P6A及类似物修饰的咪唑啉的合成、自由基清除和溶栓活性研究  

Synthesis, Free Radical Scavenging and Thrombolytic Activities of Nitronyl Nitroxide Modified Peptide 6A and Analogues

作　　者：张桂娟[1] 江蔚新[1] 刘俊岭[1] 赵明[1] 彭师奇[1] 张建伟[1] 

机构地区：[1]首都医科大学化学生物学与药学院

出　　处：《首都医科大学学报》2005年第1期42-42,共1页Journal of Capital Medical University

摘　　要：NO与缺血及缺血再灌注引起的脑损伤之间的相关性 ,以及缺血性脑损伤和缺血再灌注性脑损伤与血栓形成及血栓溶解之间的相关性 ,使得在药物设计中综合考虑自由基清除和溶栓变得十分重要。考虑到咪唑啉在清除自由基方面的特殊能力以及寡肽 (ARPAK、GRPAK和QRPAK)的确切溶栓能力 ,通过6步反应以 2 7%的总收率把 [1 ( 1’ ,3’ 二氧 4’ ,4’ ,5’ ,5’ 四甲基咪唑啉 2 基 )苯基 4 基 ]氧乙酸 ( 1 )引入到ARPAK、GRPAK和QRPAK的N端 ,制备了ARPAK、GRPAK和QRPAK修饰的咪唑啉 2a c。ESR测定表明 2a c给出与 1一样的谱图 ,是稳定的自由基。体外自由基清除实验、体外优球蛋白溶解实验和体内血栓溶解实验表明这种化学组合确实可以实现活性组合。例如作为H2 O2 清除剂 2a c和 1的EC50 分别为 98.1、95 .4、94.2和 1 0 0 .0 μmol/L。作为·OH清除剂 2a c和 1的EC50 分别为 98.1、95 .4、94.2和1 0 0 .0 μmol/L。作为NO清除剂 2a c和 1的EC50 分别为 89.1、92 .3、91 .8和 91 .2 μmol/L。与 1相比大多数情况下自由基清除活性都呈增加趋势。给予 1 0 .0 μmol/L 2a c、1、UK和NS后血栓减重分别为( 1 9.91± 3.5 9)mg、( 1 9.70± 3.76)mg、( 2 8.85± 3.80 )mg、( 1 5 .89± 2 .5 3)mg、( 2 5 .40± 2 .5 0 )mg?Nitric oxide is involved in ischemia/reperfusion brain injury. Ischemic brain in jury and ischemia/reperfusion brain injury always associate with thrombogenesis and thrombolysis. Considering the specific ability scavenging free radicals of n itronyl nitroxides and the thrombolytic activity of the oligopeptides (ARPAK, GR PAK and QRPAK), [1-(1',3'-dioxyl-4',4',5',5'-tetra-methyldihydroimidazol -2-yl)phenyl-4-yl]oxyacetic acid (1) was introduced into their N-terminal via six reactions in 27% tota l yield. The ESR measurement demonstrates that the conjugates N-[1- (1',3' -dioxyl-4',4',5',5'-tetramethyldihydroimidazol-2-yl)-phenyl-4-yl]oxya cetyl-ARPAK (2a), -GRPAK (2b) and -QRPAK (2c) are stable NO free radicals and ha ve substantially same spectroscopy as that of 1 . The free radical scavenging tests in vitro, euglobulin lys is tests in vitro and the thrombolysis tests in vivo indicated that couplling 1 and P6A or its analogues re sulted in the combination of free radical scavenging and thrombolysis actions. F or instance as H 2O 2 scavenger the EC 50 of 2a -c and 1 is 28.1, 25.4, 24.1 and 30.2 μmol/L, respectively. As ·OH scavenger the E C 50 of 2a-c and 1 is 98.1, 95.4, 94.2 and 100.0 μmol/L . As NO scavenger the EC 50 of 2a-c and 1 is 89.1, 9 2.3, 91.8 and 91.2 μmol/L. Comparing to 1 the free radical scavenging activities are increased. After adm inistration of 10.0 μmol/L of 2a-c,1, UK and NS the reduced thrombus mass is ( 19.91± 3.59)mg,( 19.70± 3.76)mg,( 28.85± 3.80)mg,( 15.89 ± 2.53)mg,( 25.40± 2.50 )mg and ( 15.11± 3.70)mg, respectively. After administration of 10.0 μmo l/L of A RPAK, GRPAK and QRPAK the reduced thrombus mass is ( 18.54± 3.28)mg,( 21 .17± 3.06)mg and ( 25.82± 2.15)mg respectively. All of the mentione d data indicated that the nitronyl nitroxide modified peptide 6A and analogues po ses both of free radicals scavenging activity and thrombolysis activity.

关 键 词：自由基清除 溶栓活性 体外 缺血再灌注 血栓 药物设计 治疗 清除剂 清除自由基 修饰 

分 类 号：R743[医药卫生—神经病学与精神病学] R285[医药卫生—临床医学]