带有特殊二糖模块的薯蓣皂苷类似物的合成及抗肿瘤活性研究

【作者】 王惠；

【导师】 程卯生；

【作者基本信息】 沈阳药科大学 ， 药物化学， 2008， 硕士

【摘要】 天然皂苷化合物业已被证明具有抗肿瘤、抗炎等多种生物活性,是许多植物药的活性成分。但由于皂苷在植物中含量很低,且分离纯化过程复杂,在一定程度上限制了对其药理作用的深入研究。化学合成方法可以有效地制备一定数量、结构多样的皂苷类化合物,由此越来越引起药物化学家们的关注。选择价廉易得的皂苷元为起始原料,参考已知的天然皂苷结构,定向地半合成各种皂苷化合物,筛选合成化合物的药理活性,进而总结出化学结构与生物活性的关系,成为当前研究皂苷药物化学的重要方法。本论文综述了近年来对活性螺甾皂苷化合物进行合成和结构改造的研究进展,指出螺甾皂苷的生物活性是苷元和糖基两个部分协同作用的结果。研究发现,具有特定化学结构的螺甾皂苷对肿瘤细胞生长具有抑制作用,其细胞毒作用主要耳义决于糖链部分的结构。本论文根据文献报道的研究工作,选用D-葡萄糖、L-鼠李糖、D-木糖、L-阿拉伯糖、D-半乳糖五种单糖以及乳糖和麦芽糖两种二糖为原料,分别合成了活性糖给体——糖基三氯乙酰亚胺酯;选用薯蓣皂素为苷元,通过逐步糖苷化反应合成了两类共九种具有相近三糖模块结构的薯蓣皂素糖基修饰物（CW1-CW9）,以考察糖链结构对生物活性的影响。初步抗肿瘤活性筛选结果表明,CW1,CW2,CW3,CW6抑制SK-OV-3细胞的IC₅₀分别为1.14,7.42,2.47,2.01,都表现出较好的抑瘤活性,说明选定的部分三糖模块能诱导螺甾皂苷的肿瘤细胞毒活性,糖链结构上的差异有显著影响。更多还原

【Abstract】 Saponins have been found out owning a broad range of promising biological properties, such as antitumor and anti-inflammatory activities, and been considered as the key components in botanic medicines. However, further pharmacological studies towards saponins are often limited due to their lower contents in plant materials and the complicated isolation and purification work. As an important access to find novel sapogenyl glycoside structures, chemical synthesis plays a dominant role and receives increasing attention. Using the definite structures of some natural saponins for reference to guide the partial synthesis of diverse saponin compounds from a certain of cheap available sapogenins, followed with the pharmacological screenings of the synthetic compounds and summarizing the corresponding structures and activities relationships (SARs), is one of the effective researching strategies for saponin medicinal chemistry.The recent developments of the researches on the synthesis and structural modification of naturally active spirostanol saponins were summarized in the first chapter of the dissertation. It is quite clear that the activities of spirostanol saponins are related to both the aglycones and the sugar units. The diversity in structures of saponins lies mainly in their sugar moieties. Many studies have disclosed that some biological functions of spirostanol saponins can be most ascribed to the carbohydrate residue.Based on the relevant literature reported, we chose five monosaccharides and two disaccharides to synthesize the active sugar donors——glycosyl trichloroacetimidates and chose diosgenin as the aglycone. Therefore, 9 compounds (CW1-CW9) with similar trisaccharide moiety structures were prepared by stepwise glycosylation. Preliminary in vitro pharmacological research showed that compound CW1, CW2, CW3, and CW6 presented inhibition against cell SK-OV-3 under the 10μM. Therefore, it can be concluded that some trisaccharide moieties can induce the cytotoxicity of spirostanol steroidal glycosides, and the structures of sugar moieties play important roles in the activities.更多还原