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

首都医科大学学报 ›› 2005, Vol. 26 ›› Issue (1): 42-42.

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

张桂娟, 江蔚新, 刘俊岭, 赵明, 彭师奇, 张建伟

首都医科大学化学生物学与药学院

收稿日期:1900-01-01 修回日期:1900-01-01 出版日期:2005-02-24 发布日期:2005-02-24
通讯作者: 张建伟

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

Zhang Guijuan, Jiang Weixin, Liu Junling, Zhao Ming, Peng Shiqi, Zhang Jianwei

School of Chemical Biology and Pharmaceutical Sciences, Capital University of Medical Sciences

Received:1900-01-01 Revised:1900-01-01 Online:2005-02-24 Published:2005-02-24

摘要/Abstract

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27%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H₂O₂清除剂2a-c和1的EC₅₀分别为98.1、95.4、94.2和100.0μmol/L。作为·OH清除剂2a-c和1的EC₅₀分别为98.1、95.4、94.2和100.0μmol/L。作为NO清除剂2a-c和1的EC₅₀分别为89.1、92.3、91.8和91.2μmol/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10.0μmol/L 2a-c、1、UK和NS后血栓减重分别为(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和(15.11±3.70)mg。给予10.0μmol/L ARPAK、GRPAK和QRPAK后血栓减重分别为(18.54±3.28)mg、(21.17±3.06)mg和(25.82±2.15)mg。可见,采用本研究的策略可以在药物设计中综合考虑自由基清除和溶栓2种治疗需求。

Abstract:

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 H₂ O₂ scavenger the EC₅₀ of 2a-c and 1 is 28.1, 25.4, 24.1 and 30.2 μmol/L, respectively. As·OH scavenger the EC₅₀ of 2a-c and 1 is 98.1, 95.4, 94.2 and 100.0 μmol/L. As NO scavenger the EC₅₀ 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.

张桂娟;江蔚新;刘俊岭;赵明;彭师奇;张建伟. 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[J]. 首都医科大学学报, 2005, 26(1): 42-42.

Zhang Guijuan;Jiang Weixin;Liu Junling;Zhao Ming;Peng Shiqi;Zhang Jianwei . Synthesis, Free Radical Scavenging and Thrombolytic Activities of Nitronyl Nitroxide Modified Peptide 6A and Analogues[J]. Journal of Capital Medical University, 2005, 26(1): 42-42.