抗肿瘤活性化合物景洪哥纳香甲素的结构修饰及岷江金丝桃的化学成分研究
其他题名Modification and Antitumor Activity of Cheliensisin A, and the Chemical Constituents of Hypericum henryi subsp. uraloids
郭娜
学位类型硕士
导师赵勤实
2008-05-27
学位授予单位中国科学院昆明植物研究所
学位授予地点昆明植物研究所
学位专业药物化学
关键词景洪哥纳香甲素 Gc-51 苯乙烯-内酯 结构修饰 构效关系
摘要本论文分为三章。第一章详细论述了具有抗肿瘤活性的天然产物景洪哥纳香甲素(GC-51)的结构修饰,探讨了其构效关系。第二章介绍了对岷江金丝桃的化学成分研究。最后一章,综述了苯乙烯-内酯类化合物抗肿瘤活性的研究进展。 第一章 景洪哥纳香甲素的结构修饰和构效关系研究 景洪哥纳香甲素 (GC-51) 是从景洪哥纳香 (Goniothalamus cheliensis) 中分离得到的苯乙烯-内酯类化合物。GC-51可以显著的抑制HL-60细胞增殖 (IC50 = 2.4 M) 并可以有效的诱导HL-60细胞凋亡,是一个非常有发展前景的抗肿瘤活性化合物。但由于GC-51制剂很不稳定,并且难以通过改变辅料和剂型来解决这一难题,而且GC-51代谢太快,半衰期非常短,所以通过对其进行结构改造,研究其构效关系,寻找更稳定活性更好的衍生物,将会是一个有意义的课题。在这一章中,我们详细叙述了GC-51的化学反应和构效关系的研究结果。为了解决GC-51不稳定的问题并研究其构效关系,对GC-51的结构修饰主要包括:(1) 将7,8位环氧转变成其它稳定的官能团;(2) 在苯环上连上取代基,考察取代基对活性的影响;(3) 破坏Michael受体,考察其对活性的影响;(4) 将5位乙酰基水解,考察其对活性的影响。对合成的15个衍生物中的13个在Hela (人宫颈癌细胞株)、HL-60 (人早幼粒细胞性白血病细胞株)、K562 (人红细胞慢性骨髓白血病细胞株) 上进行了细胞毒活性筛选,其中化合物1-5, 8, 15, 16表现了不同程度的细胞毒活性。构效关系研究表明:(1) 3,4位双键与2位羰基构成的Micheal受体是该化合物的活性中心,破坏Micheal受体,细胞毒活性完全丧失。(2) 六元内酯环变成五元内酯环活性丧失或显著降低。(3) 三元氧环是一个次要的活性中心,在保持活性的前提条件下可以转变成更稳定的基团。(4) 把分子中的羟基保护起来,增加了脂溶性,可以显著提高活性。(5) 苯环的邻位连上硝基有利于提高活性。 在这部分工作中我们证实了Micheal受体是GC-51的活性中心,发现了六元内酯环是活性必需的,三元氧环是次要活性中心,通过结构修饰来寻找更稳定活性更好的衍生物是可行的。为该化合物的进一步研究奠定了基础。 第二章 岷江金丝桃的化学成分研究 岷江金丝桃 (Hypericum henryi subsp. uraloids) 是藤黄科金丝桃属 (Hypericum) 植物,由于金丝桃属植物多具有抗抑郁、抗病毒、抗菌和抗肿瘤等多种药理活性,我们对采自云南省金平县的岷江金丝桃的化学成分进行了研究,分离得到了12个化合物,包括3个新的多异戊烯基间苯三酚类衍生物 (即贯叶金丝桃素类化合物),2个三萜、2个黄酮、4个口山酮和1个环氧化合物。 第三章 苯乙烯-内酯类化合物的抗肿瘤活性研究进展 总结了苯乙烯-内酯类化合物的的构效关系,对这类化合物的抗肿瘤活性的研究进展进行了综述。 关键词:景洪哥纳香甲素,GC-51,苯乙烯-内酯,结构修饰,构效关系
其他摘要This dissertation is composed of three chapters. The first chaper reported the modification and SAR of cheliensisin A and its analogues in detail. The second chapter introduced the isolation and identification of chemical consitituents from Hypericum henryi subsp. uraloids. In the third chapter, SAR and current advance in the antitumor activity of styryl lactones have been reviewed. Chapter 1. The modification and Structure-Activitity Relationship of Cheliensisin A Cheliensisin A (GC-51), a styryl lactone isolated from Goniothalamus cheliensis, is a potent antitumor compound. It can not only remarkably inhibite the proliferation of HL-60 cell line, but also efficiently induce the apoptosis of HL-60 cell line. The preparation of GC-51 is not stable, and the metabolization of GC-51 is too rapid. Therefore, through modification and the SAR studies on GC-51 are important for searching for more stable and more active analogs. In this chapter, we described the modification of GC-51 and the discussion of SAR. The modification of GC-51 contined: convertion the 7,8-epoxy to more stable unit, introduction of substituent group into benzene ring, destruction of Micheal receptor and hydrolysis of acetyl group at C-5. The cytotoxicity of obtained thirteen derivatives were evaluated against three tumor cell lines (Hela, HL-60, K562). Some derivatives (1-5, 8, 15, 16) showed different activity against the tumor cell lines. The SAR studies showed that: (1) Michaeal receptor composed of carbonyl group of C-2 and double bond between C-3 and C-4 is an active center of GC-51, derivatives without Michaeal receptor showed no activity against Hela, HL-60 and K562. (2) The convertion of six-membered lactone to five-membered lactone would significantly decreased the activity or show no activity. (3) The protection of hydroxyl groups can remarkably enhance the activity. (4) Introduction nitro group into C-10 might increase activity. Chapter 2. Study on Chemical Constituents of Hypericum Henryi subsp. uraloids. Many species of genus Hypericum have shown various pharmacologic activities such as antidepressant, antivirus, antibacterial, and antitumor. As a part of our systematic bioactive and chemical study about the constituents of this genus, we investigated the chemical constituents of Hypericum henryi subsp. uraloids. collected in County Jinpin of Yunnan province. Twelve compounds including three new polyisoprenylated benzoylphloroglucinol derivatives, two terpenoids, two flavonoids, four xanthones and an epoxy compound were isolated and identified. Compounds from Hypericum henryi subsp. uraloids. are listed as follow 1. uraloidin A (1)* 2. uraloidin B (2)* 3. uraloidin C (3)* 4. oleanolic acid (4) 5. betulinic acid (5) 6. quercetin(6) 7. quercetin 3-O--L-rhamnopyranoside (7) 8. 1,5,6-trihydroxy-3-methoxyxanthone (8) 9. 1,3,5,6-tetrahydroxyxanthone (9) 10. kielcorin (10) 11. 1,3,5,6-tetrahydroxy-4-prenylxanthone (11) 12. (-)-epoxycyclohexenol carboxylic acid (12) Note:  *new compounds Chapter 3. Review In this review, the SAR of styryl lactones has been summarized, and the current advance in the antitumor activity of them were presented. Key words: cheliensisin A, styryl lactone, activity, structure-activity relationship
页数63
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/354
专题昆明植物所硕博研究生毕业学位论文
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郭娜. 抗肿瘤活性化合物景洪哥纳香甲素的结构修饰及岷江金丝桃的化学成分研究[D]. 昆明植物研究所. 中国科学院昆明植物研究所,2008.
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