【作者】 钟武；

【导师】 李松；

【作者基本信息】 中国人民解放军军事医学科学院 ， 药物化学， 2004， 博士

【摘要】 本文以AGEs交联为靶点，进行逆转老年性和糖尿病型血管硬化药物的研究。根据先导化合物ALT-711的作用机理和结构特征，设计新类型的虚拟先导优化组合化合物库，采用MOPAC方法计算活性位点的负净电荷，对化合物库进行虚拟筛选，确定优选化合物；构建虚拟先导发现组合库，采用DiverseSolution的BCUT描述符定义类药性分子的化学空间和活性分子的化学空间，并进行多样性和类药性评价。基于上述设计思想，合成硒唑类化合物2个、硒吩类化合物11个、噻吩类化合物10个和咪唑并硒唑类化合物18个，共计四大类41个化合物。化合物的结构都经IR、1HNMR、MS和元素分析等确证。在合成研究中发现一步法合成2-氨基硒唑的新方法和一步法合成咪唑并硒唑类化合物的新方法，能够缩短反应步骤，提高产率，适合于组合化学大规模平行合成。完成化合物体外裂解AGEs的活性研究，结果表明有20个化合物在0． 1mmol浓度下，17个化合物在0． 01或者0． 001mmol浓度下裂解AGE-BSA-胶原交联结构的能力优于阳性化合物ALT711。体内试验表明化合物ZW1能够显著降低体内RBC-IgG交联的含量；显著降低总外周阻力，提高全身动脉顺应性和改善胶原蛋白对水解酶的敏感性。初步急性毒性试验研究表明优选化合物ZW1，ZW6，ZW7，ZW20， ZW21和ZW22均低于阳性药物ALT711。构效关系分析结果表明咪唑并硒唑类化合物结构中C9，N10和Se14上的电荷密度和裂解能力密切相关，N10位是可能的质子化位点；季胺盐类化合物分子的最低空轨道和次一级空轨道的差值(△L)对化合物的裂解活性有着重要作用；C2的净电荷对活性也至关重要， 2位上负电荷密度越大，化合物的裂解活性越强，提示在C2上引入对其净电荷负值起贡献的基团将会使化合物的裂解活性增强。在基于KBase的软件平台上，构建了季胺盐类目标化合物结构和裂解活性的定量构效关系(QSAR)模型。基于描述符的QSAR方程结果表明化合物的裂解活性和Charg2、 QV、I和JT四种描述符代表的性质密切相关；基于碎片的QSAR方程结果表明四种主要的结构碎片对裂解活性起重要的贡献;建立的模型预测18个己知的化合物的裂解活性，结果与其实验值能够较好吻合。两个QSAR模型的建立为快速预测化合物的活性和对虚拟组合化合物库进行筛选提供可信工具;提供了先导化合物优化的策略。 本文通过设计、合成和生物活性研究，优选出候选化合物ZWI，该化合物具有明显的裂解AGES交联结构能力，对由AGEs交联结构引起的糖尿病大鼠动脉硬化症状具有明显改善作用，毒性较低，可以作为逆转老年性和糖尿病型血管硬化的候选药物进一步研究。更多还原

【Abstract】 We designed new drugs reversing arterial stiffening in aging and diabetes targeted AGEs crosslinks. According to the proposed mechanism of breaking of AGEs crosslinks and ALT711’s structure characteristics, we designed new lead optimization visual combinatorial libraries, and visually screened the libraries by calculating the charge using MOPAC. The results led to compound ZW1 with high cleavage in vivo and in vitro. We also build lead discovery visual combinatorial libraries, and defined different chemical space of the compounds in libraries.Based on our design, 2, 11, 10, 18 compounds belong to selenazole, selenophen, thiophene and imidazole[2,1-b]selenazole respectively have been synthesized and the structure of 41 compounds have been identified by IR, ’HNMR.and MS. A novel one-pot synthesis which avoided high-toxic and unstable starting material, selenourea and was easy to operate had been used in synthesis of 2-amino-l, 3-selenazoles; a new one-pot method of synthesis of imidazole[2,l-b]selenazole had been also developed. Both were feasible in parallel synthesis of combinatorial libraries.The results in vitro assay indicated that the breaking ratio of 20 compounds at 0.1mmol and 17 compounds at O.lmmol was higher than that of ALT711’s. The in vivo study with compound ZW1 had resulted in improvement in the elasticity of stiffened vascular and increment of the solubility of diabetic tail tendon collagen.The relationship between the structure and activities of the compounds have been studied by Ab initio calculation. The QSAR model of imidazole[2,l-b]selenazole showed that there was a good multivariate linear relationship between the activity and the charge of C9,N10 and Se14 ; the QSAR model of others showed that the activities will increase attributing to the L or the charge of C2.The knowledge-based quantitative structure and activities relationships were used to predict the cleavage ability of AGEs crosslinks breakers. One of the Kbase QSARmodels showed that there was a good multivariate linear relationship between the activity and four major indices; the other one showed that four major fragments could enhance the activity of AGEs cleavage. 18 compounds’ cleavage could be accurately predicted by the model. Both QSAR models could be used in synthetic strategies during lead optimization and new vitual libraries prediction.Overall, the design, synthesis and screening of AGEs Cross-links breakers have been researched . The new compound ZW1 have potent ability of decreasing AGEs crosslinks in diabetic rat, improving the existing vascular and myocardial stiffness and was worth to further research as a candidate new drug.更多还原