新型双靶标化合物的合成与其抗高原缺氧损伤活性研究  

Synthesis and Its Activity of Anti-hypoxia Injury of a New Dual-target Compound

作　　者：景临林[1] 马慧萍[1] 杨芳芳[1] 葸慧荣 樊鹏程[1] 贾正平[1] 

机构地区：[1]兰州军区兰州总医院全军高原损伤防治重点实验室,兰州730050

出　　处：《解放军医药杂志》2016年第6期5-8,13,共5页Medical & Pharmaceutical Journal of Chinese People’s Liberation Army

基　　金：国家自然科学基金项目(81571847;81202458);甘肃省自然科学基金面上项目(145RJZA089);中国博士后科学基金(2012M521926)

摘　　要：目的根据"双靶标药物设计原理",设计合成出一种兼具自由基清除活性和碳酸酐酶抑制活性的新型双靶标化合物,并研究其抗高原缺氧活性。方法将乙酰唑胺(碳酸酐酶抑制剂)与氮氧自由基(新型自由基清除剂)通过桥联基结合,设计具有双靶标联合作用的目标化合物,并经过小鼠常压密闭、急性减压和化学性中毒3种缺氧耐受力实验评价其抗缺氧活性。结果所合成的化合物结构经过电子顺磁共振、ESI-MS和元素分析进行确认。与缺氧模型组、乙酰唑胺组和氮氧自由基组相比,目标化合物组可以明显延长小鼠在常压密闭缺氧环境中的存活时间(P<0.05,P<0.01),降低急性减压缺氧小鼠1 h内死亡率(P<0.01),延长氰化钾、亚硝酸钠和盐酸异丙肾上腺素3种化学性中毒缺氧小鼠的存活时间(P<0.05,P<0.01)。结论新型双靶标抗缺氧损伤化合物合成方法简便,产率较高,并且表现出了较好的抗缺氧活性。Objective To design and synthesize a new dual-target compound with free radicals cleaning and carbonic anhydrase inhibiting activities according to the principle of dual-target drug design and to study its anti-hypoxia activity. Methods A new compound with dual-target combination activity was designed in combination of Acetazolamide（ carbonic anhydrase inhibitor） and nitronyl nitroxide radical（ free radical scavenger） using a linker,and its anti-hypoxia activity was evaluated using three kinds of hypoxia tolerance tests of normobaric hypoxia,acute decompression and chemical poisoning. Results The construction of target compound was identified with the use of electron paramagnetic resonance（ EPR）,electric stimulation-induced contractions（ ESI-MS） and element analysis. Compared with those in anoxia models,Acetazolamide and nitronyl nitroxide radical groups,survival time of mice under normobaric hypoxic situation was significantly prolonged（ P〈0. 05,P〈0. 01）,and the death rate within 1 h under acute decompression hypoxic situation was reduced（ P〈0. 01）,and survival times of chemical poisoning induced by Potassium Cyanide,Sodium Nitrite and Isoprenaline Hydrochloride were also significantly prolonged in target compound group（ P〈0. 05,P〈0. 01）.Conclusion The new dual-target compound can be easily synthesized with high yield and good anti-hypoxia activity.

关 键 词：氮氧自由基 乙酰唑胺 双靶标药物 抗缺氧活性 小鼠 近交BALB C 

分 类 号：R594.3[医药卫生—内科学]