【作者】 孟庆国；

【导师】 王国荃； 沈竞康；

【作者基本信息】 新疆医科大学 ， 劳动卫生与环境卫生学， 2002， 博士

【摘要】 组合化学是20世纪90年代初发展起来的寻找及优化新药先导化合物的新颖研究方法，其特点是改变了传统的逐一合成、逐一纯化、逐一筛选的模式，以合成和筛选化学库的形式完成寻找及优化药物先导化合物，极大地加快了药物先导化合物出现的速度。固相平行组合合成技术因具有分离纯化简单等优点而成为目前组合化学研究采取的主要方法；丙谷胺是60年代创制的治疗消化性溃疡的胃泌素受体拮抗剂。从中药蜀五加中提取出的丙谷胺经药理免疫活性筛选证明具有很强的免疫增强活性。本文报告以丙谷胺为先导化合物，采用固相平行合成技术构建基于丙谷胺的小分子化合物库，期望找到比丙谷胺免疫活性强的化合物作进一步研究。 结论： 1．建立了D、L-Fmoc-Glu-OAllyl和D、L-Fmoc-Asp-OAllyl新的合成方法； 2．首次建立了丙谷胺及其类似物的固相合成方法； 3．以天然分离得到的丙谷胺为先导化合物，构建了含384个丙谷胺类似物的小分子化合物库，并分离得到部分副产物； 4．对合成和分离得到的434个丙谷胺类似物进行了体外免疫生物活性筛选，从中发现了9个免疫活性比先导化合物丙谷胺更强的化合物。更多还原

【Abstract】 Combinatorial chemistry is a new strategy for discovery and optimization of lead compounds in drug design in the early 1990s. It makes a big difference from traditional method with which pure compounds are synthesized, purified and screened one by one. Combinatorial chemistry is a type of synthetic and screening strategy which leads to large chemical libraries and extremely accelerates the rate of finding and optimizing new lead compounds. Solid-phase parallel approach is the main method in the study of combinatorial chemistry for its advantage of easy separating and purifying compounds; Proglumide is a gastrin receptor antagonist synthesized in the middle of 1960s which can be used in the treatment of peptic ulcer. Proglumide isolated from Chinese traditional medicine Acanthopanax setchuenensis is proved that it has high immunocompetence in the past experiments. In this project, we want to make proglumide as lead compound, construct the small-molecular library related to proglumide adopting solid-phase parallel approach, and expect to find some compounds which show higher immunocompetence than proglumide for further research. Conclusion:1 .established a novel synthesis method of D> L-Fmoc-Glu-OAllyland D^ L-Fmoc-Asp-OAllyl; 2.established the solid-phase synthesis method of proglumide andits analogues; 3.constructed the small-molecular library including 384 compoundsrelated to natural proglumide, and separated some by-products; 4.found 9 compounds which show higher immunocompetence thanproglumide in this small-molecule library.更多还原