Gomisin M1、Eriocalyxin B及Przewalskin B的合成及生物活性研究
其他题名Synthesis and Bioactive Evaluation of Gomisin M1, Eriocalyxin B and Przewalskin B
刘靖平
学位类型博士
导师孙汉董
2009-05-27
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
学位专业植物学
关键词Gomisin M1 Eriocalyxin b Przewalskin b 联苯环辛二烯木脂素 抗hiv-1活性 抗肿瘤活性 全合成
摘要本论文共由四章组成。第一章报道了联苯环辛二烯木脂素Gomisin M1的全合成及其联苯衍生物在抗HIV-1中的应用。第二章报道了Eriocalyxin B的结构修饰及其抗肿瘤活性筛选研究。第三章报道了对Przewalskin B二萜化合物的全合成研究。第四章详细述综述了1990年至2008年以来对联苯环辛二烯类木脂素的全合成研究进展。 Gomisin M1最初是从传统中药五味子中分离得到的联苯环辛二烯类木脂素,我们研究组近年来的研究表明Gomisin M1对HIV-1病毒复制具有显著的抑制作用,它对C8166细胞的毒性(CC50)为26.91μg/mL;对HIV-1感染C8166细胞致细胞病变抑制试验的EC50为0.12 μg/mL,治疗指数(TI值)为178.61。我们以没食子酸为原料完成了Gomisin M1的消旋合成,和天然产物进行活性对比后发现,消旋的Gomisin M1治疗指数为144.18,联苯的构型并没有影响到联苯环辛二烯木脂素抗病毒的活性。为寻找结构更加简单,合成方法更加简化的联苯衍生物,我们合成了16个联苯衍生物并进行了抗HIV-1活性测试,发现化合物24对C8166细胞的毒性较低(CC50=85.31μg/mL),治疗指数TI=473.94,远大于天然产物;对HIV-1诱导C8166细胞形成合胞体抑制的EC50=0.18μg/mL,TI=257.60;对MT-4细胞保护作用非常明显,TI>196.08,有望作为治疗艾滋病的候选药物分子进行进一步的研究。 Eriocalyxin B是从香茶菜属植物(Isodon eriocalyx (Dunn) Hara)中分离得到的一个二萜化合物,具有显著的抗肿瘤活性。我们对其B环6位的羟基进行了烷基化修饰,增加其脂溶性。共合成了10个衍生物,并对5个细胞株(BEL-7402, A549, HT-29, HL60, MOIL-4)进行了抗肿瘤活性筛选。系列衍生物都对这5个瘤株呈现出了不同的活性,但和母体结构-eriocalyxin B相比时,没有一个经过修饰后的衍生物活性超过毛萼乙素,我们分析原因可能是破坏了A环的α,β不饱和自身结构单元所致。 Przewalskin B是从甘西鼠尾草(Salvia Przewalskii Maxim)中分离得到的一个[5,6]螺环二萜,具有一定的抗HIV-1活性(EC50=30.32μg/mL,SI=3.32)。我们以环己酮为原料,完成了模型分子-化合物12的合成,成功构建B,C,D环。另一条路线以异丁醛和甲基乙烯基酮(MVK)为起始原料,通过Diels-Alder反应完成了A,B两个环的构建。 第四章主要概括了1990年至2008年以来,对合成联苯环辛烯类木脂素所采用的新试剂和新方法进行了综述,为开发木脂素类药物研究提供参考。
其他摘要This dissertation is composed of four chapters. The total synthesis of racemic Gomisin M1 and its biphenyl derivatives are described in Chapter One, in which studies towards anti-HIV activity of the synthesized compounds are also presented. Studies on the synthesis and bioactivities of eriocalyxin B derivatives are described in Chapter Two. The total synthesis of Przewalskin B was reported in Chapter Three. In Chapter Four, a review of strategies used previously for the total synthesis of dibenzocyclooctadiene lignans is provided. Gomisin M1 is a dibenzocyclooctadiene lignan isolated firstly from the Chinese medicinal herb Schisandra chinensis. In our previous research for natural products as anti-HIV agents, Gomisin M1 showed significant activity, with CC50, EC50 and TI values of 26.91μg/mL, 0.12 μg/mL and 178.61, respectively. Compared racemic Gomisin M1 (with similar activity, TI=144.18) to its natural counterpart, we found that the biphenyl configuration had little effect on the antiviral activity of dibenzocyclooctadiene lignans. Encouraged by this result, we synthesized a number of biphenyl derivatives with simplified structure. To our delight, compound 24 demonstrated the best inhibitory activity against HIV-1 (EC50=0.18μg/mL,TI=257.60) with low toxicity (CC50=85.31μg/mL, TI=473.94), and exerted protective activity on HIV-1 infected MT-4 host cells from dying with TI values of >196.08. Compound 24 might deserve as a promising candidate for further biological evaluation. Eriocalyxin B is a diterpene compound isolated from Isodon eriocalyx (Dunn) Hara, and possesses significant antitumor activities. In chapter 2, we mainly focused on the modification of the B ring system of eriocalyxin B by attaching a lipophilic alkyl side chain to the C-6 hydroxyl group. Ten derivatives were synthesized, and evaluated against five tumor cell lines (BEL-7402, A549, HT-29, HL60, MOIL-4), moderate activities were observed. However, all derivatives were less potent than its parent compound-eriocalyxin B. Our results suggest that the moiety of α, β-unsaturated ketone in A-ring also plays a role in the anti-tumor activity. In the absence of the A-ring α, β-unsaturated ketone unit, all derivatives showed reduced activities. Przewalskin B is a diterpene with a [5, 6] spiro ring firstly isolated from Salvia Przewalskii Maxim, and possesses moderate anti-HIV-1 activity (EC50=30.32μg/mL,SI=3.32). The synthesis of B, C, D ring of model molecule (compound 12) was completed using cyclohexanone as starting material. Another route towards the synthesis of Przewalskin B was performed using isobutyraldehyed and methyl vinyl ketone (MVK) as starting material, and A, B ring was established through a Diels-Alder reaction. New reagents and methods utilized in the total synthesis of dibenzocyclooctadiene lignans are reviewed (from 1990 to 2008).
页数138
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/248
专题昆明植物所硕博研究生毕业学位论文
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刘靖平. Gomisin M1、Eriocalyxin B及Przewalskin B的合成及生物活性研究[D]. 昆明植物研究所. 中国科学院昆明植物研究所,2009.
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