，14(3)：4-7
[28] 孔淑青．肉桂酸．邻氨基苯甲酸席夫碱的合成及铜的测定[J]．江西师范大学学报，1999，23(4)：373-374
[29] 周丽丽，张晓宏，吴世康．利用腙类化合物作为检验阴离子的敏感器化学学报，2003，61(9)：1508-1510
[30] Costa, P. R. R.; Castro, R. N, ; Farias, F. M. CAutunes, O. A. C.; Bergter, L. Tetrahedron: Asymme 1993, 4, 1499
[31] Anrieta, A.; Carrillo, J. R.; Cossio, F. P.; Diaz-Oritz, A.;. Comez-Escalonilla, M, J.; Hoz, A. L.; Lang, F. Moreno, A. Tetrahedron 1998, 54, 13167
[32] Chen, L.; Bao, J.Q.; Yao, Z. P. Chin. J. Org. Chem. 2000, 20(2): 255
[33] 魏丹毅，李冬成，姚克敏．稀土元素与β—丙氨酸席夫碱双核配合物的合成与表征及催化活性[J]．无机化学学报，1998，14(2)：209-213
[34] YONG L,HUAH J L, LIAN B,. Synthesis of titanium (Ⅳ)complexes with Schiff bases ligand and their catalytic activities for polymerization of ethylene and etyrene [J].Chinese Journal of Chemistry,2001,19(4):429-432
[35] 张维平，姚小泉，等．一种新型手性席夫碱的合成及其在不对称环丙烷化反应中的催化性能[J]．催化学报，2000，21(3)：289-291
[36] 仇敏，刘国生，姚小泉，等．手性铜(Ⅱ)席夫碱配合物催化苯乙烯不对称环丙烷化反应[J]．催化学报，2001，22(1)：77-80
[37] 范谦，黎耀忠，程克梅，等．组氨酸席夫碱锰配合物及合成环己催化氧化[J]．四川大学学报(自然科学版)，2001，38(2)：230-234
[38] 彭清静，佛伟昌，邹晓勇．钯—席夫碱催化环己烯合成环己酮[J]．化学世界，2001，(10)：539-541
[39] DrainD. J., Goodacre C. L., Seymour D. E. J. Pharm. Pharmacol [J], 1949, 1: 784-787
[40] Jones D. H., Slack R,, Squires S.. J. Med Chem. J, 1965, 8(5): 676-680
[41] Wilson H. R,Revankar G. R., Tolman R. L.. J. Med. Chem. J, 1974, 17(7): 760-761
[42] Lin L. F., Lee S. J., Chen C. T.. Heterocycles [J], 1977, 7(1): 347-352
[43] 周茂，孙楠，杨忠愚，等．杂环基缩胺硫脲的合成及其抗癌活性的研究Ⅱ[J]．浙江工业大学学报，1998，26(3)：195-198
[44] 胡惟孝，杨忠愚：杂环基缩胺硫脲的合成[J]．现代应用药学，1996，13(增刊)：22-23
[45] 孙楠，胡惟孝，杨忠愚．缩胺硫脲的合成及抗癌活性的研究报告[J]．高等学校 化学学报，1998，19(增刊)：304
[46] Klayman D L, Bartosevich J F, Griffin T S,. 2-acetylpyridine thiosecarbazones. 1. a new class of potential antimalarial agents[J]. J Med Chem, 1979,22 (7):855-862
[47] Chem.Abstr,1969,70,11223w
[48] Lieber.E,Ray.H.P,Can.J.Chem, 1959,37:101
[49] Maryinez Aguilar.M.T, Cano Pavon.J.M,Pino.F,Anal.Chim.Axta,1977,90:335
[50] Daniel L.KIayman,Joseph F.Bartosevich,ScoctGrifin.T,J.Med.Chem.1979,22(7), 855
[51] Andson.F.E,Duca. C.J,Scudi.J.V,J.Am.Chem.Soc, 1951,75:4967
[52] Sdllay.S,Childress.S.J,U.S.Patent,3406180,1968
[53] Lieber.E,Pillai.C.N,Hite.R.D,Can.J.Chem, 1957,35,832
[54] Daniel L. Klayman, John.P. Scovill,F. Bartoseyich, J.Med.Chem 1979,22(11),136
[1] 胡惟孝，孙楠，杨忠愚．缩胺硫脲类化合物的合成及其抗癌活性研究．中国医药化学杂志．2001，11(3)：129-134
[2]胡 惟孝，孙楠，杂环基缩胺硫脲类化合物的合成及其抗癌活性研究．浙江工业大学学报．2000，28(2)：135-137
[1] 杨高文，夏小平，涂欢等．Schiff碱、咪唑金属配合物合成及抗癌活性的荧光筛选研究[J]．化学研究与应用，1995，7(1)：41-45
[2] Praveen K Sharma,Ram N Handa. Synthesis and Characterization of Some Transition Metal Complexes of N-(2-Hydroxy-1-Naphthylidene) Amino Acids. Synth. React [J]. Inorg Met Org Chem, 1996,26(7):1219-1230
[3] A.Angoso, J.M.Martin-Llorente, J.L.Manzano,. Preparation and Study of amino acid (DL-leucine, L-isoleucine,L-histidine) Schiffbases with ethyl-α-ketocyelopentyl earboxylate and the corresponding Copper(Ⅱ)Complexes[J]. Inorganic Chimica Aeta, 1992, 195(1):45-49
[4] 王积涛，许育明，杨晓萍等．含氨基酸．Schiff碱-金属手性配合物的合成及其相关反应的进展[J]．有机化学，1995，15：449-460
[5] Virinder So Parmar, Amarjit Singh, Kirpal S. Bisht,. Schiff Base of Amino Acid Esters as New Substrates for the Enantioselective Enzymatic Hydrolysis and Accompanied Asymmetric Transformations in Aqueous Organic Solvents [J]. J Org Chem, 19,96,61: 1223-1227
[6] L.E. Khoo,J.P.Charland,E.J,Gabe,.Synthesis and Structural Studies for a series of Aromatic Schiff Bases Complexes with Triphenyltin Chloride and Triphenyltin Isothiocyanate[J], Inorganica Chimina Acta, 1987,128:139-145
[7] Mukhopadhyay R, Bhattacharjee S, Pal C K,. Generation ofmanganese-(Ⅲ) versus-(Ⅳ) complexes with a conjugated ONS donor set controlling effect of ligand substituents[J]. J Chem Soc, Dalton Trans, 1997,2267
[8] Tian Y-P, Duan C-Y, Lu Z-L,. Crystal structure and spectroscopic studies on metal complexes containing NS donor ligands derived from S-benzyldithiocarbazate and p-dimethylaminobenzaldehyde[J]. Polyhedron, 1996,15:2263
[9] Akbar Ali M, Bose R N. Transition metal complexes of furfurnal benzyl Schiffbases derived from S-benzyldithiocarbazate[J]. Polyhedron,1984,3:517
[7] 徐寿昌．有机化学．北京：高等教育出版社．1999，284
[8] Hu, Wei-xiao; Sun, Nan; Yang, Zhong-yu. Synthesis and anti-cancer activity of heterocyclic thiosemicabazones. (Ⅰ): 4-(2-pyridinyl)-1-piperazinecarbothioic acid [1-(2-pyrimidinyl)ethylidene]hydrazide. Zhejiang Gongye Daxue Xuebao.2000, 28(2):134-137
[9] Paul F, Hudrlik,. Reactions of α,β-Epoxysilanes with Grignard Reagents. Generation and Trapping a-Trimethylsilyl Aldehydes and Ketones[J]. J.Org.Chem., 1980, 45(22): 4444-4448
[10] Ruben P. van Summeren,. Catalyti casymmetric synthesis of enantiopure isoprenoid building blocks: application in the synthesis of apple leafminer pheromones. Chem.Commun.,2005, 1387-1389
[11] Busby, Reginald E.; Parrick, John; Rizvi, S. Mumtaz H.; Shaw, C. J. Granville. eactions of halomethanes in the vapor phase. Part 3. Reactions of chloroform with pyrazoles, indazole, and other heterocycles at 555 ~C. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) 1979, (11), 2786-2788
[12] 范秀荣，李广武，沈萍．微生物学实验第2版[M]北京：高等教育出版社，198：114-190
[13] 戴自英．临床抗菌药物学．北京人民出版社，1985：378
[1] 童雪莹．哌嗪的生产应用和市场．河北化工．2003，6：19-21
[2] 张竞．哌嗪的合成及市场．四川化工与腐蚀控制．2002，5(5)：49-52
[3] 杜会霞，吴纬纬，夏炽中．1-(2-嘧啶基)-4-(3-氨丙基)哌嗪的合成山西大学学报(自然科学版)．2003 26(2)：150-152
[4] 胡惟孝，杨忠愚．杂环基缩胺硫脲的合成[J]．现代应用药学，1996，13(增刊)：22-23
[5] 孙楠，胡惟孝，杨忠愚．缩胺硫脲的合成及抗癌活性的究报告[J]．高等学校化学学报，1998，19(8，增刊)：304
[6] Howard KL, Stewart HW, Conroy EA,. Piperazines (Ⅱ) 1-Heterocyclic piperazines and 1-heterocyclic-4-carbethoxy-piperazines[J]. J Org Chem, 1953, 18: 1484-1488
[7] 孙楠，孙雅泉，杨忠愚，胡惟孝．1-(2-吡啶基)哌嗪的合成．中国医药工业杂志．2001，32(3)：133-134
[8] Eric Brenner, Raphael Schneider and Yves Fort Nickel-catalysed selective N-arylation or N,N′-arylation of secondary diamines Tetrahedron, 2002,58(34), 6913-6924
[9] K. L. HOWARD,' H. W. STEWART, E. A. CONROY, AND J. J. DENTOK PIPERAZIKES. Ⅱ. 1-HETEROCYCLICPIPERBZINES AXD 1-HETEROCYCLIC-4-CARBETHOXYPIPERAZINES J. Org. Chem.; 1953,1484,18
[10] Riblet, Leslie A.; Eison, Michael S.(USA). 1-(2-Pyrimidinyl)piperazine for the treatment of anxiety. U.S., 4409223, 11 Oct 1983
[11] Kuo, David L.; Voeffray, Robert. Process for the preparation of piperazinylpyrimidine derivatives. Eur. Pat. Appl., 491329, 24 Jun 1992
[12] Kuo, David L. Process for the preparation of piperazinylpyrimidine derivatives. Eur. Pat. Appl., 491328, 24 Jun 1992
[13] Dischino, D. D.; Covington, R. R.; Combs, C. M.; Gammans, R. E. Synthesis of tetradeuterated buspirone. Journal of Labelled Compounds and Radiopharmaceuticals. 1988, 25(4), 359-367
[14] 徐燕,朱志宏,童志杰,彭东明,段立新．丁螺环酮的合成．中国医药工业杂志．1993,24(2)：49-51
[15] Wolinski, Jerzy; Kujawa, Tadeusz; Lempke, Tadeusz. Search for compounds with dopaminergic activity. I. A modification of the synthesis of piribedil and its intermediates. Acta Poloniae Pharmaceutica.1984, 41(5), 525-528
[16] Covington, R. R.; New, J. S.; Yevich, J. P.; Temple, D. L., Jr. Preparation of specifically-labeled buspirone-14C and buspirone-15N2. Journal of Labelled Compounds and Radiopharmaceuticals. 1983, 20(10), 1207-1211
[17] Busby, Reginald E.; Parrick, John; Rizvi, S. Mumtaz H.; Shaw, C. J. Granville. eactions of halomethanes in the vapor phase. Part 3. Reactions of chloroform with pyrazoles, indazole, and other heterocycles at 555℃. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) 1979, (11), 2786-2788
[18] International Tables for X-ray Crystallography(Kynoch press:Birminghan, Englang; Present distributor:Kluwer Academic Publishers,Dordrecht,1974 4,72-98
[1] Riblet, Leslie A. 1-(2-Pyrimidinyl)piperazine for the treatment of anxiety. U.S., 4409223, 11 Oct 1983
[2] 杜会霞，吴纬纬，夏炽中．1-(2-嘧啶基)-4-(3-氨丙基)哌嗪的合成．山西大学学报(自然科学版)．2003 26(2)：150-152
[3] 胡惟孝，杨忠愚。杂环基缩胺硫脲的合成[J]．现代应用药学，1996，13(增刊)：22-23
[4] 孙楠，胡惟孝，杨忠愚．缩胺硫脲的合成及抗癌活性的究报告[J_]．高等学校化学学报，1998，19(8，增刊)：304
[5] 李和平，郭灿城，阮建明，黄伯云．哌嗪取代卟啉的合成、表征及其抗癌活性．有机化学．2004，24(7)：783-787
[2] 胡育新．21世纪的癌症诊疗技术前进论坛．2000，6：29-30
[3] 程广源．适形放疗是21世纪放射肿瘤学的发展方向．立体定向和功能性神经外科杂志．2003，16(4)：240-244
[4] 潘启超，胥彬．肿瘤药理学与化学治疗学．郑州：河南医科大学出版社，2000，1-9
[5] 李薇，梁春利．抗肿瘤药物研究进展．现代中医药．2004，3：64-65
[6] 丁健．抗肿瘤药物的研究进展与发展策略．江西医学院学报．2001，41(2)：33-39
[7] Mosmann T. Rapid Colorimetric Assay for cellular Growth and Survival; Applecation to Proliferation and Cytotoxcity Assays. J Immunol Methods 1983,65:55
[8] Scudiero-DA,. Evaluation of Soluble terragoliam formagan for cell growth and drug seusitivity in calture using human and tumorcell lines. Caneer-Res 1988, 48(17): 4827-4833
[9] Carmichael-J,. Chemosensitivity testing of human lung cancer cell liner using the MTT assay. Br J cancer. 1988,57(6):540
[10] Pieters, R. Relation of cellular drug resistance to loug-tem clinical outcome in childhood acate lymphoblastic leuraemia. Lancef, 1991,388(8764):399-403
[11] Ohyama S. Chemoseusitivity test for gastriccancer by in vitro MTT assay Gran to Kagaku Ryoho 1991, 18(10): 1593-7
[12] 席易人等．急性白血病化疗药物体外敏感性MTT法的研究．中华血液．1990，11(3)：116
[13] 王青素等．SRB显色法用于抗癌药物敏感性试验的研究．科技通报．2000，16(2)：104-107
[14] 杨高文，夏小平，涂欢等．Schiff碱、咪唑金属配合物合成及抗癌活性的荧光筛选研究[J]．化学研究与应用．1995，7(1)：4l-45
[15] Praveen K, Sharma, Ram N Handa,. Synthesis and Characterization of Some Transition Metal Complexes o fN-(2-Hydroxy-1-Naphthylidene) Amino Acids. Synth. React [J]. Inorg Met Org Chem, 1996,26(7):1219-1230
[16] A.Angoso,J.M.Martin-Llorente,J.L.Manzano,. Preparation and Study of amino acid (DL-leucine, L-isoleucine,L-histidine) Schiff bases with ethyl-α-ketocy- clopentyl carboxylate and the corresponding Copper(Ⅱ)Complexes[J]. Inorganic Chimica Acta,1992, 195(1):45-49
[17] 王积涛，许育明，杨晓萍等．含氨基酸．Schiff碱-金属手性配合物的合成及翼相关反应的进展[J]．有机化学，1995，15：449-460
[18] Virinder So Parmar, Amarjit Singh,Kirpal S.Bisht,.SchiffBase of Amino Acid Esters as New Substrates for the Enantioselective Enzymatic Hydrolysis and Accompanied Asymmetric Transformations in Aqueous Organic Solvents[J]. J Org Chem, 1996,61:1223-1227
[19] L.E. Khoo,J.P.Charland,E.J.Gabe,.Synthesis and Structural Studies for a series of Aromatic Schiff Bases Complexes with Tdphenyltin Chloride and Triphenyltin Isothiocyanate[J]. Inorganica Chimina Acta, 1987,128:139-145
[20] Hodnett EM, dunn DJ.Strucreantitumor or acivity correlation of some Schiff base[J]. J Med Chem, 1970, 13(4):768-770
[21] Desai S B,Desai p b, Desai k b.Synthesis of some schiff bases thiazolidinones and azetidinones form 2,6-diaminobozol-[1,2-d:4,5-d]bisthiazole and their anticancer activities [J].Hetercyl Commun,2001,7(1):83-90
[22] 吴自慎，严振寰．钴、镍、铜、锌对(α-羟基乙基)水杨醛亚胺螯合物的合成及其抗癌活性的初步试验[J]．无机化学，1986，1：108-112
[23] 冯英，刘义．D-氨基葡萄糖Schiff碱及其金属配体的抗菌活性[J]．物理化学学报，1996，8：747
[24] 郭应臣，陈欣，卓立宏．水杨酰肼席夫碱的合成、表征、抑菌活性[J]．化学应用与研究，2004，16(4)：580-583
[25] 常光萍，田江红等．第三届全国配位化学会议论文摘要集[C]，1997，B：103
[26] 汪焱钢，叶文法．氨基苯氧乙酸度夫碱的合成和激素活性的研究[J]．武汉大学学报，1996，42(2)：191-194
[27] 袭著革，李官贤，张华山等，2，4-二硝基苯腙的色谱分离分析条件的研究[J]．中国环境检测1998，14(3)：4-7
[28] 孔淑青．肉桂酸．邻氨基苯甲酸席夫碱的合成及铜的测定[J]．江西师范大学学报，1999，23(4)：373-374
[29] 周丽丽，张晓宏，吴世康．利用腙类化合物作为检验阴离子的敏感器化学学报，2003，61(9)：1508-1510
[30] Costa, P. R. R.; Castro, R. N, ; Farias, F. M. CAutunes, O. A. C.; Bergter, L. Tetrahedron: Asymme 1993, 4, 1499
[31] Anrieta, A.; Carrillo, J. R.; Cossio, F. P.; Diaz-Oritz, A.;. Comez-Escalonilla, M, J.; Hoz, A. L.; Lang, F. Moreno, A. Tetrahedron 1998, 54, 13167
[32] Chen, L.; Bao, J.Q.; Yao, Z. P. Chin. J. Org. Chem. 2000, 20(2): 255
[33] 魏丹毅，李冬成，姚克敏．稀土元素与β—丙氨酸席夫碱双核配合物的合成与表征及催化活性[J]．无机化学学报，1998，14(2)：209-213
[34] YONG L,HUAH J L, LIAN B,. Synthesis of titanium (Ⅳ)complexes with Schiff bases ligand and their catalytic activities for polymerization of ethylene and etyrene [J].Chinese Journal of Chemistry,2001,19(4):429-432
[35] 张维平，姚小泉，等．一种新型手性席夫碱的合成及其在不对称环丙烷化反应中的催化性能[J]．催化学报，2000，21(3)：289-291
[36] 仇敏，刘国生，姚小泉，等．手性铜(Ⅱ)席夫碱配合物催化苯乙烯不对称环丙烷化反应[J]．催化学报，2001，22(1)：77-80
[37] 范谦，黎耀忠，程克梅，等．组氨酸席夫碱锰配合物及合成环己催化氧化[J]．四川大学学报(自然科学版)，2001，38(2)：230-234
[38] 彭清静，佛伟昌，邹晓勇．钯—席夫碱催化环己烯合成环己酮[J]．化学世界，2001，(10)：539-541
[39] DrainD. J., Goodacre C. L., Seymour D. E. J. Pharm. Pharmacol [J], 1949, 1: 784-787
[40] Jones D. H., Slack R,, Squires S.. J. Med Chem. J, 1965, 8(5): 676-680
[41] Wilson H. R,Revankar G. R., Tolman R. L.. J. Med. Chem. J, 1974, 17(7): 760-761
[42] Lin L. F., Lee S. J., Chen C. T.. Heterocycles [J], 1977, 7(1): 347-352
[43] 周茂，孙楠，杨忠愚，等．杂环基缩胺硫脲的合成及其抗癌活性的研究Ⅱ[J]．浙江工业大学学报，1998，26(3)：195-198
[44] 胡惟孝，杨忠愚：杂环基缩胺硫脲的合成[J]．现代应用药学，1996，13(增刊)：22-23
[45] 孙楠，胡惟孝，杨忠愚．缩胺硫脲的合成及抗癌活性的研究报告[J]．高等学校 化学学报，1998，19(增刊)：304
[46] Klayman D L, Bartosevich J F, Griffin T S,. 2-acetylpyridine thiosecarbazones. 1. a new class of potential antimalarial agents[J]. J Med Chem, 1979,22 (7):855-862
[47] Chem.Abstr,1969,70,11223w
[48] Lieber.E,Ray.H.P,Can.J.Chem, 1959,37:101
[49] Maryinez Aguilar.M.T, Cano Pavon.J.M,Pino.F,Anal.Chim.Axta,1977,90:335
[50] Daniel L.KIayman,Joseph F.Bartosevich,ScoctGrifin.T,J.Med.Chem.1979,22(7), 855
[51] Andson.F.E,Duca. C.J,Scudi.J.V,J.Am.Chem.Soc, 1951,75:4967
[52] Sdllay.S,Childress.S.J,U.S.Patent,3406180,1968
[53] Lieber.E,Pillai.C.N,Hite.R.D,Can.J.Chem, 1957,35,832
[54] Daniel L. Klayman, John.P. Scovill,F. Bartoseyich, J.Med.Chem 1979,22(11),136
[1] 胡惟孝，孙楠，杨忠愚．缩胺硫脲类化合物的合成及其抗癌活性研究．中国医药化学杂志．2001，11(3)：129-134
[2]胡 惟孝，孙楠，杂环基缩胺硫脲类化合物的合成及其抗癌活性研究．浙江工业大学学报．2000，28(2)：135-137
[1] 杨高文，夏小平，涂欢等．Schiff碱、咪唑金属配合物合成及抗癌活性的荧光筛选研究[J]．化学研究与应用，1995，7(1)：41-45
[2] Praveen K Sharma,Ram N Handa. Synthesis and Characterization of Some Transition Metal Complexes of N-(2-Hydroxy-1-Naphthylidene) Amino Acids. Synth. React [J]. Inorg Met Org Chem, 1996,26(7):1219-1230
[3] A.Angoso, J.M.Martin-Llorente, J.L.Manzano,. Preparation and Study of amino acid (DL-leucine, L-isoleucine,L-histidine) Schiffbases with ethyl-α-ketocyelopentyl earboxylate and the corresponding Copper(Ⅱ)Complexes[J]. Inorganic Chimica Aeta, 1992, 195(1):45-49
[4] 王积涛，许育明，杨晓萍等．含氨基酸．Schiff碱-金属手性配合物的合成及其相关反应的进展[J]．有机化学，1995，15：449-460
[5] Virinder So Parmar, Amarjit Singh, Kirpal S. Bisht,. Schiff Base of Amino Acid Esters as New Substrates for the Enantioselective Enzymatic Hydrolysis and Accompanied Asymmetric Transformations in Aqueous Organic Solvents [J]. J Org Chem, 19,96,61: 1223-1227
[6] L.E. Khoo,J.P.Charland,E.J,Gabe,.Synthesis and Structural Studies for a series of Aromatic Schiff Bases Complexes with Triphenyltin Chloride and Triphenyltin Isothiocyanate[J], Inorganica Chimina Acta, 1987,128:139-145
[7] Mukhopadhyay R, Bhattacharjee S, Pal C K,. Generation ofmanganese-(Ⅲ) versus-(Ⅳ) complexes with a conjugated ONS donor set controlling effect of ligand substituents[J]. J Chem Soc, Dalton Trans, 1997,2267
[8] Tian Y-P, Duan C-Y, Lu Z-L,. Crystal structure and spectroscopic studies on metal complexes containing NS donor ligands derived from S-benzyldithiocarbazate and p-dimethylaminobenzaldehyde[J]. Polyhedron, 1996,15:2263
[9] Akbar Ali M, Bose R N. Transition metal complexes of furfurnal benzyl Schiffbases derived from S-benzyldithiocarbazate[J]. Polyhedron,1984,3:517
[7] 徐寿昌．有机化学．北京：高等教育出版社．1999，284
[8] Hu, Wei-xiao; Sun, Nan; Yang, Zhong-yu. Synthesis and anti-cancer activity of heterocyclic thiosemicabazones. (Ⅰ): 4-(2-pyridinyl)-1-piperazinecarbothioic acid [1-(2-pyrimidinyl)ethylidene]hydrazide. Zhejiang Gongye Daxue Xuebao.2000, 28(2):134-137
[9] Paul F, Hudrlik,. Reactions of α,β-Epoxysilanes with Grignard Reagents. Generation and Trapping a-Trimethylsilyl Aldehydes and Ketones[J]. J.Org.Chem., 1980, 45(22): 4444-4448
[10] Ruben P. van Summeren,. Catalyti casymmetric synthesis of enantiopure isoprenoid building blocks: application in the synthesis of apple leafminer pheromones. Chem.Commun.,2005, 1387-1389
[11] Busby, Reginald E.; Parrick, John; Rizvi, S. Mumtaz H.; Shaw, C. J. Granville. eactions of halomethanes in the vapor phase. Part 3. Reactions of chloroform with pyrazoles, indazole, and other heterocycles at 555 ~C. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) 1979, (11), 2786-2788
[12] 范秀荣，李广武，沈萍．微生物学实验第2版[M]北京：高等教育出版社，198：114-190
[13] 戴自英．临床抗菌药物学．北京人民出版社，1985：378
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[2] 张竞．哌嗪的合成及市场．四川化工与腐蚀控制．2002，5(5)：49-52
[3] 杜会霞，吴纬纬，夏炽中．1-(2-嘧啶基)-4-(3-氨丙基)哌嗪的合成山西大学学报(自然科学版)．2003 26(2)：150-152
[4] 胡惟孝，杨忠愚．杂环基缩胺硫脲的合成[J]．现代应用药学，1996，13(增刊)：22-23
[5] 孙楠，胡惟孝，杨忠愚．缩胺硫脲的合成及抗癌活性的究报告[J]．高等学校化学学报，1998，19(8，增刊)：304
[6] Howard KL, Stewart HW, Conroy EA,. Piperazines (Ⅱ) 1-Heterocyclic piperazines and 1-heterocyclic-4-carbethoxy-piperazines[J]. J Org Chem, 1953, 18: 1484-1488
[7] 孙楠，孙雅泉，杨忠愚，胡惟孝．1-(2-吡啶基)哌嗪的合成．中国医药工业杂志．2001，32(3)：133-134
[8] Eric Brenner, Raphael Schneider and Yves Fort Nickel-catalysed selective N-arylation or N,N′-arylation of secondary diamines Tetrahedron, 2002,58(34), 6913-6924
[9] K. L. HOWARD,' H. W. STEWART, E. A. CONROY, AND J. J. DENTOK PIPERAZIKES. Ⅱ. 1-HETEROCYCLICPIPERBZINES AXD 1-HETEROCYCLIC-4-CARBETHOXYPIPERAZINES J. Org. Chem.; 1953,1484,18
[10] Riblet, Leslie A.; Eison, Michael S.(USA). 1-(2-Pyrimidinyl)piperazine for the treatment of anxiety. U.S., 4409223, 11 Oct 1983
[11] Kuo, David L.; Voeffray, Robert. Process for the preparation of piperazinylpyrimidine derivatives. Eur. Pat. Appl., 491329, 24 Jun 1992
[12] Kuo, David L. Process for the preparation of piperazinylpyrimidine derivatives. Eur. Pat. Appl., 491328, 24 Jun 1992
[13] Dischino, D. D.; Covington, R. R.; Combs, C. M.; Gammans, R. E. Synthesis of tetradeuterated buspirone. Journal of Labelled Compounds and Radiopharmaceuticals. 1988, 25(4), 359-367
[14] 徐燕,朱志宏,童志杰,彭东明,段立新．丁螺环酮的合成．中国医药工业杂志．1993,24(2)：49-51
[15] Wolinski, Jerzy; Kujawa, Tadeusz; Lempke, Tadeusz. Search for compounds with dopaminergic activity. I. A modification of the synthesis of piribedil and its intermediates. Acta Poloniae Pharmaceutica.1984, 41(5), 525-528
[16] Covington, R. R.; New, J. S.; Yevich, J. P.; Temple, D. L., Jr. Preparation of specifically-labeled buspirone-14C and buspirone-15N2. Journal of Labelled Compounds and Radiopharmaceuticals. 1983, 20(10), 1207-1211
[17] Busby, Reginald E.; Parrick, John; Rizvi, S. Mumtaz H.; Shaw, C. J. Granville. eactions of halomethanes in the vapor phase. Part 3. Reactions of chloroform with pyrazoles, indazole, and other heterocycles at 555℃. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) 1979, (11), 2786-2788
[18] International Tables for X-ray Crystallography(Kynoch press:Birminghan, Englang; Present distributor:Kluwer Academic Publishers,Dordrecht,1974 4,72-98
[1] Riblet, Leslie A. 1-(2-Pyrimidinyl)piperazine for the treatment of anxiety. U.S., 4409223, 11 Oct 1983
[2] 杜会霞，吴纬纬，夏炽中．1-(2-嘧啶基)-4-(3-氨丙基)哌嗪的合成．山西大学学报(自然科学版)．2003 26(2)：150-152
[3] 胡惟孝，杨忠愚。杂环基缩胺硫脲的合成[J]．现代应用药学，1996，13(增刊)：22-23
[4] 孙楠，胡惟孝，杨忠愚．缩胺硫脲的合成及抗癌活性的究报告[J_]．高等学校化学学报，1998，19(8，增刊)：304
[5] 李和平，郭灿城，阮建明，黄伯云．哌嗪取代卟啉的合成、表征及其抗癌活性．有机化学．2004，24(7)：783-787