L-苯丙氨酸衍生物的一锅法合成及其抗/促凝活性

doi:10.11944/j.issn.1000-0518.2017.02.160042

摘要/Abstract

摘要：

氨基酸及其衍生物在止血/抗凝活性方面有一定的应用。以L-苯丙氨酸为起始原料,经磺化引入磺酸基,再与甲醇、乙醇、丙醇、异丙醇和正丁醇脱水酯化,一锅法合成了6种未见报道的L-苯丙氨酸的磺酸酯类衍生物(L1~L6),以期获得具有的较强血液生理活性的潜在药物。实验中采用了质谱、核磁共振进行结构表征。该合成方法产率高(78%~95%),后处理简单,不失为合成该类衍生物的好方法。衍生物的凝血四项实验表明:抗促凝效果是内源性和外源性凝血途径共同作用的结果。血浆复钙实验表明:衍生物均具有一定的抗凝活性,其抗凝效果随浓度变化而变化,但是随R链的长度增加,抗凝效果并未见规律性。衍生物的抗凝活性主要受磺酸基及酯基的影响,因此在设计合成抗血栓化合物时可以考虑引入磺酸基及酯类基团。

关键词: L-苯丙氨酸, 酯类衍生物, 抗/促凝活性

Abstract:

Amino acids and their derivatives have some applications in coagulant/anticoagulant activities. L-phenylalanine was used as starting material and sulfonated for introducing sulfonic acid group, and then dehydrated with methanol, ethanol, propanol, isopropanol, and n-butanol to synthesize six derivatives L1~L6. Six novel sulfonic acid esterified derivatives of L-phenylalanine L1~L6 were synthesized in one pot in order to obtain strong physiological activity for potential coagulant/anticoagulant drugs. The structures of the six derivatives were characterized by mass spectrometry and nuclear magnetic resonance. The yield by this synthetic method is high(78%~95%) and the post-treatment is simple for the synthesis of such derivatives. Four items of blood coagulation of derivatives show that anticoagulant and pro-coagulant effects are the result of the interaction of endogenous and extrinsic coagulation pathways. The plasma re-calcification time shows that the derivatives have certain anticoagulant activity, and their anticoagulant effects are changed with the concentration, but the anticoagulant effect does not have such a regular relationship with the increase of R chain. The anticoagulant activity of the derivative is mainly affected by sulfonic and ester groups, so the introduction of sulfonic acid and ester groups can be considered for designing and synthesizing antithrombotic compounds.

Key words: L-phenylalanine, synthesis, ester derivatives, anti/pro-coagulant activity

刘建建, 程辉, 林发全, 罗轩, 王立升, 林翠梧. L-苯丙氨酸衍生物的一锅法合成及其抗/促凝活性[J]. 应用化学, 2017, 34(2): 139-145.

LIU Jianjian, CHENG Hui, LIN Faquan, LUO Xuan, WANG Lisheng, LIN Cuiwu. One-pot Synthesis of L-Phenylalanine Derivatives and Their Anti/Pro-coagulational Properties[J]. Chinese Journal of Applied Chemistry, 2017, 34(2): 139-145.

参考文献

[1]	Li J B,Sha Y W. A Convenient Synthesis of Amino Acid Methyl Esters[J]. Molecules,2008,13(5):1111-1119.
[2]	He M Z,Yuan D K,Lin W. Synthesis and Assay of Isoquinoline Derivatives as HIV-1 Tat-TAR Interaction Inhibitors[J]. Bioorg Med Chem Lett,2005,15(17):3978-3981.
[3]	Alagille D,Pfeiffer B,Scalbert E,et al.Design and Synthesis of Indole and Tetrahydroisoquinoline Hydantoin as Chymase Inhibitors[J]. J Enzyme Inhib Med Chem,2004,19(2):137-143.
[4]	Mallakpour S,Barati A. Preparation and Characterization of Novel Optically Activepoly(vinyl alcohol-co-vinyl ester) in Nonaqueous Medium Using L-Phenylalanine as a Chiral Material[J]. Amino Acids,2012,42(4):1287-1295.
[5]	LI Qian,HUANG Li,LIN Cuiwu,et al.Technological Research on the Extraction and Purification of Amino Acids from Blumea riparia(Bl.)DC[J]. Lishizhen Med Mater Med Res,2010,21(3):659-661(in Chinese). 李倩,黄丽,林翠梧,等. 滇桂艾纳香中氨基酸的提取工艺研究[J]. 时珍国医国药,2010,21(3):659-661.
[6]	LI Qian. Preliminary Study of the Hemostatic Activity of Free Amino Acids and Saponins from Blumea riparia DC[D]. Nanning:Guangxi University,2010(in Chinese). 李倩. 滇桂艾纳香氨基酸和皂甙成分及其止血活性的初步研究[D]. 南宁:广西大学,2010.
[7]	Gao P J,Zhu D L,Zhan Y M. L-Phenylalanine and Smooth Muscle Cell Proliferation from SHR and WKY Rats[J]. Acta Physiol Sin,1980,50(4):401-408.
[8]	Wang H,Peng L,Zhao M. 2-Substituted(S)-2-(3,3-dimethyl-1-oxy-10,10a-dihydroimidazo[1,5-b]isoquinolin-2(1H,3H,5H)-yl)acetic Acids:Conformational Prediction, Synthesis, Anti-Thrombotic and Vasodilative Evaluation[J]. Bioorg Med Chem,2011,19(2):871-882.
[9]	Zhang X Y,Wang W,Cheng S L,et al.2,3-Diamino acid Modifying 3S-Tetrahydroisoquinoline-3-carboxylic Acids:Leading to a Class of Novel Agents with Highly Unfolded Conformation, Selective in vitro Anti-platelet Aggregation and Potent in vivo Anti-thrombotic Activity[J]. Bioorg Med Chem,2010,18(4):1536-1554.
[10]	Zheng M Q,Zhang X Y,Zhao M.(3S)-N-(L-Aminoacyl)-1,2,3,4-tetrahydroisoquinolines, a Class of Novel Antithrombotic Agents:Synthesis, Bioassay, 3D QSAR, and ADME Analysis[J]. Bioorg Med Chem,2008,16(21):9574-9587.
[11]	JI Ancheng,HAN Hang,WANG Chaoqun,et al.Synthesis of Bortezomib[J]. Pharm Clin Res,2014,22(2):121-123(in Chinese). 纪安成,韩航,王超群,等. 硼替佐米的合成工艺改进[J]. 药学与临床研究,2014,22(2):121-123.