抗肿瘤药物九节龙皂苷I 的分离纯化、结构修饰及药效学初步研究
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摘要
目前,恶性肿瘤已经成为一种严重威胁人类健康的常见病和多发病,癌症患者不断增多,全球每年新增肿瘤病人900万,死亡600多万,已成为仅次于心血管病的第二大杀手。治疗恶性肿瘤的化疗药物存在副作用大、肿瘤细胞耐药等问题,使得临床应用受到一定限制,因此寻找高效低毒的抗肿瘤药物乃是当务之急。随着中草药治疗肿瘤研究的不断深入,其独特的疗效和较低的毒副作用,越来越引起人们的关注。以天然活性成分为先导化合物进行结构修饰,从而发现一些新的具有良好生物活性和低生物毒性的化合物,成为发现抗肿瘤药物的有效途径。
九节龙皂苷Ⅰ(ArdipusillosideⅠ,ADSⅠ)是从天然植物九节龙中提取分离得到的一种结构新颖的皂苷类化合物,具有一定的抗肿瘤活性,但是活性较低、毒性较大、不适合注射给药。因此,本文首先提取分离九节龙皂苷I,并以此为先导化合物,进行结构修饰,再进一步研究九节龙皂苷Ⅰ及其衍生物的抗肿瘤活性。本文主要完成了以下研究工作:
一、九节龙皂苷I的提取、分离和纯化
本文通过对九节龙皂苷I的提取分离工艺的研究,建立了一种将提取工艺与色谱分离相结合的分离九节龙皂苷I单体的方法,筛选出了的最佳提取条件是:75%乙醇,第一次8倍量(g/mL)提取4 h,第二次6倍量(g/mL)提取3 h,提取所得九节龙皂苷I的干浸膏得率94%;制备色谱条件:色谱条件:色谱柱(10.0 mm×250 mm,sinochrom ODS-BP为柱填充料);流动相:甲醇-水(80:20);流速:1.5 mL/min;检测波长:205 nm。最终产物纯度可达到99%。
二、九节龙皂苷I的结构修饰与改造
本文首次以九节龙皂苷I为先导化合物分别与盐酸羟胺和苯胺盐酸盐反应合成了schiff碱A1和A2;
1.将化合物A1和分别与Zn(II)、Cu(II)、Co(II)、Cr(III)、Ni(II)金属离子配位,合成了一系列金属配合物C1-C5;
2.首次合成了九节龙皂苷I的苷元B1;
3.苷元B1与盐酸羟胺和苯胺盐酸盐反应合成了schiff碱B2和B3;
4.将化合物B2和分别与Zn(II)、Cu(II)、Co(II)、Cr(III)、Ni(II)金属离子配位,合成了合成一系列金属配合物E1-E5。
三、初步药效学研究
本文对九节龙皂苷I衍生物A1及C1-C5进行了药效药效学研究,肿瘤细胞实验表明,受试药物在300μg/mL剂量下均可显著抑制肿瘤细胞的增殖,其肿瘤抑制率与对照组比有明显差异(P <0.01),其中化合物C2和C4的肿瘤抑制率明显高于原料药九节龙皂苷I及其它受试药物。
Cancer is one of the most serious diseases that threaten humans. Every year, about 9 million people suffer from cancer, and 6 million people die from it. This equates to one person dying from cancer every second. Now, cancer has become the second greatest cause of death following cardiovascular disease. The anticancer drugs of chemotherapy have high side effects, toleration and so on. These shortages limit its use at clinic. Finding new drugs with good biological activity and low biotoxicity have become the first task for medical and chemical workers. In the clinical setting, a combination of some methods is always needed. Chinese traditional and herbal drugs have gained recent attention due to their special anticancer effects and their decreased side effects in comparison with traditional anticancer drugs. Finding new compounds with good biological activity and low biotoxicity through structural modification of naturally active components is an effective way to discover new anti-tumor drugs.
ArdipusillosideⅠ(ADSⅠ) is a kind of new saponins with the original structure extracted and separated from Ardisia pusilla A. DC.. ADSⅠhas some certain antineoplasmic activities, it is not suitable for clinical application due to its low activity, large toxicity, and unsuitable injection administration. So this artic makes some Separation、purification, structural modification and reconstitution of ADSⅠas lead compound. And then, we research the anticancer activity of these compounds. Synthesis mainly includes the following three parts:
First, extraction, separation and purification research on ADS I.
As the content of ADS I is rarely about 1% in Ardisia pusilla A. DC., it is difficult to separated and purified. As a result we established a combinative method of traditional exaction technology and modern chromatographic fractionation according to technical research on its exaction and separation. It was exacted 4 times by ethanol (75%, v/v, 1000 mL) for 4 hours to obtain dry extractum at rate of 19.47%. HPLC condition:Chromatographic condition :Chromatographic column(10.0 mm×250 mm,sinochrom ODS-BP);Moving phase:CH3OH-H 2O(80:20);Flow rate:1.5 mL/min;Detect wavelength:205 nm。Its purity could reach 99%. Second, structural modification and structural modification of ADS I.
1. use ADS I for lead compounds, and hydroxylamine hydrochloride and phenylamine hydrochlorate for raw material, Synthesize 2 similarity (A1、A2).
2. design the synthesis of aglycon with ADS I. use this aglycon for lead compound, and hydroxylamine hydrochloride and phenylamine hydrochlorate for raw material, synthesize 2 similarity B1、B2
3. use A1 for raw material, react with Zn(II)、Cu(II)、Co(II)、Cr(III)、Ni(II), synthesize a series of metal-complexes C1-C5
4. use B2 for raw material, react with Zn(II)、Cu(II)、Co(II)、Cr(III)、Ni(II), synthesize a series of metal-complexes E1-E5
Third, preliminary biological activity research.
Cell tests on ADS I Schiff bases and their metal-complexes revealed that drug concentrations at 300μg/ml inhibited tumor cell proliferation significantly and had significant difference towards control group (P<0.01). Tumor control rate of E2 and E4 was obviously higher than that of crude drug.
九节龙皂苷Ⅰ(ArdipusillosideⅠ,ADSⅠ)是从天然植物九节龙中提取分离得到的一种结构新颖的皂苷类化合物,具有一定的抗肿瘤活性,但是活性较低、毒性较大、不适合注射给药。因此,本文首先提取分离九节龙皂苷I,并以此为先导化合物,进行结构修饰,再进一步研究九节龙皂苷Ⅰ及其衍生物的抗肿瘤活性。本文主要完成了以下研究工作:
一、九节龙皂苷I的提取、分离和纯化
本文通过对九节龙皂苷I的提取分离工艺的研究,建立了一种将提取工艺与色谱分离相结合的分离九节龙皂苷I单体的方法,筛选出了的最佳提取条件是:75%乙醇,第一次8倍量(g/mL)提取4 h,第二次6倍量(g/mL)提取3 h,提取所得九节龙皂苷I的干浸膏得率94%;制备色谱条件:色谱条件:色谱柱(10.0 mm×250 mm,sinochrom ODS-BP为柱填充料);流动相:甲醇-水(80:20);流速:1.5 mL/min;检测波长:205 nm。最终产物纯度可达到99%。
二、九节龙皂苷I的结构修饰与改造
本文首次以九节龙皂苷I为先导化合物分别与盐酸羟胺和苯胺盐酸盐反应合成了schiff碱A1和A2;
1.将化合物A1和分别与Zn(II)、Cu(II)、Co(II)、Cr(III)、Ni(II)金属离子配位,合成了一系列金属配合物C1-C5;
2.首次合成了九节龙皂苷I的苷元B1;
3.苷元B1与盐酸羟胺和苯胺盐酸盐反应合成了schiff碱B2和B3;
4.将化合物B2和分别与Zn(II)、Cu(II)、Co(II)、Cr(III)、Ni(II)金属离子配位,合成了合成一系列金属配合物E1-E5。
三、初步药效学研究
本文对九节龙皂苷I衍生物A1及C1-C5进行了药效药效学研究,肿瘤细胞实验表明,受试药物在300μg/mL剂量下均可显著抑制肿瘤细胞的增殖,其肿瘤抑制率与对照组比有明显差异(P <0.01),其中化合物C2和C4的肿瘤抑制率明显高于原料药九节龙皂苷I及其它受试药物。
Cancer is one of the most serious diseases that threaten humans. Every year, about 9 million people suffer from cancer, and 6 million people die from it. This equates to one person dying from cancer every second. Now, cancer has become the second greatest cause of death following cardiovascular disease. The anticancer drugs of chemotherapy have high side effects, toleration and so on. These shortages limit its use at clinic. Finding new drugs with good biological activity and low biotoxicity have become the first task for medical and chemical workers. In the clinical setting, a combination of some methods is always needed. Chinese traditional and herbal drugs have gained recent attention due to their special anticancer effects and their decreased side effects in comparison with traditional anticancer drugs. Finding new compounds with good biological activity and low biotoxicity through structural modification of naturally active components is an effective way to discover new anti-tumor drugs.
ArdipusillosideⅠ(ADSⅠ) is a kind of new saponins with the original structure extracted and separated from Ardisia pusilla A. DC.. ADSⅠhas some certain antineoplasmic activities, it is not suitable for clinical application due to its low activity, large toxicity, and unsuitable injection administration. So this artic makes some Separation、purification, structural modification and reconstitution of ADSⅠas lead compound. And then, we research the anticancer activity of these compounds. Synthesis mainly includes the following three parts:
First, extraction, separation and purification research on ADS I.
As the content of ADS I is rarely about 1% in Ardisia pusilla A. DC., it is difficult to separated and purified. As a result we established a combinative method of traditional exaction technology and modern chromatographic fractionation according to technical research on its exaction and separation. It was exacted 4 times by ethanol (75%, v/v, 1000 mL) for 4 hours to obtain dry extractum at rate of 19.47%. HPLC condition:Chromatographic condition :Chromatographic column(10.0 mm×250 mm,sinochrom ODS-BP);Moving phase:CH3OH-H 2O(80:20);Flow rate:1.5 mL/min;Detect wavelength:205 nm。Its purity could reach 99%. Second, structural modification and structural modification of ADS I.
1. use ADS I for lead compounds, and hydroxylamine hydrochloride and phenylamine hydrochlorate for raw material, Synthesize 2 similarity (A1、A2).
2. design the synthesis of aglycon with ADS I. use this aglycon for lead compound, and hydroxylamine hydrochloride and phenylamine hydrochlorate for raw material, synthesize 2 similarity B1、B2
3. use A1 for raw material, react with Zn(II)、Cu(II)、Co(II)、Cr(III)、Ni(II), synthesize a series of metal-complexes C1-C5
4. use B2 for raw material, react with Zn(II)、Cu(II)、Co(II)、Cr(III)、Ni(II), synthesize a series of metal-complexes E1-E5
Third, preliminary biological activity research.
Cell tests on ADS I Schiff bases and their metal-complexes revealed that drug concentrations at 300μg/ml inhibited tumor cell proliferation significantly and had significant difference towards control group (P<0.01). Tumor control rate of E2 and E4 was obviously higher than that of crude drug.
引文
[1] Hideka Kobayashi, Elvira de Mej’?a.The genus Ardisia: a novel source of health-promoting compounds and phytopharmaceuticals,J. Journal of Ethnopharmacology, 96(2005) 347–354.
[2] 王晓娟,张清华.毛茎紫金牛(九节龙)化学成分的研究. 中国中药杂志1990,l5,98.
[3] 张清华,王晓娟,缪振春,冯锐.川产九节龙皂苷的化学研究.药学学报,1993,28(9):673-678.
[4] 梁克明,王四旺,王晓娟.九节龙皂苷 8 株人癌细胞的抑制作用[J].第四军医大学学报,2001,22(7):671-672.
[5] 陶小军,王佩贤,杨孝江,姚鸿萍,刘静,曹永孝.九节龙皂苷Ⅰ对小鼠 Lewis 肺癌和裸鼠肝癌 SMMC-7721 的抑制作用[J].中药材,2006,28(7):574-577.
[6] 陶小军,龙静雯,贺建宇,姚鸿萍,刘静,曹永孝.九节龙皂苷Ⅰ的抗肿瘤作用和免疫调节作用[J].中国药理学通报,2005,21(9):1070-1073.
[7] 戴荣斌.抗癌金属配合物的研究[J].天津学刊,1998,13(5):22-26.
[8] 胡桂香,张金超,唐婷,龚钰秋.非经典铂类配合物的研究近况.化学研究与应用,1999,11 (3):235-240.
[9] 叶幼珠.试谈我国抗癌药物发展态势.海峡药学,1995,7 (3):63-64.
[10] 周永义,郭启华,谷学新.抗癌药物研究动态简介.化学教育,2004,5:10-13.
[11] 朱瑾 ,徐丽华,孙萌,李桂凤.抗癌中草药现代药理研究进展.World Health Digest,2007,4(11):12-15.
[12] 刘峰,魏新庭,王冬冬,孙德志,李林尉.抗癌药物的研究现状[J].聊城大学学报,2006,19(1):39-43.
[13] Friedman,O.M.,Myles,A.and Colvin,M..Cyclophophamide and related phosphoramide mustards.Current status and future prospets.Advances in Cancer Chemotherapy,Vol 4 edited by A.Rosowsky,1979,143-204,New York:Marcel Dekker.
[14] Goren,M.P.,Wright,R.K..Dechloroethylation of ifosfamide and neurotoxicity,Lancet.1986:1219-1220.
[15] Kramer MJ.5’-Deoxy-5-Fluorouridine-A New Orally Active Antitumor Agent,Comparative Activity With 2’-Deoxy-Fluorouridine and Ftorafur Against Transplantable Tumors in Mice and Rats ,Proc.AM.Assoc.Cancer.Res.1979,20:20.
[16] 上海药物所.溶癌呤(AT-1438)抗癌作用的研究.中国科学,1997,6:217-227.
[17] 牟永平,吴刚,周立社,和彦苓.抗肿瘤金属配合物药物及其药理作用的研究进展.中国药理学通报,2007,23(11):1409-1413.
[18] 吕华东,王志强,潘玉榕.福建省胃癌高中低发区人与癌症患者锌铜硒的比较.微量元素与健康研究,1998,15(2):37-38.
[19] 李伟,李星,申姜颖.胃癌及癌旁组织中微量元素含量研究.微量元素与健康研究,2001,18(3):11-14.
[20] Rosenberg B,Camp L V,Trosko J E,Mansour V H.Nature,1969,222:385—386.
[21] 王联红(Wang L H),刘芸(Liu Y) ,尤启冬(You Q D),苟少华(Gou S H). 非经典铂类抗肿瘤药物研究.化学进展(Progress in Chem.),2004, 16 (3):456—461.
[22] 王联红(Wang L H), 刘芸(Liu Y), 苟少华(Gou S H), 尤启冬(You Q D). 符合经典构效关系的抗肿瘤铂类药物.化学通报(Chem. ) , 2003 , 12 : 828 —836.
[23] Lippard S J,Pil P.Encyclopedia of Cancer,Cis2platin andRelated Drugs. San Diego,California:Academic Press,1997,392—410.
[24] Wong E, Giandomenico C M.Chem. Rev.,1999,99:2451—2466.
[25] 徐刚,崔玉波,崔凯.非铂类金属抗肿瘤药物的研究进展.化学进展,2006,18(1):108-113.
[26] 朱解方,朱国芳.抗癌金属配合物的研究综述.现代食品与药品杂志. 2007,17(4):22-25.
[27] Cussler EL,Moggridge GD.Chemical Product Design [M].UK:Cambridge University Press,2001,2.
[28] 钱延龙,陈新滋. 金属有机化学与催化 [M]. 北京:化学工业出版社,1997,889-891.
[29] Lebwohl D,Ganetta R.Clinical development of platinum complexes in cancer therapy:an historical perspective and an update [J].Eur Cancer,1998,34(10):1522.
[30] Rixe O,Ortuzar W,Alvarez M.Oxaliplatin,tetraplatin,cisplatin and carbolatin:spectrum of activity in drug-resistant cell lines of the National Cancer Institue’s Anticancer Drug Screen Panel [J].Biochem Pharmacol,1996,52(12):1855-1865.
[31] Dunn T A,Schmoll H J,Grunwald V. Comparative cytotxicity of oxaliplatin and cisplatin in non-seminomatous germ cell cancer cell lines [J].Invest New Drugs,1997,15(2):109-114.
[32] Gamelin E,Le Bouil A,Boisdron-Celle M.Cumulative pharmacokinetic study of oxaliplatin,adminstered every three weeks,combined with 5-fluorouracil in colorectal cancer patients [J].Clin Cancer Res,1997,3(6):891-899.
[33] Stanfer M.Investigation in the field of organogermanium chemistry[J].Erfahrungsheikunde,1980,29:646-649.
[34] 李连之,周立国,王俊礼.金属配合物的药学作用[J].聊城师院学报(自然科学版).1994, 7(3):61.
[35] 尹汉东,马春林.具有抗癌活性金属化合物的研究进展[J].化学研究, 1999, 10(4): 58.
[36] 戴荣斌.抗癌金属配合物的研究[J].天津学刊, 1998,13 (5):23-24.
[37] 张志刚,杨频.二茂钛二甘氨酸盐酸盐的体外抗肿瘤活性及其 DNA 的作用研究[J].高等学校化学学报,1999,20(11):1682.
[38] 韦捷敏,田华,王麟生.抗癌金属配合物的研究新进展[J].化学世界,2003,11:605.
[39] 刘晶莹,王国清,王鸿刚.金属配合物抗癌活性的研究进展[J].化学试剂,2003,25(5):275-276.
[40] 吴振,高国辉.稀土丙二酸类配合物的合成和体外抗癌活性的初步研究[J].黑龙江大学自然科学学报,2003, 20(4):104-107.
[41] Kopf-Maier P,Kopf-Maier H,Neuse EW.Ferroceniumsalt the first antineoplastic iron compounds [J].AngewChem Int Ed Engl,1984,23:456-457.
[42] 李连之,周立国.金属配合物的药学作用[J].聊城师院学报(自然科学版),1994,7(3):61.
[43] 尹富玲,申佳,邹佳嘉,李荣昌.2,2’-联吡啶和去甲基斑蝥酸根桥联双核铜( Ⅱ )配合物的合成、结构表征及抗癌活性的研究[J].化学学报,2003,61(4):556-561.
[44] 刘训峰.“十五”期间我国乙烯工业的发展趋势[J].石油化工技术经济,2001,17(5):4-8.
[45] 卢文贯,陶家洵,王大奇.二正丁基锡( Ⅳ )双(二茂铁硫代甲酸酯)配合物的合成、结构表征及其体外抗癌活性研究[J].化学学报,2004,62(2):160.
[46] 刘晶莹,王国清,王鸿刚.金属配合物抗癌活性的研究进展[J].化学试剂,2003,25(5):275-276.
[47] 席晓岚,黎植昌.氨基 Schiff 碱及其金属配合物的抑菌抗癌活性的研究进展[J].氨基酸和生物资源,1998,20(4):40.
[48] 刘建宁,董彦杰,王国维.缩氨基硫脲过渡金属配合物及其抗癌活性[J].甘肃科学学报,1998,10(2):69.
[49] 刘建宁,董彦杰,高贵香.苯甲醛缩氨基硫脲过渡金属配合物及其抗癌活性[J].肿瘤,1998,18(3):168.
[50] 刘建宁,帅淑霞,高虹.苯甲醛缩氨基硫脲与 Cu2+、Co2+、Ni2+、Zn2+、Mn2+ (SCN))2 配合物的抗癌活性研究[J].兰州医学院学报,1997,23(1):22.
[51] 陈建华,李常胜,李习俊.N-(2-羟基萘甲醛)甘氨酸 schiff 碱及其铜( Ⅱ )、镍(Ⅱ)配合物的合成、表征和抗癌活性[J].中国药物化学杂志,1995,5(3):192.
[52] 孔德源,章雄文,朱勤.氨基酸类 schiff 碱稀土配合物的合成及抗肿瘤活性Ⅰ [J].中国药物化学杂志,1998,9(4):245.
[53] 孔德源,谢毓元.氨基酸类 schiff 碱稀土配合物的合成及抗肿瘤活性Ⅱ [J]. 中国药物化学杂志,1999,9(3):162.
[54] 嵇汝运.改造与创新——论改造中草药成分的化学结构以开发创新药物.中国处方药,2003,1(1):36-39.
[55] 雷英杰.天然抗癌药物喜树碱及其衍生物的研究进展.化学研究与应用,2001,13 (4):359-362.
[56] 郭丽仪.喜树碱类抗癌药的研究开发.中国药业,2000,9(3):11-12
[57] 田少霄,赵树林,束爱堂.去甲斑蛩素氟基酸衍生物的合成与抗癌活性.药学学报,1993,28(11):870-875.
[58] 方苗,田少霄,李克庆.去甲斑蛩素去氧脱氧蜘类似蜘的合成与抗癌活性.药学学报,1993,28(12):931-935.
[59] 王志光,马雏勇.黄火等鬼臼毒素类的化学与抗肿 I 茸活性研究. 中国药物化学杂志,1993,3(1):l7-22.
[60] 尹述凡,庄武,马堆募.4-S—(5-酰氨基-1,3,4-噻二唑-2-基)-4-脱氧-4’-去甲基表鬼臼毒素衍生物的合成与抗肿瘤活性.药学学报,1993,28(10):762-765.
[61] 刘明生,各掣红,陈英燕.齐墩果酸磷酸醢单钠的合成.中国药物化学杂志,1993,3(1):42-43.
[62] 岳琴,方起程,粱晓置.紫杉醇的半合成.药学学报,1996,31(12):911-917.
[63] 陶遵威,管军.我国中草药活性成分结构改造及合成的研究概况.中国药物化学杂志,1998,8(2):149-156.
[64] 姚新生. 天然药物化学第二版.北京人民卫生出版社,1995: 360-362
[65] 国家自然科学基金委员会.自然科学学科发展战略调研报告:有机化学.北京科学出版社,1994.
[66] 张继杰.中药化学.北京人民卫生出版,1986.
[67] 单磊,张卫东,张川.皂苷类成分抗肿瘤活性的研究进展.中草药,2005,36(2):295-298.
[68] 赵阳,马百平,王升启.中药所含甾体皂苷与三萜皂苷防治心血管疾病的研究进展[J].中国药学杂志, 2003,38 (1):3.
[69] 朱玮,贾夏,张鞍灵.刺楸属植物化学成分及生物活性研究进展[J].西北林学院学,2004, 19(3):119.
[70] 宋少江,卢立明,彭缨.龙牙木活性部位中分得的新三萜皂苷[J].沈阳药科大学学报,2001,18(6):462.
[71] 曹沛,吴凤锷,丁立生.银莲花属植物的化学及药理研究概况[J].天然产物研究与开发,2004, 116(16):581.
[72] 宿树兰,李永辉.中草药中三萜皂苷成分抗肿瘤活性研究概况.时珍国医国药. 2006,17(7):1153-1155.
[73] Sun X B.Soy saponins and its anticarcinogenic effect [J].Bull Bot R es (木本植物研究),2000,20 (3):328-331.
[74] Wang X Y,Jin H, Xu Z Q.Effect of momo ridica saponins on immune function in senile mice bearing sarcoma 180 [J].J Prev Med China PLA (解放军预防医学杂志),2000,20(3):160.
[75] Zhang C H, Wang H, Ni Q C.Experimental study of role of astragalus saponin in antitumor activity [J].Clin Med J China (中国临床医学),2002, 9(3):215.
[76] Xu C F,Wang B,Ren S T.The suppressive effect of gypenosides on murine S180 sarcoma and cultured ery-throleukemia cell line K562 [J].J X i’an Med Univ(西安医科大学学报),2002,23(3):217.
[77] Ye H J,Zou B,Du Y P.Effect of acanthophopanax sentocotus on cell cycle of hepatocellular carcinoma cells [J].Chin J Clin Hepatol (临床肝胆病杂志), 2002, 18(3):162.
[78] Wei W L,Wei X L,Ru X B.Effect of gypenosides on the expression of P388 proto-oncogene of rats with leukemia [J ].Chin Pharmacol Bull(中国药理学通报),2000,16(3):299.
[79] Chen T M,Wang Y P,Chen D L.Experimental studyon effect of apop to sis of K562 cells treated w ith TSPG [J ].Chin Tradit Herb Drugs (中草药),2003,34(3):2351.
[80] Xing J H,Chen Y Q,J iM X.Clinacal study on effectof ginseno side in inducing rectal cancer cell apoptosis [J].Chin J Integrated Tradit Chin W est Med(中国中西医结合杂志),2001,21(4):260.
[81] Fei X F,Wang B X,Tashiro S. Apoptotic effects of ginsenoside Rh2 on human malignantmelanoma A 3752S2 cells [J]. Acta Pharmacol Sin(中国药理学报),2002,24(3):315.
[82] Zhang M Y,An J H,Li C H.Effect of acanthophopanax senticosus on cell cycle of line of pulmonary carcinoma cells [J].J Jilin Univ-Med Sci(吉林大学学报· 医学版),2002,28(1):37.
[83] Weng X Y,Yu L J,Ma R D.Induction of apoptosis in human nasopharyngeal carcinoma cell line CHE-2Z by tubteimoside [J].Chin P harm acol Bull(中国药理学通报),2003,19(2):186.
[84] Tao H L,Gao F, Liu H Y.Experiment of antimetastasis effect of 20 (R ) -ginsenoside Rh2 on carcinoma cells [J].Genseng Res(人参研究),2002,14(4):17.
[85] 王四旺,谢艳华,刘佳,王晓娟.川产九节龙皂苷 I 在小鼠体内的抗肿瘤作用.第四军医大学学报,2000,21(12):236-237.
[86] 李茂,李伟芳,覃良,周军.九节龙皂苷体内的抗肿瘤作用.广西中医学院学报. 2004,7(2):11-12.
[87] 李茂,李伟芳,覃良,周军,韦宝伟.川产九节龙皂苷对小鼠免疫功能的影响.广西医学,2004,26(8):1096-1098.
[2] 王晓娟,张清华.毛茎紫金牛(九节龙)化学成分的研究. 中国中药杂志1990,l5,98.
[3] 张清华,王晓娟,缪振春,冯锐.川产九节龙皂苷的化学研究.药学学报,1993,28(9):673-678.
[4] 梁克明,王四旺,王晓娟.九节龙皂苷 8 株人癌细胞的抑制作用[J].第四军医大学学报,2001,22(7):671-672.
[5] 陶小军,王佩贤,杨孝江,姚鸿萍,刘静,曹永孝.九节龙皂苷Ⅰ对小鼠 Lewis 肺癌和裸鼠肝癌 SMMC-7721 的抑制作用[J].中药材,2006,28(7):574-577.
[6] 陶小军,龙静雯,贺建宇,姚鸿萍,刘静,曹永孝.九节龙皂苷Ⅰ的抗肿瘤作用和免疫调节作用[J].中国药理学通报,2005,21(9):1070-1073.
[7] 戴荣斌.抗癌金属配合物的研究[J].天津学刊,1998,13(5):22-26.
[8] 胡桂香,张金超,唐婷,龚钰秋.非经典铂类配合物的研究近况.化学研究与应用,1999,11 (3):235-240.
[9] 叶幼珠.试谈我国抗癌药物发展态势.海峡药学,1995,7 (3):63-64.
[10] 周永义,郭启华,谷学新.抗癌药物研究动态简介.化学教育,2004,5:10-13.
[11] 朱瑾 ,徐丽华,孙萌,李桂凤.抗癌中草药现代药理研究进展.World Health Digest,2007,4(11):12-15.
[12] 刘峰,魏新庭,王冬冬,孙德志,李林尉.抗癌药物的研究现状[J].聊城大学学报,2006,19(1):39-43.
[13] Friedman,O.M.,Myles,A.and Colvin,M..Cyclophophamide and related phosphoramide mustards.Current status and future prospets.Advances in Cancer Chemotherapy,Vol 4 edited by A.Rosowsky,1979,143-204,New York:Marcel Dekker.
[14] Goren,M.P.,Wright,R.K..Dechloroethylation of ifosfamide and neurotoxicity,Lancet.1986:1219-1220.
[15] Kramer MJ.5’-Deoxy-5-Fluorouridine-A New Orally Active Antitumor Agent,Comparative Activity With 2’-Deoxy-Fluorouridine and Ftorafur Against Transplantable Tumors in Mice and Rats ,Proc.AM.Assoc.Cancer.Res.1979,20:20.
[16] 上海药物所.溶癌呤(AT-1438)抗癌作用的研究.中国科学,1997,6:217-227.
[17] 牟永平,吴刚,周立社,和彦苓.抗肿瘤金属配合物药物及其药理作用的研究进展.中国药理学通报,2007,23(11):1409-1413.
[18] 吕华东,王志强,潘玉榕.福建省胃癌高中低发区人与癌症患者锌铜硒的比较.微量元素与健康研究,1998,15(2):37-38.
[19] 李伟,李星,申姜颖.胃癌及癌旁组织中微量元素含量研究.微量元素与健康研究,2001,18(3):11-14.
[20] Rosenberg B,Camp L V,Trosko J E,Mansour V H.Nature,1969,222:385—386.
[21] 王联红(Wang L H),刘芸(Liu Y) ,尤启冬(You Q D),苟少华(Gou S H). 非经典铂类抗肿瘤药物研究.化学进展(Progress in Chem.),2004, 16 (3):456—461.
[22] 王联红(Wang L H), 刘芸(Liu Y), 苟少华(Gou S H), 尤启冬(You Q D). 符合经典构效关系的抗肿瘤铂类药物.化学通报(Chem. ) , 2003 , 12 : 828 —836.
[23] Lippard S J,Pil P.Encyclopedia of Cancer,Cis2platin andRelated Drugs. San Diego,California:Academic Press,1997,392—410.
[24] Wong E, Giandomenico C M.Chem. Rev.,1999,99:2451—2466.
[25] 徐刚,崔玉波,崔凯.非铂类金属抗肿瘤药物的研究进展.化学进展,2006,18(1):108-113.
[26] 朱解方,朱国芳.抗癌金属配合物的研究综述.现代食品与药品杂志. 2007,17(4):22-25.
[27] Cussler EL,Moggridge GD.Chemical Product Design [M].UK:Cambridge University Press,2001,2.
[28] 钱延龙,陈新滋. 金属有机化学与催化 [M]. 北京:化学工业出版社,1997,889-891.
[29] Lebwohl D,Ganetta R.Clinical development of platinum complexes in cancer therapy:an historical perspective and an update [J].Eur Cancer,1998,34(10):1522.
[30] Rixe O,Ortuzar W,Alvarez M.Oxaliplatin,tetraplatin,cisplatin and carbolatin:spectrum of activity in drug-resistant cell lines of the National Cancer Institue’s Anticancer Drug Screen Panel [J].Biochem Pharmacol,1996,52(12):1855-1865.
[31] Dunn T A,Schmoll H J,Grunwald V. Comparative cytotxicity of oxaliplatin and cisplatin in non-seminomatous germ cell cancer cell lines [J].Invest New Drugs,1997,15(2):109-114.
[32] Gamelin E,Le Bouil A,Boisdron-Celle M.Cumulative pharmacokinetic study of oxaliplatin,adminstered every three weeks,combined with 5-fluorouracil in colorectal cancer patients [J].Clin Cancer Res,1997,3(6):891-899.
[33] Stanfer M.Investigation in the field of organogermanium chemistry[J].Erfahrungsheikunde,1980,29:646-649.
[34] 李连之,周立国,王俊礼.金属配合物的药学作用[J].聊城师院学报(自然科学版).1994, 7(3):61.
[35] 尹汉东,马春林.具有抗癌活性金属化合物的研究进展[J].化学研究, 1999, 10(4): 58.
[36] 戴荣斌.抗癌金属配合物的研究[J].天津学刊, 1998,13 (5):23-24.
[37] 张志刚,杨频.二茂钛二甘氨酸盐酸盐的体外抗肿瘤活性及其 DNA 的作用研究[J].高等学校化学学报,1999,20(11):1682.
[38] 韦捷敏,田华,王麟生.抗癌金属配合物的研究新进展[J].化学世界,2003,11:605.
[39] 刘晶莹,王国清,王鸿刚.金属配合物抗癌活性的研究进展[J].化学试剂,2003,25(5):275-276.
[40] 吴振,高国辉.稀土丙二酸类配合物的合成和体外抗癌活性的初步研究[J].黑龙江大学自然科学学报,2003, 20(4):104-107.
[41] Kopf-Maier P,Kopf-Maier H,Neuse EW.Ferroceniumsalt the first antineoplastic iron compounds [J].AngewChem Int Ed Engl,1984,23:456-457.
[42] 李连之,周立国.金属配合物的药学作用[J].聊城师院学报(自然科学版),1994,7(3):61.
[43] 尹富玲,申佳,邹佳嘉,李荣昌.2,2’-联吡啶和去甲基斑蝥酸根桥联双核铜( Ⅱ )配合物的合成、结构表征及抗癌活性的研究[J].化学学报,2003,61(4):556-561.
[44] 刘训峰.“十五”期间我国乙烯工业的发展趋势[J].石油化工技术经济,2001,17(5):4-8.
[45] 卢文贯,陶家洵,王大奇.二正丁基锡( Ⅳ )双(二茂铁硫代甲酸酯)配合物的合成、结构表征及其体外抗癌活性研究[J].化学学报,2004,62(2):160.
[46] 刘晶莹,王国清,王鸿刚.金属配合物抗癌活性的研究进展[J].化学试剂,2003,25(5):275-276.
[47] 席晓岚,黎植昌.氨基 Schiff 碱及其金属配合物的抑菌抗癌活性的研究进展[J].氨基酸和生物资源,1998,20(4):40.
[48] 刘建宁,董彦杰,王国维.缩氨基硫脲过渡金属配合物及其抗癌活性[J].甘肃科学学报,1998,10(2):69.
[49] 刘建宁,董彦杰,高贵香.苯甲醛缩氨基硫脲过渡金属配合物及其抗癌活性[J].肿瘤,1998,18(3):168.
[50] 刘建宁,帅淑霞,高虹.苯甲醛缩氨基硫脲与 Cu2+、Co2+、Ni2+、Zn2+、Mn2+ (SCN))2 配合物的抗癌活性研究[J].兰州医学院学报,1997,23(1):22.
[51] 陈建华,李常胜,李习俊.N-(2-羟基萘甲醛)甘氨酸 schiff 碱及其铜( Ⅱ )、镍(Ⅱ)配合物的合成、表征和抗癌活性[J].中国药物化学杂志,1995,5(3):192.
[52] 孔德源,章雄文,朱勤.氨基酸类 schiff 碱稀土配合物的合成及抗肿瘤活性Ⅰ [J].中国药物化学杂志,1998,9(4):245.
[53] 孔德源,谢毓元.氨基酸类 schiff 碱稀土配合物的合成及抗肿瘤活性Ⅱ [J]. 中国药物化学杂志,1999,9(3):162.
[54] 嵇汝运.改造与创新——论改造中草药成分的化学结构以开发创新药物.中国处方药,2003,1(1):36-39.
[55] 雷英杰.天然抗癌药物喜树碱及其衍生物的研究进展.化学研究与应用,2001,13 (4):359-362.
[56] 郭丽仪.喜树碱类抗癌药的研究开发.中国药业,2000,9(3):11-12
[57] 田少霄,赵树林,束爱堂.去甲斑蛩素氟基酸衍生物的合成与抗癌活性.药学学报,1993,28(11):870-875.
[58] 方苗,田少霄,李克庆.去甲斑蛩素去氧脱氧蜘类似蜘的合成与抗癌活性.药学学报,1993,28(12):931-935.
[59] 王志光,马雏勇.黄火等鬼臼毒素类的化学与抗肿 I 茸活性研究. 中国药物化学杂志,1993,3(1):l7-22.
[60] 尹述凡,庄武,马堆募.4-S—(5-酰氨基-1,3,4-噻二唑-2-基)-4-脱氧-4’-去甲基表鬼臼毒素衍生物的合成与抗肿瘤活性.药学学报,1993,28(10):762-765.
[61] 刘明生,各掣红,陈英燕.齐墩果酸磷酸醢单钠的合成.中国药物化学杂志,1993,3(1):42-43.
[62] 岳琴,方起程,粱晓置.紫杉醇的半合成.药学学报,1996,31(12):911-917.
[63] 陶遵威,管军.我国中草药活性成分结构改造及合成的研究概况.中国药物化学杂志,1998,8(2):149-156.
[64] 姚新生. 天然药物化学第二版.北京人民卫生出版社,1995: 360-362
[65] 国家自然科学基金委员会.自然科学学科发展战略调研报告:有机化学.北京科学出版社,1994.
[66] 张继杰.中药化学.北京人民卫生出版,1986.
[67] 单磊,张卫东,张川.皂苷类成分抗肿瘤活性的研究进展.中草药,2005,36(2):295-298.
[68] 赵阳,马百平,王升启.中药所含甾体皂苷与三萜皂苷防治心血管疾病的研究进展[J].中国药学杂志, 2003,38 (1):3.
[69] 朱玮,贾夏,张鞍灵.刺楸属植物化学成分及生物活性研究进展[J].西北林学院学,2004, 19(3):119.
[70] 宋少江,卢立明,彭缨.龙牙木活性部位中分得的新三萜皂苷[J].沈阳药科大学学报,2001,18(6):462.
[71] 曹沛,吴凤锷,丁立生.银莲花属植物的化学及药理研究概况[J].天然产物研究与开发,2004, 116(16):581.
[72] 宿树兰,李永辉.中草药中三萜皂苷成分抗肿瘤活性研究概况.时珍国医国药. 2006,17(7):1153-1155.
[73] Sun X B.Soy saponins and its anticarcinogenic effect [J].Bull Bot R es (木本植物研究),2000,20 (3):328-331.
[74] Wang X Y,Jin H, Xu Z Q.Effect of momo ridica saponins on immune function in senile mice bearing sarcoma 180 [J].J Prev Med China PLA (解放军预防医学杂志),2000,20(3):160.
[75] Zhang C H, Wang H, Ni Q C.Experimental study of role of astragalus saponin in antitumor activity [J].Clin Med J China (中国临床医学),2002, 9(3):215.
[76] Xu C F,Wang B,Ren S T.The suppressive effect of gypenosides on murine S180 sarcoma and cultured ery-throleukemia cell line K562 [J].J X i’an Med Univ(西安医科大学学报),2002,23(3):217.
[77] Ye H J,Zou B,Du Y P.Effect of acanthophopanax sentocotus on cell cycle of hepatocellular carcinoma cells [J].Chin J Clin Hepatol (临床肝胆病杂志), 2002, 18(3):162.
[78] Wei W L,Wei X L,Ru X B.Effect of gypenosides on the expression of P388 proto-oncogene of rats with leukemia [J ].Chin Pharmacol Bull(中国药理学通报),2000,16(3):299.
[79] Chen T M,Wang Y P,Chen D L.Experimental studyon effect of apop to sis of K562 cells treated w ith TSPG [J ].Chin Tradit Herb Drugs (中草药),2003,34(3):2351.
[80] Xing J H,Chen Y Q,J iM X.Clinacal study on effectof ginseno side in inducing rectal cancer cell apoptosis [J].Chin J Integrated Tradit Chin W est Med(中国中西医结合杂志),2001,21(4):260.
[81] Fei X F,Wang B X,Tashiro S. Apoptotic effects of ginsenoside Rh2 on human malignantmelanoma A 3752S2 cells [J]. Acta Pharmacol Sin(中国药理学报),2002,24(3):315.
[82] Zhang M Y,An J H,Li C H.Effect of acanthophopanax senticosus on cell cycle of line of pulmonary carcinoma cells [J].J Jilin Univ-Med Sci(吉林大学学报· 医学版),2002,28(1):37.
[83] Weng X Y,Yu L J,Ma R D.Induction of apoptosis in human nasopharyngeal carcinoma cell line CHE-2Z by tubteimoside [J].Chin P harm acol Bull(中国药理学通报),2003,19(2):186.
[84] Tao H L,Gao F, Liu H Y.Experiment of antimetastasis effect of 20 (R ) -ginsenoside Rh2 on carcinoma cells [J].Genseng Res(人参研究),2002,14(4):17.
[85] 王四旺,谢艳华,刘佳,王晓娟.川产九节龙皂苷 I 在小鼠体内的抗肿瘤作用.第四军医大学学报,2000,21(12):236-237.
[86] 李茂,李伟芳,覃良,周军.九节龙皂苷体内的抗肿瘤作用.广西中医学院学报. 2004,7(2):11-12.
[87] 李茂,李伟芳,覃良,周军,韦宝伟.川产九节龙皂苷对小鼠免疫功能的影响.广西医学,2004,26(8):1096-1098.