CN106317193B - 含Tyr-Val片段的肽,其合成、活性和应用 - Google Patents
含Tyr-Val片段的肽,其合成、活性和应用 Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明公开了含Tyr‑Val片段的(AA1‑AA2‑AA3‑AA4‑AA5‑Tyr‑Val)4种肽。公开了它们的制备方法,公开了它们的镇痛活性,公开了它们的抗炎活性,公开了他们的抗肿瘤活性,公开了它们的抗血栓活性及公开了它们的溶血栓活性,因而本发明公开了它们在制备镇痛药、抗炎药、抗肿瘤药物和抗血栓药物、溶血栓药物中的应用。
Description
技术领域
本发明涉及通式I代表的4种肽AA1-AA2-AA3-AA4-AA5-Tyr-Val的4种肽,涉及它们的制备方法、涉及它们的镇痛活性,涉及它们的抗炎活性,涉及它们的抗肿瘤活性,涉及它们的抗血栓活性及涉及它们的溶血栓活性,因而本发明涉及它们在制备镇痛药、抗炎药、抗肿瘤药物、抗血栓药物和溶血栓药物的应用。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、抗凝血和镇痛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,通式AA1-AA2-AA3-AA4-AA5-Tyr-Val的4种肽是集镇痛作用、抗炎作用、抗肿瘤作用、抗血栓作用和溶血栓作用为一体的寡肽。
发明内容
本发明的第一个内容是提供AA1-AA2-AA3-AA4-AA5-Tyr-Val的4种肽(当AA1= Asn,AA2=Pro,AA3=Pro,AA4=Asp,AA5=Asp时AA1-AA2-AA3-AA4-AA5-Tyr-Val为 Asn-Pro-Pro-Asp-Asp-Tyr-Val;当AA1=Leu,AA2=Arg,AA3=Ala,AA4=Pro,AA5=Leu 时AA1-AA2-AA3-AA4-AA5-Tyr-Val为Leu-Arg-Ala-Pro-Leu-Tyr-Val;当AA1不存在, AA2=Glu,AA3=Thr,AA4=Ala,AA5=Pro时AA1-AA2-AA3-AA4-AA5-Tyr-Val为 Glu-Thr-Ala-Pro-Tyr-Val;当AA1和AA2都不存在,AA3=Glu,AA4=Leu,AA5=Phe时 AA1-AA2-AA3-AA4-AA5-Tyr-Val为Glu-Leu-Phe-Tyr-Val)。
本发明的第二个内容是提供AA1-AA2-AA3-AA4-AA5-Tyr-Val的4种肽(当AA1= Asn,AA2=Pro,AA3=Pro,AA4=Asp,AA5=Asp时AA1-AA2-AA3-AA4-AA5-Tyr-Val为 Asn-Pro-Pro-Asp-Asp-Tyr-Val;当AA1=Leu,AA2=Arg,AA3=Ala,AA4=Pro,AA5=Leu 时AA1-AA2-AA3-AA4-AA5-Tyr-Val为Leu-Arg-Ala-Pro-Leu-Tyr-Val;当AA1不存在, AA2=Glu,AA3=Thr,AA4=Ala,AA5=Pro时AA1-AA2-AA3-AA4-AA5-Tyr-Val为 Glu-Thr-Ala-Pro-Tyr-Val;当AA1和AA2都不存在,AA3=Glu,AA4=Leu,AA5=Phe时 AA1-AA2-AA3-AA4-AA5-Tyr-Val为Glu-Leu-Phe-Tyr-Val)的合成方法,该方法包括:
(1)Glu-Leu-Phe-Tyr-Val的制备方法
(1-1)在DCC和HOBt的催化下按照标准方法制备Boc-Tyr-Val-OBzl;
(1-2)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;
(1-3)在DCC和HOBt的催化下制备Boc-Leu-Phe-OBzl;
(1-4)Boc-Leu-Phe-OBzl在H2,Pd/C催化下,转化成Boc-Leu-Phe;
(1-5)在DCC和HOBt的催化下制备Boc-Leu-Phe-Tyr-Val-OBzl;
(1-6)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;
(1-7)在DCC和HOBt的催化下制备Boc-Glu(OBzl)-Leu-Phe-Tyr-Val-OBzl;
(1-8)Boc-Glu(OBzl)-Leu-Phe-Tyr-Val-OBzl在Pd/C催化下氢解 Boc-Glu-Leu-Phe-Tyr-Val;
(1-9)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;
(2)Leu-Arg-Ala-Pro-Leu-Tyr-Val的制备方法:
(2-1)在DCC和HOBt的催化下按照标准方法制备Boc-Tyr-Val-OBzl;
(2-2)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;
(2-3)在DCC和HOBt的催化下制备Boc-Ala-Pro-OBzl;
(2-4)Boc-Ala-Pro-OBzl在Pd/C催化下氢解转化成Boc-Ala-Pro;
(2-5)在DCC和HOBt的催化下制备Boc-Leu-Tyr-Val-OBzl;
(2-6)Boc-Leu-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-Tyr-Val-OBzl;
(2-7)在DCC和HOBt的催化下制备Boc-Ala-Pro-Leu-Tyr-Val-OBzl;
(2-8)Boc-Ala-Pro-Leu-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Ala-Pro-Leu-Tyr-Val-OBzl;
(2-9)在DCC和HOBt的催化下制备Boc-Leu-Arg(NO2)-OBzl;
(2-10)Boc-Leu-Arg(NO2)-OBzl在浓度为2N的NaOH水溶液中0℃转化成 Boc-Leu-Arg(NO2);
(2-11)在DCC和HOBt的催化下制备Boc-Leu-Arg(NO2)-Ala-Pro-Leu-Tyr-Val-OBzl;
(2-12)Boc-Leu-Arg(NO2)-Ala-Pro-Leu-Tyr-Val-OBzl在三氟醋酸和三氟甲磺酸中0℃脱保护转化成Leu-Arg-Ala-Pro-Leu-Tyr-Val;
(3)Asn-Pro-Pro-Asp-Asp-Tyr-Val的合成方法:
(3-1)在DCC和HOBt的催化下按照标准方法制备Boc-Tyr-Val-OBzl;
(3-2)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;
(3-3)在DCC和HOBt的催化下制备Boc-Asp(OBzl)-Tyr-Val-OBzl;
(3-4)Boc-Asp(OBzl)-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Asp(OBzl)-Tyr-Val-OBzl;
(3-5)在DCC和HOBt的催化下制备Boc-Asp(OBzl)-Asp(OBzl)-Tyr-Val-OBzl;
(3-6)Boc-Asp(OBzl)-Asp(OBzl)-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Asp(OBzl)-Asp(OBzl)-Tyr-Val-OBzl;
(3-7)在DCC和HOBt的催化下制备Boc-Pro-Pro-OBzl;
(3-8)Boc-Pro-Pro-OBzl在浓度为4N的氯化氢-乙酸乙酯溶液中0℃脱Boc,转化成Pro-Pro-OBzl;
(3-9)在DCC和HOBt的催化下制备Boc-Asn-Pro-Pro-OBzl;
(3-10)Boc-Asn-Pro-Pro-OBzl在Pd/C催化下氢解转化成Boc-Asn-Pro-Pro;
(3-11)在DCC和HOBt的催化下制备Boc-Asn-Pro-Pro-Asp(OBzl)- Asp(OBzl)-Tyr-Val-OBzl;
(3-12)Boc-Asn-Pro-Pro-Asp(OBzl)-Asp(OBzl)-Tyr-Val-OBzl在三氟醋酸和三氟甲磺酸中0℃脱保护转化成Asn-Pro-Pro-Asp-Asp-Tyr-Val;
(4)Glu-Thr-Ala-Pro-Tyr-Val的制备方法:
(4-1)在DCC和HOBt的催化下按照标准方法制备Boc-Tyr-Val-OBzl;
(4-2)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;
(4-3)在DCC和HOBt的催化下制备Boc-Ala-Pro-OBzl;
(4-4)Boc-Ala-Pro-OBzl在Pd/C催化下氢解转化成Boc-Ala-Pro;
(4-5)在DCC和HOBt的催化下制备Boc-Ala-Pro-Tyr-Val-OBzl;
(4-6)Boc-Ala-Pro-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Ala-Pro-Tyr-Val-OBzl;
(4-7)在DCC和HOBt的催化下制备Boc-Thr-Ala-Pro-Tyr-Val-OBzl;
(4-8)Boc-Thr-Ala-Pro-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Thr-Ala-Pro-Tyr-Val-OBzl;
(4-9)在DCC和HOBt的催化下制备Boc-Glu(OBzl)-Thr-Ala-Pro-Tyr-Val-OBzl;
(4-10)Boc-Glu(OBzl)-Thr-Ala-Pro-Tyr-Val-OBzl在三氟醋酸和三氟甲磺酸中0℃脱保护转化成Glu-Thr-Ala-Pro-Tyr-Val。
本发明的第三个内容是评价AA1-AA2-AA3-AA4-AA5-Tyr-Val的镇痛作用。
本发明的第四个内容是评价AA1-AA2-AA3-AA4-AA5-Tyr-Val的抗炎作用。
本发明的第五个内容是评价AA1-AA2-AA3-AA4-AA5-Tyr-Val的抗肿瘤作用。
本发明的第六个内容是评价AA1-AA2-AA3-AA4-AA5-Tyr-Val的抗血栓作用。
本发明的第七个内容是评价AA1-AA2-AA3-AA4-AA5-Tyr-Val的溶血栓作用。
附图说明
图1 Glu-Leu-Phe-Tyr-Val(GQ-E)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℃。
图2 Glu-Thr-Ala-Pro-Tyr-Val(GQ-Q)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℃;iv)2N NaOH,0℃;v)三氟醋酸(TFA),三幅甲磺酸(TFMSA)。
图3 leu-Arg-Ala-Pro-Leu-Tyr-Val(GQ-L)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)4NHCl/EA,0℃; iv)2N NaOH,0℃;v)三氟醋酸(TFA),三幅甲磺酸(TFMSA)。
图4 Asn-Pro-Pro-Asp-Asp-Tyr-Val(GQ-N)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)4NHCl/EA,0 ℃;iv)2N NaOH,0℃;v)三氟醋酸(TFA),三幅甲磺酸(TFMSA)。
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(10 mmol)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 ℃.(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制备Boc-Ala-Pro-OBzl
按照实施例1的方法,1.89g(10mmol)Boc-Ala和2.03g(10mmol)Pro-OBzl得到2.04g(54.3%)标题化合物,为无色油状物。ESI+-MS(m/e):377[M+H]+。
实施例11制备Boc-Ala-Pro-OH
按照实施例4的方法,从3.76g(10mmol)Boc-Ala-Pro-OBzl得到2.83g(99%)标题化合物,为无色粉末。ESI+-MS(m/e):287[M+H]+。
实施例12制备Boc-Leu-Tyr-Val-OBzl
按照实施例1的方法,2.31g(10mmol)Boc-Leu和3.7g(10mmol)Tyr-Val-OBzl得到3.67g(63.0%)标题化合物,为无色粉末。ESI+-MS(m/e):491[M+H]+。
实施例13制备Leu-Tyr-Val-OBzl
按照实施例2的方法,从5.83g(10mmol)Boc-Leu-Tyr-Val-OBzl得到4.95g(99.9%) 标题化合物,为黄色粉末。ESI+-MS(m/e):391[M+H]+。
实施例14制备Boc-Ala-Pro-Leu-Tyr-Val-OBzl
按照实施例1的方法,从2.86g(10mmol)Boc-Ala-Pro和4.83g(10 mmol)Leu-Tyr-Val-OBzl,得到3.32g(44.5%)标题化合物,为无色粉末。ESI+-MS(m/e): 659[M+H]+。
实施例15制备Ala-Pro-Leu-Tyr-Val-OBzl
按照实施例2的方法,从7.51g(10mmol)Boc-Ala-Pro-Leu-Tyr-Val-OBzl得到6.05g(92.5%)标题化合物,为无色粉末。ESI+-MS(m/e):559[M+H]+。
实施例16制备Boc-Leu-Arg(NO2)-OBzl
按照实施例1的方法,2.31g(10mmol)Boc-Leu和3.09g(10mmol)Arg(NO2)-OBzl 得到白色油状物3.64g(69.7%)。ESI+-MS(m/e):524[M+H]+。
实施例17制备Boc-Leu-Arg(NO2)-OH
冰浴下将5.22g(10mmol)Boc-Leu-Arg(NO2)-OBzl溶解于甲醇,搅拌10min,逐滴加入2N NaOH溶液,调节pH到13-14。保持冰浴反应4个小时,反应完全。冰浴下反应液用饱和KHSO4溶液调节pH到中性,先减压浓缩除甲醇,再用饱和KHSO4溶液调节pH 到2。反应液用乙酸乙酯萃取3遍。得到的溶液用饱和NaCl溶液洗至中性,用无水Na2SO4干燥12小时,过滤,滤液减压浓缩,得到4.89g(100%)标题化合物,为无色油状物。 ESI+-MS(m/e):433[M+H]+。
实施例18制备Boc-Leu-Arg(NO2)-Ala-Pro-Leu-Tyr-Val-OBzl
按照实施例1的方法,4.31g(10mmol)Boc-Leu-Arg(NO2)和6.51g(10 mmol)Ala-Pro-Leu-Tyr-Val-OBzl,得到3.24g(31.6%)标题化合物,为无色果冻状化合物。ESI+-MS(m/e):973[M+H]+;1H-NMR(300MHz,DMSO-d6):δ/ppm=9.14(s,1H), 8.51(s,1H),8.20(m,2H),7.78(m,4H),7.36(m,5H),6.93(d,J=8.4Hz,3H),6.59(d,J=8.4 Hz,2H),5.13(s,2H),4.50(m,2H),4.31.89(m,2H),4.18(m,2H),3.94(m,1H),3.52(s,2H), 3.13(m,2H),2.89(m,1H),2.63(m,1H),2.05(m,2H),1.89(m,2H),1.72(m,1H),1.50(m, 6H),1.37(m,13H),1.16(d,J=7.5Hz,3H),0.835(m,18H)。
实施例19制备Leu-Arg-Ala-Pro-Leu-Tyr-Val(GQ-L)
冰浴下将106mg(0.1mmol)Boc-Leu-Arg(NO2)-Ala-Pro-Leu-Tyr-Val-OBzl用4mLTFA(三氟醋酸)溶解,搅拌10min,加入1mL TFMSA(三氟甲磺酸),反应30min 后,反应基本完成,原料点消失。将无水乙醚加入茄瓶中,用塑料铲磨洗,倾倒乙醚;重复操作三次。最终获得棕黄色粉末,用三蒸水溶解,用氨水调pH至7,走Sephdex G10,收集得到78mg(72.9%)标题化合物,为白色粉末。ESI+-MS(m/e):804[M+H]+;Mp 159.5 ~16.2℃.(c=0.09,甲醇).IR:3297,2965,1656,1518,1469,1346,1239, 1224,1167,1027,831,762,636,578.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.58(d, J=7.5Hz,1H),8.22(s,2H),8.06(s,3H),7.87(m,1H),7.40(m,3H),6.97(d,J=8.4Hz,2H), 6.60(d,J=8.4Hz,2H),4.61(m,2H),4.32(m,2H),4.15(m,3H),3.81(m,3H),3.39(m, 1H),3.09(d,J=4.5Hz,2H),2.06(m,1H),1.40-1.95(m,10H),1.02-1.49(m,9H),0.85(m, 18H)。
实施例20制备Boc-Asp(OBzl)-Tyr-Val-OBzl
按照实施例1的方法,3.23g(10mmol)Boc-Asp(OBzl)和3.7g(10 mmol)Tyr-Val-OBzl得到4.87g(72%)标题化合物,为无色油状物。ESI+-MS(m/e):677 [M+H]+。
实施例21制备Asp(OBzl)-Tyr-Val-OBzl的制备
按照实施例2的方法,从6.75g(10mmol)Boc-Asp(OBzl)Tyr-Val-OBzl得到5.43g(94.4%)标题化合物,为无色粉末。ESI+-MS(m/e):577[M+H]+。
实施例22制备Boe-Asp(OBzl)-Asp(OBzl)-Tyr-Val-OBzl
按照实施例1的方法,3.23g(10mmol)Boc-Asp(OBzl)和5.75g(10 mmol)Asp(OBzl)-Tyr-Val-OBzl得到4.92g(44.9%)标题化合物,为无色粉末。 ESI+-MS(m/e):882[M+H]+。
实施例23制备Asp(OBzl)-Asp(OBzl)-Leu-Tyr-Val-OBzl
按照实施例2的方法,从7.51g(10mmol) Boc-Asp(OBzl)-Asp(OBzl)-Leu-Tyr-Val-OBzl得到7.7g(98.2%)标题化合物,为无色粉末。 ESI+-MS(m/e):782[M+H]+。
实施例24制备Boc-Pro-Pro-OBzl
按照实施例1的方法,2.15g(10mmol)Boc-Pro和2.05g(10mmol)Pro-OBzl得到2.34g(77.5%)标题化合物,为无色油状物。ESI+-MS(m/e):403[M+H]+。
实施例25制备Pro-Pro-OBzl
按照实施例2的方法,从4.02g(10mmol)Boc-Pro-Pro-OBzl得到2.99g(99%)标题化合物,为无色粉末.ESI+-MS(m/e):303[M+H]+。
实施例26制备Boc-Asn-Pro-Pro-OBzl
按照实施例1的方法,2.46g(10mmol)Boc-Asn和3.02g(10mmol)Pro-Pro-OBzl得到2.58g(48.7%)标题化合物,为无色油状物。ESI+-MS(m/e):518[M+H]+。
实施例27制备Boc-Asn-Pro-Pro
按照实施例4的方法,从5.30g(10mmol)的Boc-Asn-Pro-Pro-OBzl得到 4.30g(97.7%)标题化合物,为无色粉末。ESI+-MS(m/e):427[M+H]+。
实施例28制备Boc-Asn-Pro-Pro-Asp-Asp-Tyr-Val-OBzl
按照实施例1的方法,4.4g(10mmol)Boc-Asn-Pro-Pro和7.8g(10 mmol)Asp(OBzl)-Asp(OBzl)-Tyr-Val-OBzl得到2.95g(24.5%)标题化合物,为无色果冻状。ESI+-MS(m/e):1190[M+H]+;1H-NMR(300MHz,DMSO-d6):δ/ppm=9.16(s,1H), 8.11(m,3H),7.78(s,1H),7.33(m,15H),7.18(s,1H),6.98(d,J=8.4Hz,2H),6.87(d,J=8.4 Hz,1H),6.62(d,J=8.4Hz,2H),5.11(s,2H),5.08(s,2H),5.04(s,2H),4.55(m,5H),4.25(m, 1H),4.18(m,1H),3.60(m,2H),3.48(m,2H),3.35(m,1H),2.97-2.52(m,6H),2.30(m,2H), 2.00(m,3H),1.82(m,6H),1.35(s,9H),0.85(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H)。
实施例29制备Asn-Pro-Pro-Asp-Asp-Tyr-Val(GQ-N)
按照实施例19的方法,从120mg(0.1mmol) Boc-Asn-Pro-Pro-Asp-Asp-Tyr-Val-OBzl得到69mg(83.1%)的标题化合物,为白色粉末。 ESI+-MS(m/e):820[M+H]+;Mp 164.8~165.9℃.(c=0.08,甲醇).IR: 2966,1721,1651,1515,1448,1223,1167,1027,909,828,761,728,697, 636.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.12(s,1H),8.03(m,4H),7.09(m,1H), 7.68(m,1H),7.30(m,1H),7.00(d,J=8.4Hz,3H),6.63(d,J=8.4Hz,2H),4.60(m,1H),4.42(m,4H),4.25(m,1H),4.10(m,3H),3.67(m,4H),3.47(m,1H),3.06(m,2H),2.69(m, 4H),2.45(m,2H),2.23(m,1H),1.88(m,8H),0.88(t,6H)。
实施例30制备Boc-Ala-Pro-OBzl
按照实施例1的方法,1.89g(10mmol)Boc-Ala和2.03g(10mmol)Pro-OBzl得到2.04g(54.3%)标题化合物,为无色油状物。ESI+-MS(m/e):377[M+H]+。
实施例31制备Boc-Ala-Pro
按照实施例4的方法,从3.76g(10mmol)Boc-Ala-Pro-OBzl得到2.83g(99%)标题化合物,为无色粉末。ESI+-MS(m/e):287[M+H]+。
实施例32制备Boc-Ala-Pro-Tyr-Val-OBzl
按照实施例1的方法,2.86g(10mmol)Boc-Ala-Pro和3.7g(10mmol)Tyr-Val-OBzl得到4.01g(63.3%)标题化合物,为无色粉末。ESI+-MS(m/e):540[M+H]+。
实施例33制备Ala-Pro-Tyr-Val-OBzl
按照实施例2的方法,从6.38g(10mmol)Boc-Ala-Pro-Tyr-Val-OBzl得到 5.29g(98.6%)标题化合物,为无色粉末。ESI+-MS(m/e):640[M+H]+。
实施例34Boc-Thr-Ala-Pro-Tyr-Val-OBzl的制备
按照实施例1的方法,2.46g(10mmol)Boc-Thr和5.38g(10 mmol)Ala-Pro-Tyr-Val-OBzl得到3.39g(44.6%)标题化合物,为无色油状物。 ESI+-MS(m/e):741[M+H]+。
实施例35制备Thr-Ala-Pro-Tyr-Val-OBzl
按照实施例2的方法,从3.7g(5mmol)Boc-Ala-Pro-Tyr-Val-OBzl得到6.03g(94.2%) 标题化合物,为无色粉末。ESI+-MS(m/e):641[M+H]+。
实施例36制备Boc-Glu(OBzl)-Thr-Ala-Pro-Tyr-Val-OBzl
按照实施例1的方法,337mg(1mmol)Boc-Glu(OBzl)和640mg (1mmol)Thr-Ala-Pro-Tyr-Val-OBzl得到530mg(55.3%)标题化合物,为无色油状物。 ESI+-MS(m/e):960[M+H]+;1H-NMR(300MHz,DMSO-d6):δ/ppm=9.17(s,1H), 8.15(d,J=7.5Hz,1H),8.05(d,J=8.1Hz,1H),7.80(d,J=8.7Hz,1H),7.67(d,J=8.1Hz,1H), 7.31(m,10H),7.02(d,J=9.6Hz,1H),6.97(d,J=8.4Hz,2H),6.77(s,1H),6.62(d,J=8.4Hz, 2H),5.12(m,4H),4.49(m,2H),4.41(m,1H),4.33(m,1H),4.18(m,2H),4.01(m,1H), 3.51(m,2H),2.80(m,2H),2.11(m,2H),1.90(m,2H),1.78(m,1H),1.59(m,2H),1.38(s, 9H),1.12(d,J=6.9Hz,3H),1.06(d,J=6.3Hz,3H),0.85(m,6H)。
实施例37制备Glu-Thr-Ala-Pro-Tyr-Val(GQ-Q)
按照实施例19的方法,从433mg(0.5mmol) Boc-Glu(OBzl)-Thr-Ala-Pro-Tyr-Val-OBzl得到304mg(89.5%)标题化合物,为微黄色粉末。ESI+-MS(m/e):680[M+H]+;Mp129.1-130.6℃.(c=0.09,甲醇).IR: 3210,3060,2973,2935,1716,1650,1614,1543,1515,1443,1374,1349,1301,1224, 1148,1114,1044,1011,918,875,830,801,665,601,558.1H-NMR(300MHz,DMSO-d6):δ/ppm=8.67(d,J=8.1Hz,1H),8.28(s,2H),8.14(d,J=7.5Hz,1H),7.82(d,J=8.4Hz,1H), 7.66(d,J=8.1Hz,1H),7.45(s,1H),6.95(m,2H),6.65(d,2H),4.43(m,2H),4.32(m,1H), 4.22(m,2H),4.16(m,1H),3.96(m,2H),3.56(m,1H),2.6-3.0(m,2H),2.28(m,2H),2.05(m, 3H),1.63(m,2H),1.20-0.78(m,12H)。
实施例38评价GQ-E、GQ-L、GQ-N、GQ-Q的镇痛活性
雄性ICR小鼠(20±2g)装到小鼠固定器中,鼠尾暴露于固定器外,于鼠尾距离尾尖三分之一处标记,作为光感感受器的感应点,照射鼠尾距离尾尖三分之二的位置。测痛仪预热30min,记时,将小鼠鼠尾遮住光感仪。灯闪烁时开始记时,鼠尾离开光感仪时停止记时,测得的时间即为小鼠产生痛感的时间,连续测定3次,每次测量间隔为5min,取平均值。未服药小鼠产生痛感的时间为基础痛感时间。服药引起的小鼠产生痛感时间变化反映了药物的镇痛活性。小鼠,随机分组,每组14只,测定基础痛感时间后,小鼠或口服0.2mLGQ-E、GQ-L、GQ-N、GQ-Q的生理盐水溶液,剂量为1 μmol/kg或口服0.2mL生理盐水或口服阿司匹林的生理盐水溶液,剂量为1200μmol/kg。测量给药后30,60,90,120,150和180min小鼠产生痛感的时间。数据用均值±SD秒表示,列如表1,用方差分析并进行t检验。数据表明,口服生理盐水30,60,90,120,150和 180min之后小鼠产生痛感的时间与口服生理盐水之前的基础痛感时间没有显著差异;口服1200μmol/kg阿司匹林60,90,120,150和180min之后小鼠产生痛感的时间显著长于口服阿司匹林之前的基础痛感时间;口服GQ-L、GQ-N1μmol/kg 30,60,90,120,150 和180min之后小鼠产生痛感的时间显著长于口服GQ-L、GQ-N之前的基础痛感时间。口服1μmol/kgGQ-L在120,150和180min之后的镇痛活性与口服1200μmol/kg阿司匹林相当。而30,60和90min之后的镇痛活性比口服1200μmol/kg阿司匹林还强。口服 1μmol/kgGQ-N在30min之后的镇痛活性比口服1200μmol/kg阿司匹林还强。
表1 GQ-L、GQ-E、GQ-N、GQ-Q的镇痛活性
n=14;a)与基础痛感时间比p>0.05;b)与基础痛感时间比p<0.05;c)与基础痛感时间比p<0.01。
实施例39评价GQ-L、GQ-E、GQ-N、GQ-Q的抗炎活性
体重20±雄性小鼠口服1μmol/kgGQ-L、GQ-E、GQ-N、GQ-Q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,肿胀度以表示。结果表明,GQ-E治疗的鼠耳肿胀度与生理盐水组相比具有显著性差异,表明化合物具有确切的抗炎活性。
表2 GQ-L、GQ-E、GQ-N、GQ-Q的抗炎活性
n=14;a)与生理盐水组比较,p<0.01。
实施例40评价GQ-L、GQ-E、GQ-N、GQ-Q的抗肿瘤活性
无菌条件下取接种于ICR小鼠7-10天的S180肉瘤,加入适量生理盐水配制成瘤细胞悬液,细胞数为2×107/mL,接种于健康雄性ICR小鼠前肢腋皮下,每只小鼠注射0.2mL。肿瘤接种24h后,小鼠每日腹腔注射0.2mLGQ-L、GQ-E、GQ-N、GQ-Q的生理盐水溶液,连续给药10天,剂量为1μmol/kg;或小鼠每日腹腔注射0.2mL阿霉素的生理盐水溶液,连续给药10天,剂量为2μmol/kg;或小鼠每日腹腔注射0.2mL生理盐水,连续给药10天。实验进行至第11天,称小鼠体重,乙醚麻醉剖取各组小鼠的肿瘤,称重并以瘤重表示化合物的活性,数据列入表3。结果表明1μmol/kgGQ-L、GQ-N、GQ-E治疗小鼠的瘤重明显小于生理盐水治疗小鼠的瘤重,显示确切的抗肿瘤活性。
表3 GQ-L、GQ-E、GQ-N、GQ-Q对S180荷瘤小鼠的瘤重的影响
n=15;a)与生理盐水比p<0.01。
实施例41评价GQ-L、GQ-E、GQ-N、GQ-Q的抗血栓活性
1)将聚乙烯管拉成一端为斜口的细管,定长为10.0cm,分别为右经静脉(管径较粗)及左颈动脉(管径较细)插管;中段聚乙烯管定长为8.0cm,血栓线压在颈动脉插管方向,插管前需在管中充满肝素。
2)体重250±雄性大鼠口服1μmol/kgGQ-L、GQ-E、GQ-N、GQ-Q或167μmol/kg阿司匹林或0.3mL/100g生理盐水30分钟后,腹腔注射20%的乌拉坦进行麻醉。仰卧位将大鼠固定于鼠板上,剪开颈部皮肤,分离右颈总动脉及左颈静脉,血管下压线,结扎远心端,静脉靠远心端处剪一小口,进行静脉端插管,注射肝素,系线固定,再用动脉夹夹住动脉近心端,靠近远心端方向剪一小口,进行动脉端结扎,系线固定后松开动脉夹,建立体外循环旁路。循环15分钟后先剪断静脉端观察血液循环是否正常,若正常从动脉端取出血栓线,在纸上沾干浮血后称重,以栓重表示化合物的活性,数据列入表4。结果表明,GQ-N、GQ-L治疗大鼠的血栓重明显小于生理盐水治疗大鼠的血栓重,显示确切的抗血栓活性。
表4化合物GQ-L、GQ-E、GQ-N、GQ-Q对SD大鼠栓重的影响
n=12;a)与生理盐水比p<0.05;b)与生理盐水比p<0.01。
实施例41评价GQ-L、GQ-N、GQ-E、GQ-Q的溶栓活性
将大鼠静息饲养一天,随机分组,每组10只,禁食不禁水。
1)将体重250±雄性SD大鼠用20%乌拉坦溶液进行麻醉(6mL/kg腹腔)。麻醉后的大鼠固定于鼠板上,分离右侧颈总动脉,于近心端夹动脉夹,近心端和远心端分别传入手术线,在远心端插取血管,松开动脉夹取约1mL动脉血。迅速将动脉血注射入垂直的造栓管(长16mm,内径2.5mm,外径5mm,管底用1mL EP管底座)中,(注意不可有气泡)每个造栓管中注入0.1mL大鼠动脉血液,往管内迅速插入血栓固定螺栓(长20mm,),血液凝固40min,用针灸针取出血栓,称取血栓重量。
2)旁路插管由三部分组成,其中中段为聚乙烯胶管,长60mm,内径3.5mm,两端为相同的聚乙烯管,长100mm,内径1mm,外景2mm,该管的一段拉成尖管,另一端的外部套一段长7mm,外径3.5mm的聚乙烯管。三段管的内壁均为硅烷化。
3)将血栓包裹的血栓固定螺栓置于中段的聚乙烯胶管内,胶管的两端分别与两根聚乙烯的加粗端相套,用注射器通过尖管端注满肝素生理盐水溶液。将充满肝素钠的生理盐水溶液一端插入左侧静脉,另一端用注射器加入准确量的肝素钠抗凝后,拔掉肝素钠的注射器,插入动脉端。用头皮针将生理盐水(3mL/kg)或者尿激酶的生理盐水溶液(20000IU/kg)或GQ-L、GQ-N、GQ-E、GQ-Q的生理盐水溶液(1μmol/kg)通过旁路管的中段,刺入远离血栓固定螺栓的近静脉处,打开动脉夹,使血流通过旁路管道从动脉流入静脉的时刻为循环起始时间,缓慢的将注射器中的液体注入到血液中(约6min),使生理盐水,尿激酶,Arg-Leu-Val-Cys-Val通过血液循环,按静脉-心脏-动脉的顺序作用到血栓上。60min后取出附有血栓的螺栓,蘸去浮血,记录重量。以血栓减重代表溶栓活性。数据列入表5。结果表明,GQ-L、GQ-N、GQ-E、治疗大鼠的血栓减重明显大于生理盐水治疗大鼠的血栓减重,显示确切的溶血栓活性。
表5 GQ-L、GQ-N、GQ-E、GQ-Q的溶栓活性
n=10;a)与生理盐水比p<0.01。
Claims (6)
1.序列为Asn-Pro-Pro-Asp-Asp-Tyr-Val的七肽。
2.权利要求1的Asn-Pro-Pro-Asp-Asp-Tyr-Val七肽的制备方法,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-β-羧基-OBzl-Asp-Tyr-Val-OBzl;
(4)Boc-β-羧基-OBzl-Asp-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β-羧基-OBzl-Asp-Tyr-Val-OBzl;
(5)在DCC和HOBt的催化下制备Boc-β-羧基-OBzl-Asp-β-羧基-OBzl-Asp-Tyr-Val-OBzl;
(6)Boc-β-羧基-OBzl-Asp-β-羧基-OBzl-Asp-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β-羧基-OBzl-Asp-β-羧基-OBzl-Asp-Tyr-Val-OBzl;
(7)在DCC和HOBt的催化下制备Boc-Pro-Pro-OBzl;
(8)Boc-Pro-Pro-OBzl在浓度为4N的氯化氢-乙酸乙酯溶液中0℃脱Boc,转化成Pro-Pro-OBzl;
(9)在DCC和HOBt的催化下制备Boc-Asn-Pro-Pro-OBzl;
(10)Boc-Asn-Pro-Pro-OBzl在Pd/C催化下氢解转化成Boc-Asn-Pro-Pro;
(11)在DCC和HOBt的催化下制备Boc-Asn-Pro-Pro-β-羧基-OBzl-Asp-β-羧基-OBzl-Asp-Tyr-Val-OBzl;
(12)Boc-Asn-Pro-Pro-β-羧基-OBzl-Asp-β-羧基-OBzl-Asp-Tyr-Val-OBzl在三氟醋酸和三氟甲磺酸中0℃脱保护转化成Asn-Pro-Pro-Asp-Asp-Tyr-Val。
3.权利要求1的Asn-Pro-Pro-Asp-Asp-Tyr-Val七肽在制备抗肿瘤药物中的应用。
4.权利要求1的Asn-Pro-Pro-Asp-Asp-Tyr-Val七肽在制备镇痛药物的应用。
5.权利要求1的Asn-Pro-Pro-Asp-Asp-Tyr-Val七肽在制备抗栓药物的应用。
6.权利要求1的Asn-Pro-Pro-Asp-Asp-Tyr-Val七肽在制备溶栓药物的应用。
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CN1687126A (zh) * | 2005-04-15 | 2005-10-26 | 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 |
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GB8723485D0 (en) * | 1987-10-07 | 1987-11-11 | Erba Farmitalia | Solution synthesis of octapeptide |
US5475089A (en) * | 1990-12-17 | 1995-12-12 | Kabushiki Kaisha Yakult Honsha | Thrombolytic peptide, production thereof, and thrombolytic agent |
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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 |
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CN103450338B (zh) * | 2012-05-29 | 2016-08-24 | 首都医科大学 | 杂环羧酸修饰的胸腺五肽,其制备,抗肿瘤作用和应用 |
CN103450342B (zh) * | 2012-06-01 | 2015-08-05 | 首都医科大学 | 四氢异喹啉-3-羧酸修饰的pargd七肽、其合成、抗血栓活性和应用 |
CN103539837A (zh) * | 2012-07-15 | 2014-01-29 | 彭莉 | 1-甲基-β-咔啉-3-甲酰RGD肽、其合成、纳米结构、抗血栓作用和应用 |
TWI568747B (zh) * | 2012-09-05 | 2017-02-01 | 上海晟順生物科技有限公司 | 同時具溶血栓、清除自由基和血栓靶向功能的新穎化合物及其製備方法和用途 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1687126A (zh) * | 2005-04-15 | 2005-10-26 | 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 |
Non-Patent Citations (2)
Title |
---|
Purification, characterization, and bioactivity of a newanalgesic-antitumor peptide from Chinese scorpion Buthus martensii Karsch;Jian-Hua Shao et al;《Peptides》;20131120;第53卷;第89-96页 |
植物源性食物中活性肽氨基酸组成的研究进展;田明慧等;《食品与发酵工业》;20141231;第40卷(第6期);第110-116页 |
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