引用本文:
施志浩, 魏运洋, 周莉萍, 顾云凯. 天冬酰胺丙酮叉在多肽合成中的应用[J]. 应用化学,
2007, 24(6): 707-711.
Citation: SHI Zhi-Hao, WEI Yun-Yang, ZHOU Li-Ping, GU Yun-Kai. Application of N,N'-Isopropylidene Asparagine in Peptide Synthesis[J]. Chinese Journal of Applied Chemistry, 2007, 24(6): 707-711.
Citation: SHI Zhi-Hao, WEI Yun-Yang, ZHOU Li-Ping, GU Yun-Kai. Application of N,N'-Isopropylidene Asparagine in Peptide Synthesis[J]. Chinese Journal of Applied Chemistry, 2007, 24(6): 707-711.
天冬酰胺丙酮叉在多肽合成中的应用
摘要:
L-天冬酰胺(Asn)与丙酮在KOH的甲醇溶液中反应得到具有丙酮叉结构的环化天冬酰胺[cAsn(acetone)]。该化合物在缩合剂1-乙基-3-(3'-二甲氨基丙基)碳化二亚胺盐酸盐(EDCI)和1-羟基苯并三氮唑(HOBt)存在下,与芴甲氧羰基(Fmoc)保护的酪氨酸(Fmoc-Tyr(Bzl)-OH)、苯丙氨酸(Fmoc-Phe-OH)和丙氨酸(Fmoc-Ala-OH)在二氯甲烷和N,N-二甲基甲酰胺溶液中反应得到新的二肽Fmoc-Tyr(Bzl)-cAsn(acetone)-OH、Fmoc-Phe-cAsn(acetone)-OH和Fmoc-Ala-cAsn(acetone)-OH,收率分别为35%、30%和30%。其中Fmoc-Tyr(Bzl)-cAsn(acetone)-OH与苯丙氨酸二肽酰胺(H-Phe-Phe-NH2)在相同的缩合条件下反应生成四肽Fmoc-Tyr(Bzl)-cAsn(acetone)-Phe-Phe-NH2,收率为70%。乙酸中Pd-C催化加氢可同时脱去酪氨酸残基上的芴甲氧羰基和苄基(Bzl)保护基,首次得到内吗啡肽-2(endomorphin-2,H-Tyr-Pro-Phe-Phe-NH2)的环化天冬酰胺类似物H-Tyr-cAsn(acetone)-Phe-Phe-NH2,收率为60%。应用核磁共振、红外、质谱和高分辨质谱测试技术对目标产物和中间体的结构进行了表征。小鼠醋酸扭体法对类似物的镇痛活性进行了初步的研究。结果表明,当剂量为2.4×10-5 g/Kg时,镇痛抑制率为45%。
English
Application of N,N'-Isopropylidene Asparagine in Peptide Synthesis
Abstract:
A cyclic amino acid,N,N'-isopropylidene Asparagine[cAsn(acetone)],was synthesized via the reaction of L-asparagine with acetone in methanol in the presence of potassium hydroxide.Fmoc protected amino acids,Fmoc-Tyr (Bzl)-OH,Fmoc-Phe-OH,and Fmoc-Ala-OH were then allowed to react with cAsn(acetone) in DMF/CH2>Cl2 in the presence of 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenztriazole (HOBt) to give dipeptides Fmoc-Tyr (Bzl)-cAsn(acetone)-OH,Fmoc-Phe-cAsn(acetone)-OH and Fmoc-Ala-cAsn(acetone)-OH in yields of 35%,30% and 30% respectively.Further coupling of the dipeptide Fmoc-Tyr (Bzl)-cAsn(acetone)-OH with H-Phe-Phe-NH2 in the presence of EDCI and HOBt led to the formation of a tetrapeptide Fmoc-Tyr (Bzl)-cAsn(acetone)-Phe-Phe-NH2 in a yield of 70%.Deprotection of the Fmoc and Bzl groups on the tyrosine residue in the tetrapeptide with H2/Pd-C in acetic acid gave a novel analogue of endomorphin-2(H-Tyr-cAsn(acetone)-Phe-Phe-NH2) in a yield of 60%.1H NMR,IR,MS and HRMS were used to characterize the structures of the titled product and the intermediates.Antinociceptive activity of the tetrapeptide was assessed in acetic acid-induced abdominal constriction tests after i.p.injected in mouse with an inhibition rate of 45% at a dose of 2.4×10-5 g/Kg.
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Key words:
- N,N'-isopropylidene Asparagine
- / endomorphin
- / tetrapeptides
- / analogue
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