【作者】 李斐；

【导师】 孙晓莉； 王晓娟；

【作者基本信息】 第四军医大学 ， 药物化学， 2008， 硕士

【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。更多还原

【Abstract】 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、B23. use A1 for raw material, react with Zn(II)、Cu(II)、Co(II)、Cr(III)、Ni(II), synthesize a series of metal-complexes C1-C54. use B2 for raw material, react with Zn(II)、Cu(II)、Co(II)、Cr(III)、Ni(II), synthesize a series of metal-complexes E1-E5Third, 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.更多还原