【作者】 林爱斌；

【导师】 郑锦鸿；

【作者基本信息】 汕头大学 ， 药理学， 2008， 硕士

【摘要】 阿魏酸属于酚类抗氧化药物,阿魏酸衍生物具有抗氧化、抗炎、抑制血小板聚集、降血糖、抗肿瘤、抗辐射等药理作用。本研究对阿魏酸进行结构改造,保留阿魏酸的酚羟基这一抗氧化药效基团,将其羧基改造成酰胺,设计合成一系列1-(5’-溴阿魏酰基)-4-苄基哌嗪盐酸盐类似物,并初步测定其药理活性。一、1-(5’-溴阿魏酰基)-4-苄基哌嗪盐酸盐类似物的合成目的:合成1-(5’-溴阿魏酰基)-4-苄基哌嗪盐酸盐类似物方法:经苯环溴代、Knoevenagel缩合反应合成5’-溴阿魏酸,再经酚羟基乙酰化、羧酸卤置换、N-酰化、脱乙酰基后得到1-(5’-溴阿魏酰基)-4-苄基哌嗪,最后与盐酸成盐得到目标化合物。结果:合成9个新化合物,为1-(5’-溴阿魏酰基)-4-苄基哌嗪盐酸盐类似物,均通过元素分析、MS、1HNMR、IR结构鉴定。结论:找到一条合成1-(5’-溴阿魏酰基)-4-苄基哌嗪盐酸盐类似物的路线。二、1-(5’-溴阿魏酰基)-4-苄基哌嗪盐酸盐类似物体外清除羟自由基活性研究目的:研究1-(5’-溴阿魏酰基)-4-苄基哌嗪盐酸盐类似物在体外清除羟自由基(?OH)的活性。方法:采用邻二氮菲-Fe2+氧化法测定1-(5’-溴阿魏酰基)-4-苄基哌嗪盐酸盐类似物、阿魏酸(FA)和抗坏血酸(Vc)在体外对Fenton反应产生?OH的清除能力,计算表观清除率(CL),采用SNK检验比较各药物最大?OH表观清除率(CLmax)的差异。结果:9个目标化合物均具有不同程度的体外清除?OH活性,且都有明显量效关系。L5的CLmax最大,L8的CLmax最小,L1、L3、L5、L7的CLmax都比FA和Vc大,L1、L3、L5、L6、L7的CLmax都比Vc大。结论:目标化合物均具有体外清除?OH活性,苄基苯环上取代基的类型和取代位置影响目标化合物均体外清除?OH的活性。苄基苯环上2-Cl、3-Cl、2-CH3、4-CH3、3-OCH3取代,可增强体外清除?OH活性;3-CH3取代,体外清除?OH活性基本不变;2-OCH3、4-OCH3取代,体外清除?OH活性降低。三、1-(5’-溴阿魏酰基)-4-苄基哌嗪盐酸盐类似物抑制小鼠耳肿胀活性研究目的:研究1-(5’-溴阿魏酰基)-4-苄基哌嗪盐酸盐类似物的抗炎活性。方法:目标化合物L5、阿魏酸、布洛芬配制成混悬剂,通过计算肿胀度和肿胀抑制率评价它们抑制巴豆油混合液所致小鼠耳肿胀的作用,运用Dunnett双侧检验比较各给药组与空白组肿胀度的差异,采用SNK检验比较各给药组间肿胀抑制率的差异。结果:目标化合物L5、阿魏酸、布洛芬在各剂量都有极显著的抑制小鼠耳肿胀作用。各剂量肿胀抑制率的大小顺序为:100mg/kg,布洛芬>阿魏酸>L5;200mg/kg,布洛芬>L5>阿魏酸;400mg/kg,L5≈阿魏酸>布洛芬。结论:目标化合物L5、阿魏酸、布洛芬在各剂量都有抗炎活性。更多还原

【Abstract】 Ferulic acid is a phenolic anti-oxidant. Ferulic acid derivatives have the pharmacology activities of anti-oxidation, anti-inflammatory, inhibiting thrombocyte congregation, lowering blood sugar, anti-tumor, radiation inhibition. In our study, we modificated the structure of ferulic acid. The carboxylic acid was transformed into amide while the phenolic hydroxyl group was reserved to keep its anti-oxidation activity. A series of 1-(5’-bromo feruloyl)-4-benzyl piperazine hydrochloride analogs were synthesized, and their pharmacology activities were evaluated.1. Synthesis of 1-(5’-bromo feruloyl)-4-benzyl piperazine hydrochloride analogsObjective: To synthesize 1-(5’-bromo feruloyl)-4-benzyl piperazine hydrochloride analogs.Methods: 5’-bromo ferulic acid was synthesized through bromo substitute and Knoevenagel reaction.1-(5’-bromo feruloyl)-4-benzyl piperazine was prepared via acetylation of phenolic hydroxyl, oxalyl chloride exchange with acid, N-acylation, removing of acetyl.Finally the target compounds were synthesized by 1-(5’-bromo feruloyl)-4-benzyl piperazine salification with hydrochloric acid.Results: 9 novel 1-(5’-bromo feruloyl)-4-benzyl piperazine hydrochloride analogs were synthe- sized. Their structures were identified by elemental analysis, 1HNMR, MS and IR.Conclusion: A synthesis route to prepare 1-(5’-bromo feruloyl)-4-benzyl piperazine hydrochlor- ide analogs was established.2. Hydroxyl radical scavenging activities in vitro of 1-(5’-bromo feruloyl)-4-benzyl piperazine hydrochloride analogsObjective: To study hydroxyl radical(?OH) scavenging activities in vitro of 1-(5’-bromo feruloyl)-4-benzyl piperazine hydrochloride analogs.Methods: The ?OH scavenging activities in vitro of target compounds,ferulic acid(FA) and L-ascorbic acid(Vc) were analysed through 1,10-phenanthroline-Fe2+ detection system. Then the ?OH clearance percentage(CL) were calculated. The ?OH maximum clearance percentage(CLmax) differences between the drugs were analysed by SNK test.Results: All target compounds showed marked ?OH scavenging activities in vitro and had obvious dose-effect relationships. L5 had the highest CLmax. L8 had the lowest CLmax. L1, L3, L5 and L7 had higher CLmax than FA and Vc. L1, L3, L5, L6 and L7 had higher CLmax than Vc.Conclusion: All target compounds showed marked ?OH scavenging activities in vitro. The activity was influenced by the type and location of the substitute on benzal benzene ring. 2-Cl, 3-Cl, 2-CH3, 4-CH3 and 3-OCH3 enhanced the activity. 3-CH3 did not change the activity. 2-OCH3 and 4-OCH3 reduced the activity.3. Ear swelling inhibition activities in rats of 1-(5’-bromo feruloyl)-4-benzyl piperazine hydrochloride analogs Objective: To study anti-inflammatory activities of 1-(5’-bromo feruloyl)-4-benzyl piperazine hydrochloride analogs.Methods: L5, ferulic acid and ibuprofen were prepared as suspensions. Swelling degrees and swelling inhibitions were calculated to evaluate the ear swelling inhibition in rats induced by croton oil mixture. The swelling degree differences between the drug groups and control were analysed by two side Dunnett test. The swelling inhibition differences between the drug groups were analysed by SNK test. Results: All measuring doses of L5,ferulic acid and ibuprofen had extremely marked ear swelling inhibition activities in rats. The sequences of swelling inhibition at each doses were the following. 100mg/kg, ibuprofen>ferulic acid>L5.200mg/kg, ibuprofen>L5>ferulic acid. 400mg/kg, L5≈ferulic acid>ibuprofen.Conclusion: All measuring doses of L5, ferulic acid and ibuprofen had anti-inflammatory activities.更多还原