基于全合成的苯安沙霉素类天然产物结构优化初步探索

发布时间：2018-08-27 14:44

【摘要】：Hsp90是一类能促进蛋白质正确折叠,并在应激条件下防止蛋白质变性的分子伴侣。它在肿瘤细胞中高度表达,是维系肿瘤生存和发展的重要因素之一。通过抑制Hsp90的功能,可引发多种原癌基因蛋白的泛素化和降解,促使肿瘤细胞的凋亡Geldanamycin和Herbimycin A等苯安沙霉素类天然产物能竞争性地占据Hsp90的N端ATP结合位点,阻断其分子伴侣功能,是一类机制新颖的抗肿瘤药物先导物。然而,其苯醌结构片段在代谢过程中所引起的肝毒性一直是限制此类安沙霉素天然产物成药的重要因素。因此,针对苯醌结构部分的改造尤为重要。通过文献检索与共晶结构数据分析发现,C18位氧原子与蛋白质并无直接相互作用,而C21位氧原子对整个分子与Hsp90蛋白质的结合影响巨大。因此,针对苯醌结构部分进行改造,并结合安沙链C4-C5、C11两个改造位点,设计了C18位去氧的非醌类安沙霉素天然产物类似物40-43。利用课题组已有的Herbimycin A全合成路线,以Sharpless不对称双羟化反应、Katuski不对称环氧化反应为关键步骤,构建了C8-C15部分的合成砌块。改进了原有路线的偶联策略,成功引入芳香片段。最后,借助二甲基锌介导的亲和加成反应,立体选择性地完成了片段链接。然而,在最后一步保护基脱除过程中,意外得到四个C15位Friedel-Crafts衍生化产物102a-102d。对其进行生物活性分析发现,C18位去氧与C15位引入大的取代基团均未引起活性的降低。其中,化合物102a的生物活性保持,化合物102b的生物活性提高十倍左右。基于以上全合成和生物活性评价研究,设计的C18位去氧苯酚类衍生物具有良好的抗肿瘤活性,丰富了此类天然产物的构效关系研究,为今后的结构优化提供了新思路。
[Abstract]:Hsp90 is a class of molecular chaperones that promote the proper folding of proteins and prevent their degeneration under stress. Its high expression in tumor cells is one of the important factors to maintain the survival and development of tumor. By inhibiting the function of Hsp90, many proto-oncogene proteins can be induced to ubiquitization and degradation, and the natural products such as Geldanamycin and Herbimycin A can competitively occupy the N-terminal ATP binding sites of Hsp90. Blocking its molecular chaperone function is a novel antitumor drug leader. However, the hepatotoxicity caused by the structural fragment of benzoquinone during metabolism has been an important factor limiting the drug. Therefore, it is very important to reconstruct the structural part of benzoquinone. Through literature retrieval and analysis of eutectic structure data, it was found that there was no direct interaction between C _ (18) oxygen atom and protein, while C _ (21) oxygen atom had a great influence on the binding of the whole molecule to Hsp90 protein. Therefore, based on the structural modification of benzoquinone and two modification sites of Ansha chain C _ 4-C _ 5N _ (11), the natural analogue of non-quinone anoxamicin at C _ (18) position was designed. In this paper, the synthetic block of Herbimycin A was constructed by using the Sharpless asymmetric double hydroxylation reaction and the asymmetric epoxidation reaction of Katuski as the key step. The coupling strategy of the original route was improved and aromatic fragments were successfully introduced. Finally, a stereoselective fragment link was completed by dimethyl zinc mediated affinity addition reaction. However, during the last step of the protection group removal, four C15-bit Friedel-Crafts derivatives 102a-102dwere accidentally obtained. The bioactivity analysis showed that the deoxygenation at C18 and the introduction of large substituents at C15 did not decrease the activity. Among them, the biological activity of compound 102a was maintained, and the biological activity of compound 102b was increased about tenfold. Based on the above studies of total synthesis and bioactivity evaluation, the designed C18 deoxyphenol derivatives have good antitumor activity, enrich the study of structure-activity relationship of these natural products, and provide a new idea for structural optimization in the future.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R914

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