CN112812152A - Glu-Leu-Phe-Tyr-Val五肽的合成及抗炎应用 - Google Patents
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Abstract
本发明公开了一种Glu‑Leu‑Phe‑Tyr‑Val五肽,公开了它的制备方法,公开了它的抗抗炎活性,因而本发明公开了它在制备抗炎药物中的应用。
Description
技术领域
本发明涉及Glu-Leu-Phe-Tyr-Val五肽,涉及它的制备方法,涉及它的抗炎活性,因而本发明涉及它在制备抗炎药物中的应用。本发明属于生物医药领域。
背景技术
发明抗肿瘤,抗血栓,溶血栓和抗凝血作用寡肽是发明人长期关注的领域。虽然发明人发明公开过一系列具有这些活性的寡肽,但是集这些活性为一体的寡肽一直没有得到。发明人发现，Glu-Leu-Phe-Tyr-Val五肽是集抗炎作用,抗肿瘤作用,抗血栓作用和溶血栓作用为一体的肽。根据这些发现发明人提出本发明。.
发明内容
本发明的提供序列为Glu-Leu-Phe-Tyr-Val的五肽在制备抗炎药物中的应用。
本发明的第二个内容是提供Glu-Leu-Phe-Tyr-Val五肽的合成方法，该方法包括：
(1)在DCC和HOBt的催化下按照标准方法制备Boc-Tyr-Val-OBzl；
(2)Boc-Tyr-Val-OBzl在浓度为4N的氯化氢-乙酸乙酯溶液中,0℃脱Boc，转化成Tyr-Val-OBzl；
(3)在DCC和HOBt的催化下制备Boc-Leu-Phe-OBzl；
(4)Boc-Leu-Phe-OBzl在H2,Pd/C催化下，转化成Boc-Leu-Phe；
(5)在DCC和HOBt的催化下制备Boc-Leu-Phe-Tyr-Val-OBzl；
(6)Boc-Leu-Phe-Tyr-Val-OBzl在浓度为4N的氯化氢-乙酸乙酯溶液中,0℃脱Boc，转化成Leu-Phe-Tyr-Val-OBzl；
(7)在DCC和HOBt的催化下制备Boc-Glu(OBzl)-Leu-Phe-Tyr-Val-OBzl；
(8)Boc-Glu(OBzl)-Leu-Phe-Tyr-Val-OBzl在Pd/C催化下氢解Boc-Glu-Leu-Phe-Tyr-Val；
(9)Boc-Glu-Leu-Phe-Tyr-Val在浓度为4N氯化氢-乙酸乙酯溶液中,0℃脱Boc转化成Glu-Leu-Phe-Tyr-Val。
附图说明
图1Glu-Leu-Phe-Tyr-Val的合成路线.i)二环己基碳二亚胺(DCC),1-羟基苯并三唑(HOBt),N-甲基吗啉(NMM),四氢呋喃(THF)；ii)H2,Pd/C iii)4N HCl/EA,0℃。
具体实施方式
为了进一步阐述本发明，下面给出一系列实施例。这些实施例完全是例证性的，它们仅用来对本发明进行具体描述，不应当理解为对本发明的限制。
实施例1制备Boc-Tyr-Val-OBzl
冰浴下，2.81g(10mmol)Boc-Tyr溶解于少量无水四氢呋喃(THF)中，加入1.36g(10mmol)HOBt，加入2.47g(12mmol)DCC与少量无水THF的溶液，活化30分钟，加入2.07g(10mmol)Val-OBzl，用NMM调节pH＝9，反应结束后过滤除去二环己基脲(DCU)。滤液减压浓缩，残留物用乙酸乙酯溶解，再次过滤DCU，滤液用NaHCO3饱和溶液洗3遍，用NaCl饱和溶液洗3遍，5％的KHSO4溶液洗3遍，NaCl饱和溶液洗3遍，5％的NaHCO3溶液萃洗3遍，NaCl饱和溶液萃洗3遍，乙酸乙酯层用无水Na2SO4干燥12小时，滤除Na2SO4，滤液减压浓缩，得到4.02g(85.5％)标题化合物，为无色粉末。ESI+-MS(m/e):472[M+H]+。
实施例2制备Tyr-Val-OBzl
冰浴下将4.7g(10mmol)Boc-Tyr-Val-OBzl用尽少量干燥过的乙酸乙酯溶解，搅拌10min，加入50mL氯化氢-乙酸乙酯溶液(4N)反应4h，原料点消失。反应混合物减压浓缩至干，残留物加40mL干燥过的乙酸乙酯溶解，得到的溶液减压浓缩至干。残留物按该操作重复3次。残留物加无水乙醚，用塑料铲研磨，减压浓缩除去乙醚。残留物按该操作重复3次。得到3.97g(99％)标题化合物，为无色粉末。ESI+-MS(m/e):372[M+H]+。
实施例3制备Boc-Leu-Phe-OBzl
按照实施例1的方法，2.31g(10mmol)Boc-Leu和2.55g(10mmol)Phe-OBzl得到3.98g(81.6％)标题化合物，为无色油状物。ESI+-MS(m/e):470[M+H]+。
实施例4制备Boc-Leu-Phe
将4.88g(10mmol)Boc-Leu-Phe-OBzl用甲醇溶解，加入488mg的10％的Pd/C。连接三通，减压抽除茄瓶中的空气后，反应瓶中充满H2，按该操作重复3次。反应20h后原料点消失。滤除Pd/C，旋干甲醇。得到3.67g(97％)标题化合物，为无色粉末。ESI+-MS(m/e):380[M+H]+。
实施例5制备Boc-Leu-Phe-Tyr-Val-OBzl
按照实施例1的方法，3.78g(10mmol)Boc-Leu-Phe和3.7g(10mmol)Tyr-Val-OBzl得到4.23g(57.9％)标题化合物，为无色粉末。ESI+-MS(m/e):732[M+H]+。
实施例6制备Leu-Phe-Tyr-Val-OBzl
按照实施例2的方法，从7.3g(10mmol)Boc-Leu-Phe-Tyr-Val-OBzl得到6.1g(98％)标题化合物，为无色粉末。ESI+-MS(m/e):632[M+H]+。
实施例7制备Boc-Glu(OBzl)-Leu-Phe-Tyr-Val-OBzl
按照实施例1的方法，3.37g(10mmol)Boc-Glu(OBzl)和6.3g(10mmol)Leu-Phe-Tyr-Val-OBzl得到3.35g(35.3％)标题化合物，为无色粉末。ESI+-MS(m/e):951[M+H]+；1H-NMR(300MHz,DMSO-d6):δ/ppm＝9.14(s,1H),8.23(d,1H),7.95(m,2H),7.71(d,1H),7.34(m,10H),7.16(m,5H),7.12(m,3H),6.63(d,2H),5.13(s,2H),5.08(s,2H),4.60(m,1H),4.40(m,1H),4.25(m,2H),3.92(m,1H),2.90(m,2H),2.51(m,2H),2.33(m,2H),2.10(m,1H),1.80(m,2H),1.54(m,1H),1.30(s,11H),0.81(s,12H)。
实施例8制备Boc-Glu-Leu-Phe-Tyr-Val
按照实施例4的方法，从950mg(1mmol)的Boc-Glu-Leu-Phe-Tyr-Val-OBzl得到750mg(95.2％)标题化合物，为无色粉末。ESI+-MS(m/e):771[M+H]+。
实施例9制备Glu-Leu-Phe-Tyr-Val(GQ-E)
按照实施例2的方法，从769mg(1mmol)Boc-Glu-Leu-Phe-Tyr-Val-OBzl得到650mg(95.1％)标题化合物，为无色粉末。ESI+-MS(m/e):671[M+H]+；Mp 166.2～167.8℃.[α]2D 0＝-18.88(c＝0.07，甲醇).IR:3273,3063,2961,2930,1710,1640,1515,1469,1443,1390,1369,1218,1030,916,828,802,746,698,610,598,554.1H-NMR(300MHz,DMSO-d6):δ/ppm＝12.35(s,2H),9.19(s,1H),8.45(s,J＝8.1Hz 1H),8.23(d,J＝8.1Hz,3H),8.04(m,2H),7.15(s,5H),7.05(d,J＝8.4Hz,2H),6.63(d,J＝8.4Hz,2H),4.54(m,2H),4.33(m,1H),4.17(m,1H),3.77(m,1H),2.90(m,2H),2.70(m,2H),2.26(m,2H),2.06(m,1H),1.81(m,2H),1.39(m,3H),0.83(m,12H)。
实施例10评价Glu-Leu-Phe-Tyr-Val的抗炎活性
体重20±雄性小鼠口服1μmol/kg Glu-Leu-Phe-Tyr-Val(GQ-E)或1200μmol/kg阿司匹林或0.2mL/20g生理盐水30分钟后，往小白鼠的左耳外廓涂二甲苯(0.04mL)，2小时后将小白鼠颈椎脱臼处死。将小鼠的左，右耳剪下，用直径7mm的打孔器在两耳的相同位置，取圆形耳片，分别称重，求出两圆耳片的重量差作为肿胀度。(肿胀度＝左耳原片重量-右耳原片重量)以肿胀度表示化合物的活性。本实验数据统计均采用t检验和方差分析，肿胀度以(x±SD mg)表示。结果表明，Glu-Leu-Phe-Tyr-Va治疗小鼠的耳肿胀度与生理盐水治疗小鼠的耳肿胀度相比具有显著性差异。表明化合物具有确切的抗炎活性。
表1Glu-Leu-Phe-Tyr-Val(GQ-E)的抗炎活性
a)与生理盐水比p<0.05；n＝14。
Claims (2)
1.一种Glu-Leu-Phe-Tyr-Val五肽在制备抗炎药物中的应用。
2.权利要求1所述的Glu-Leu-Phe-Tyr-Val五肽在制备抗炎药物中的应用，其特征在于，所述的Glu-Leu-Phe-Tyr-Val五肽由以下方法制备：
(1)在DCC和HOBt的催化下按照标准方法制备Boc-Tyr-Val-OBzl；
(2)Boc-Tyr-Val-OBzl在浓度为4N的氯化氢-乙酸乙酯溶液中,0℃脱Boc，转化成Tyr-Val-OBzl；
(3)在DCC和HOBt的催化下制备Boc-Leu-Phe-OBzl；
(4)Boc-Leu-Phe-OBzl在Pd/C催化下，转化成Boc-Leu-Phe；
(5)在DCC和HOBt的催化下制备Boc-Leu-Phe-Tyr-Val-OBzl；
(6)Boc-Leu-Phe-Tyr-Val-OBzl在浓度为4N的氯化氢-乙酸乙酯溶液中,0℃脱Boc，转化成Leu-Phe-Tyr-Val-OBzl；
(7)在DCC和HOBt的催化下制备Boc-γ-羧基-OBzl-Glu-Leu-Phe-Tyr-Val-OBzl；
(8)Boc-γ-羧基-OBzl-Glu-Leu-Phe-Tyr-Val-OBzl在Pd/C催化下氢解Boc-Glu-Leu-Phe-Tyr-Val；
(9)Boc-Glu-Leu-Phe-Tyr-Val在浓度为4N氯化氢-乙酸乙酯溶液中,0℃脱Boc转化成Glu-Leu-Phe-Tyr-Val。
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| US5475089A (en) * | 1990-12-17 | 1995-12-12 | Kabushiki Kaisha Yakult Honsha | Thrombolytic peptide, production thereof, and thrombolytic agent |
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| CN1312176C (zh) * | 2005-04-15 | 2007-04-25 | 赵恩成 | 一种蝎毒多肽及其制备方法 |
| CN101437517A (zh) * | 2006-04-14 | 2009-05-20 | 夏尔有限责任公司 | 提高共价结合的化合物的镇痛效果、减少其副作用和防止其滥用的组合物和方法 |
| CN102477075B (zh) * | 2010-11-30 | 2013-08-14 | 首都医科大学 | 用于抗血栓的寡肽及其制备方法和应用 |
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| CN102485747B (zh) * | 2010-12-01 | 2013-09-25 | 首都医科大学 | 具有靶向性溶血栓活性的寡肽、其制备方法和应用 |
| CN104610424B (zh) * | 2011-12-13 | 2018-08-17 | 首都医科大学 | Lys(Pro-Ala-Lys)姜黄素衍生物、其合成及在医学中的应用 |
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| Publication number | Publication date |
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| CN110105429A (zh) | 2019-08-09 |
| CN112812152B (zh) | 2022-09-02 |
| CN110105428B (zh) | 2022-08-05 |
| CN112794879A (zh) | 2021-05-14 |
| CN110105429B (zh) | 2021-06-08 |
| CN110105428A (zh) | 2019-08-09 |
| CN106317193A (zh) | 2017-01-11 |
| CN112794879B (zh) | 2022-09-02 |
| CN106317193B (zh) | 2019-07-26 |
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