【作者】 董晓武；

【导师】 胡永洲；

【作者基本信息】 浙江大学 ， 药物化学， 2009， 博士

【摘要】 类黄酮衍生物是一类含C₆-C₃-C₆基本骨架的天然产物,具有广泛的生物学活性,由于类黄酮性质温和（毒副作用低）,在预防和治疗慢性疾病方面引起了人们广泛的关注。流行病学研究发现,食用类黄酮能明显降低冠心病的死亡率,心肌梗死和中风的发生率。研究证明天然类黄酮衍生物具有抑制低密度脂蛋白的氧化、抗血小板凝集和舒张血管等心血管保护作用;在整体动物实验中天然类黄酮具有明显降低胆固醇和血压的作用,但天然类黄酮衍生物常常存在生物利用度差、活性不够强等缺点。本论文针对改善天然类黄酮的亲脂性能提高其血管舒张活性的特点,通过引入烯丙基、减少A环的羟基数目等提高类黄酮的亲脂性,系统地研究了亲脂性的改变、不同类黄酮母核对血管舒张活性的影响,首轮设计、合成了28个类黄酮衍生物,在活性筛选的基础上,对该类化合物的构效关系作了进一步的验证和完善。然后根据活性筛选结果并结合文献报道的血管舒张剂,建立了2D-QSAR模型（SVM）与3D-QSAR模型（CoMFA）用于指导新一轮的设计,在此基础上,合成了28个预测活性较强的异戊烯基类黄酮衍生物。活性结果表明,实验结果和预测结果具有较好的相关性,多数化合物表现出较强的血管舒张活性,明显好于阳性对照槲皮素。进一步的机制和内皮损伤保护作用研究发现,活性较强的代表性化合物1-16g主要表现为内皮依赖性血管舒张,并能有效抑制焦性没食子酸引起的内皮氧化应激损伤。部分类黄酮衍生物的神经保护作用研究表明,多数化合物在缺氧缺糖（OGD）条件下能有效抑制OGD诱导的PC12细胞损伤。上述研究,为研发新型心血管疾病治疗药物提供了实验依据。同时,本论文应用骨架跃迁和分子杂合原理,在查儿酮骨架上引入不同的NO供体（包括硝酸酯和氮杂呋咱）;以二氢吡啶类钙拮抗剂为骨架,引入不同取代的查儿酮衍生物,以期保留NO供体和Ca²⁺拮抗剂药物活性的同时发挥类黄酮心血管保护作用。共合成了查儿酮杂合体11个。大多数杂合体分子的血管舒张活性优于类黄酮本身,其中化合物1-32c作用最强(EC₅₀=2.9μM,E_max=104.0%)。此外,本论文还依据半胱氨酰白三烯（CysLTs）能导致多种心血管疾病的生理、病理反应,CysLT₁受体拮抗剂具有治疗心脑血管疾病的应用价值这一原理,采用Catalyst/HypoGen程序建立了CysLT₁拮抗剂的药效团模型,同时结合前人发现的CysLT₁拮抗剂的药效特征,共设计、合成了18个查儿酮羧基衍生物。活性结果表明部分化合物具有强效的CysLT₁拮抗活性。为了更加准确地了解CysLT₁受体和拮抗剂的结合模式,本论文还首次采用同源模建程序构建了CysLT₁受体的3D结构,分子对接研究发现强效的拮抗剂可通过静电、氢键和疏水等作用稳定地结合至CysLT₁受体的活性空腔,这为进一步设计先导分子提供了重要的CysLT₁受体与配体结构信息。本论文还系统地研究了微波辅助的2-羟基查儿酮衍生物Mannich反应以及“一锅法”合成3-苄基黄酮衍生物的反应。这两种合成方法均具有操作简便、易纯化及收率高等优点,为进一步快速、高效地合成这两类黄酮衍生物提供了新的途径。更多还原

【Abstract】 Flavonoids are natural compounds bearing a C₆-C₃-C₆ skeleton with diverse pharmacological properties.Due to their low toxicity,the chemopreventive effects of flavonoids on chronic diseases（e.g.cardiovascular diseases） have been paid much attention.The epidemiological studies demonstrated that people can lower incidence of heart diseases if they have a high dietary intake of flavonoids.Flavonoids have been found to possess antiatherogenic and antiaggregant effects and vasodilatory effects in isolated vascular preparation and animal models.However,there are some drawbacks of flavonoids limited their further application,such as low bioavailability and not enough potent activities.Previously,it was found that the vasorelaxant activities of flavonoids had positive correlation with their Log P values.Herein,we described the synthesis of twenty eight lipophilic flavonoid derivatives and investigated more systematically about the correlation between their CLogP and vasorelaxant activities through introduction of allyl,reduction of hydroxyl group or aleration of the skeleton.According to the results of above work and the vasodilator or nonvasodilator in other reference,2D-QSAR and 3D-QSAR models were established by SVM and CoMFA,respectively.Successively, twenty eight prenylflavonoids with promising activities were selected and synthesized. Among them,most compounds showed potent vasorelaxant activies.The theoretical results of them were consistent with their experimental values.Further vasorelaxant mechanism and vascular protective studies indicated that 1-16g,one of the most potent compounds,mainly exhibited endothelium-dependent vasorelaxant activities and could remarkable protect the vascular endothelium against oxidative stress.In addition,the neuroprotective effects of twelve prenylflavonoids were evaluated and most of the tested compounds could significantly inhibit the PC12 cell injury induced by OGD.The above studies could provide the basis of development novel cardiovascular agents.With the aim to develop hybrid cardiovascular agents,the scaffold hoping and molecular hybrid strategies were applied.Eleven hybrid compounds including chalcone derivatives bearing different NO donor（including Nitrate and Furaxan）,and 4-phenyl-1,4-dihydropyridines derivatives bearing different chalcones were synthesized. Gratifyingly,most compounds showed good vasorelaxant activities and are much more potent than the chalcones.The compound 1-32c is the most potent one(EC₅₀=2.9μM, E_max=104.0%).According to that CysLTs result in atherosclerosis and other cardiovascular diseases and CysLT antagonists showed potential value for treatment of cardiovascular diseases.A novel pharmacophore model（Hypol） of CysLT₁ antagonists was constructed by Catalyst/HypoGen and used to "In Silico" evaluated the novel designed carboxyl chalcone derivatives.Then,eighteen compounds were selected and synthesized.Some of them showed potent CysLT₁ antagonistic activities.Furthermore, the 3D structure of CysLT₁ was firstly constructed by homology modelling.Molecular docking studies indicated that 2-39k could bind very well to CysLT₁ through hydrophobic,hydrogen bond and Electrostatic interaction.The results provide important structural information of CysLT₁ and its antagonist for further design of novel and more potent CysLT₁ antagonists.In addition,we have developed an efficient and rapid microwave-assisted synthesis of a range of Mannich base derivatives of 2-hydroxychalcones,as well as a facile method of one-pot synthesis of 3-benzyl-flavone derivatives.The distinct features of these two methodology included simple procedure,easy purification and good yields.The methods provided a rapid and efficient approach for preparation of these two series of compounds.更多还原