【作者】 刘改枝；

【导师】 于德泉； 刘宏民；

【作者基本信息】 郑州大学 ， 药物化学， 2010， 博士

【摘要】 丁烯内酯是一大类重要的天然和人工合成的生物活性分子。γ-丁烯内酯结构单元广泛存在于天然产物中,也是天然产物的重要合成中间体。丁烯内酯类化合物具有广泛的生物活性,在医药及农药等方面有广泛应用,开发应用前景广阔。丁烯内酯类化合物的全合成、类似物的合成以及生物活性研究长久以来倍受关注。本文基于β取代和α，β双取代的γ丁烯内酯,设计合成了新型的γ取代丁烯内酯类化合物：卢帕他定类似物、罗非昔布衍生物、氯西加酮及其类似物以及其他γ取代的丁烯内酯衍生物,并对所合成化合物的相应生物活性进行了评价。具体研究工作如下：一、以抗组胺药卢帕他定为先导,根据电子等排原理,设计合成了系列新型包含丁烯内酯结构单元的卢帕他定类似物。共合成卢帕他定类似物20个,其中新化合物18个,并通过NMR, HRMS和IR等波谱学方法对其结构进行了确证。通过组胺诱导的离体豚鼠回肠收缩试验对所合成的部分化合物的抗组胺活性进行了评价,所评价化合物均表现出了抗组胺活性,、其中化合物7,8a和8g表现出了良好的抗组胺活性,均好于阳性对照药氯雷他定,其中化合物7优于对照药地洛他定。初步的构效关系研究发现,丁烯内酯环的引入对三环类抗组胺药的活性有利。最终从所合成的化合物中筛选出了化合物7,8a和8g作为抗过敏药物研发的候选化合物。二、罗非昔布的心血管不良反应可能是由于其内酯环结构的5位碳在体内被氧化的代谢物毒性所致。基于这一研究结果,以罗非昔布及其两个类似物为先导,本论文通过一步插烯缩合的方法设计并合成3个系列48个5位亚烷基取代的罗非昔布衍生物,所合成的化合物均未见有文献报道。用COX(ovine) Inhibitor Screening Assay Kit的方法对所合成部分化合物的选择性COX-2抑制活性进行了评价,结果表明部分化合物表现出了选择性COX-2抑制活性,其中化合物Ⅱ-3的选择性COX-2抑制活性好于阳性对照罗非昔布。上述结果表明,所发现新化合物既有选择性的COX-2抑制活性也能够避免其在体内产生心脑血管毒性的5位氧化代谢产物。除此之外,通过MTT试验评价了部分化合物对前列腺癌细胞的细胞毒活性。结果表明,化合物Ⅱ-3,Ⅱ-6,Ⅱ-7,Ⅱ-11,Ⅱ-12,Ⅲ-3,Ⅲ-11,Ⅲ-16对前列腺癌细胞的IC50值均小于50μM,其中化合物Ⅱ-7的IC50值约12.5μM,化合物Ⅱ-12的IC50值约15μM,化合物Ⅲ-3的IC50值约20μM,化合物Ⅲ-11、Ⅲ-16的IC50值约22μM,而罗非昔布对照药及其2个卤素取代基的类似物均没有表现出对前列腺癌细胞明显的细胞毒活性。通过上述研究筛选出了两个有进一步研究价值的候选化合物。三、以异戊烯酸为起始原料通过一系列反应合成四个系列的新型3,5-取代-γ丁烯内酯类小分子化合物。评价了部分化合物的抗菌活性、细胞毒活性。部分化合物表现出中等的抗菌活性和细胞毒活性,其中化合物1d表现出中等的抗金黄色葡萄球菌活性,MIC值40μg/mL。化合物9’d对Ec9706细胞表现出了较好的抑制活性,IC50值39.39μg/mL,与阳性对照药5-氟尿嘧啶(IC50=37.74μg/mL)想当。四、以3-甲氧基呋喃酮为原料,通过水相一步插烯缩合对3-取代的丁烯内酯药物分子氯西加酮的合成工艺进行了研究,且通过结晶的方法可得顺反选择比例大于96%(反/顺)的产物。探索了手性诱导条件下的非对映选择性合成,反/顺值约50%。除此之外合成了12个氯西加酮的类似物及其他们的非对映异构体,其中6个类似物为新化合物。总之,通过上述研究工作,设计合成了多个系列共116个新型的多取代γ丁烯内酯类衍生物,其中新化合物105个。通过活性筛选发现,具有进一步研究价值的抗组胺药物候选化合物3个,选择性COX-2抑制剂1个,并且该化合物既有选择性的COX-2抑制活性,同时有可能避免罗非昔布的心脑血管毒副作用；抗前列腺癌增生活性候选化合物5个。为开发具有自主知识产权的新药奠定基础。更多还原

【Abstract】 Butenolides are an important class of natural products or synthetic bioactive molecules, of whichγ-alkylidene butenolides widely present in natural products, also can be used as synthetic intermediates of natural products. For the significant physiological activity of such compounds, they have great prospects for the development and application in medicine and pesticide and so on. And in organic synthesis has a strong application value. The total synthesis of these compounds and their analogues long since have attracted researcher’s attention.In this thesis, on the basis ofβandα,βsubstituted butenolides, we designed and synthesized series of newγ-butenolide:rupatadine derivatives, rofecoxib derivatives, losigamone and its analogues and other smallγ-butenolide moleculers. Their corresponding activities were evaluated. The corresponding work was described as follows:First, with antihistamines rupatadine as the lead compounds, replacement of the 5-methyl-3-pyridine of rupatadine byα,β-unsaturated-γ-alkylidenebutenolide, a series of derivatives were stereoselectively synthesized. The first time, tricyclic antihistamines and butenolides were combined by five-numbered lactone ring, which expanded the structural types of antihistamines. Twenty rupatadine analogues were synthesized, eighteen were new compounds. All compounds obtained were characterized by NMR, IR and HR MS spectras. Some of their anti-histamine activities were also evaluated. For the evaluation of H1 antihistamine activity, the in vitro histamine-induced contraction of the guinea-pig ileum assay (HC) was used. A preliminary structure-activity relationship was analysized. Their H1 antihistamine activities have shown a high dependence on the exact nature of the substituent in the lactone ring. Optimum structures 7,8a and 8g display potent activity inhibiting histamine-induced effects, which were better than the positive control loratadine.Second, rofecoxib (vioxx) is selective COX-2 (cyclooxygenase-2) inhibitors. However, the research finding of significant elevation of adverse cardiovascular events in people already at risk has triggered the withdrawal from use of one of the most widely used COX-2 inhibitors. Studies have shown that the facile oxidation of the conjugate base of rofecoxib is a possible contributor to chronic human toxicity. In order to avoid or reduce this side effect, fourty eight rofecoxib derivatives were stereoselectively synthesised, all of them were new compounds. All compounds obtained were characterized by NMR, IR and HR MS spectras. Some of their COX-2 inhibitory activities and cytotoxic activities were evaluated. The selective COX-2 inhibitory activity of candidate compoundsⅡ-3 was better than the control drug rofecoxib. The cytotoxic activity on prostate cancer cells showed that the IC50 values of compoundsⅡ-3,Ⅱ-6,Ⅱ-7,Ⅱ-11,Ⅱ-12,Ⅲ-3,Ⅲ-11 andⅢ-16 all less than 50μM. The IC50 value of optimum structuresⅡ-7 was about 12.5μM, but the positive control rofecoxib has no antiproliferative effect. It showed that rofecoxib and its analogues onγ-alkylidene butenolides derivatives is a very effective modification.Third, four series of newγ-alkylidene butenolide andγ-hydroxyalkyl butenolide were prepared. Their bioactivities such as antibacterial activity and cytotoxic activity were evaluated. Preliminary evaluation results showed that some of the compounds showed moderate to good antibacterial activity and cytotoxic activity, among them compound 1d exhibited good antibacterial activity against staphylococcus aureus with the MIC value was 40μg/mL.Compound 9’d showed good cytotoxic activity against Ec9706 cell, the IC50 value was 39.39μg/mL, which was comparative to the positive drug fluorouracil(IC50=37.74μg/mL).Finally, with losigamone as the lead compounds, a series of losigamone analogues were synthesized. Twelve losigamone analogues were synthesized, six were new compounds. The de value of crystalline losigamone was about 96%. The diastereoselective synthesis conditions were explored, the de value was about 50%, less than the original process’diastereoselectivity.In summary, more than 116 of novelγ-alkylidene butenolides derivatives were obtained.105 of them were new compounds. Some of their bioactivities and structure-bioactivity relationship were investigated. As candidates, a few compounds were valuable to further investigate for new drug development.更多还原