新型土震素B类似物的合成及其生物活性研究

【作者】 蒋翔锐；

【导师】 赵昱；

【作者基本信息】 浙江大学 ， 药物分析学， 2005， 博士

【摘要】 早老性痴呆即阿尔茨海默病（Alzheimer’s Disease,AD）是一种以进行性高级认知功能障碍和记忆功能丧失为特征的老年性疾病。目前临床上一类治疗AD比较成功的药物是乙酰胆碱酯酶（AChE）抑制剂。其作用机制基于AD发病机制的“胆碱能假说”,通过阻止乙酰胆碱的水解而增加胆碱能神经递质的作用。 土震素B（territrem B）是由中国台湾科学家从土麴菌稻米培养液中首次发现的具强效AChE抑制活性的化合物,IC₅₀达7.8 nmol·L^-1。其作用机制不同于现有的AChE抑制剂,具有高选择性等优点,是发展新的AChE抑制剂理想的先导化合物。 目前人们对这类化合物的主要药效基团的了解还不多,构效关系研究也停留在比较初步的阶段。为了详细的研究territrem B类化合物的药效基团,为进一步的药物分子设计提供更多依据,并在此基础上发现结构全新的AChE抑制剂,我们做了以下的工作。首先,保持territrem B结构中的D/E环不变,将A/B环视为缺电子基团对其进行结构简化,我们设计合成了结构通式为3.1和3.2的化合物3.10～3.32:设计合成了A/B环类似物2.5～2.8。然后,对所合成的化合物的体外AChE抑制活性和细胞毒活性进行测定,借助计算机辅助药物设计方法对其活性数据进行研究并得出初步的结论,在此基础上进一步设计并合成出新一批结构通式为4.2～4.5、4.8的四个系列化合物及结构为4.6、4.7、4.9的化合物。全文共合成了96个目标化合物和中间体,其中未见文献报道的新化合物71个。 对第三章合成的目标化合物的体外AChE抑制活性、六种人类肿瘤细胞株的细胞毒活性进行了测定。据不完全活性筛选结果:化合物3.14、3.24、3.25、3.27具有较好的AChE的抑制活性,其IC₅₀分别为9.1×10^-5 mol·L^-1、16.0×10^-5mol·L^-1、8.6×10^-5 mol·L^-1、7.2×10^-5 mol·L^-1。少数化合物表现出较好的细胞毒活性,其中化合物3.27对口腔表皮癌（KB）细胞、肺癌细胞（A549）、宫颈癌细胞（Hela）、鼻咽癌细胞（CNE）的IC₅₀分别为8.9×10^-5 mol·L^-1、17.4×10^-5 mol·L^-1、8.2×10^-5 mol·L^-1、3.6×10^-5 mol·L^-1。对进一步设计的目标化合物的生物活性测定正在进行之中。更多还原

【Abstract】 Alzheimer’s disease （AD） is a disorder associated with progressive degeneration in memory and in the recognition functions of old people. According to the cholinergic deficiency hypothesis of AD, one of therapeutic methods is the employment of acetylcholinesterase （AChE） inhibitors which act through inhibiting the hydrolysis of acetylcholine.Territrem B was first isolated from the culture broth of Aspergillus terreus by Chinese scientists in Taiwan. It shows potent inhibitory activity against AChE with IC50 value of 7.8 nmol.L^-1. Moreover, its inhibitory mechanism is different from the other known AChE inhibitors. Its high selectivity against AChE makes territrem B become the ideal lead compound in developing new AChE inhibitors.Up to present, detailed SAR investigations of territrem B have not been successful. Simplification on the A/B ring system should allow one to produce sufficient amounts of derivatives that can be subjected to an SAR study under different aspects.Hence, two types of parent compounds 3.1 and 3.2, including compounds 3.10 3.32, were designed and synthesized, in which N- and O- atoms were introduced. When analysis the structures of territrem B and the parent compounds, it is evident that the electron-poor enone A-ring was attached with the pyranone D-ring by a three-bond-linker. Moreover, we synthesized the A/B ring analogues 2.5 2.8.The biological evaluation, involving AChE inhibitory activities and cytotoxicities towards six different human tumor cell lines, and molecular modeling on SYBYL software indicated that the planar conformation of whole molecular was necessary for most actives compounds. Furthermore, we designed and synthesized four types of parent compounds, including 4.2, 4.3, 4.4 and 4.5. In addition, two compounds 4.6 and 4.7, in which sp³ C-atom was displaced with different sp² C-atom at 7-position, were synthesized.This thesis comprises five chapters altogether. The first chapter introduces the present situation of AD therapeutic development and territrem B studying development in latest years. The second chapter describes the viewpoints on designing series of new target compounds. The preparation of designed compounds was described in chapter three. We evaluated the AChE inhibitory and cytotoxicities of these compounds in chapter four and analyzed the data with the aid of SYBYLsoftware. Then four series compounds were designed. Chapter five described the preparation of newly designed compounds.By the incompletely biological activity screening results, the most-efficient inhibitors were compounds 3.14, 3.24, 3.25, 3.27, which exhibited IC50 values at 9.1 x 10"5 mol-L"1, 16.0 x 10"5 mol-L’1, 8.6 x 10"5 mol-L"1, 7.2 x 10"5 mol-L"1, respectively. Only a few compounds were mildly cytotoxic towards, for example 3.27 showed IC50 values of 8.9 x 10"5 mol-L"1, 1.7 x 10"4 mol-L’1, 8.2 x 10’5 mol-L"1, 3.6 x 10"5 mol-L"1, respectively towards KB, A549, Hela, CNE cell lines.更多还原