含氟香豆素透明质酸衍生物的合成及其荧光性能

doi:10.3724/SP.J.1095.2014.30493

摘要/Abstract

摘要： 以间氨基苯酚与三氟乙酰乙酸乙酯反应生成4-三氟甲基-7-氨基香豆素，其与氯乙酰氯反应生成-4-三-氟甲基-7-氯乙酰氨基香豆素。该化合物与透明质酸钠反应得到了含氟香豆素透明质酸衍生物。利用荧光光谱等分析技术研究了浓度、pH值和温度变化对该透明质酸衍生物荧光强度的影响，同时研究了金属离子对其荧光强度的影响。结果表明，一定浓度范围内，荧光强度随透明质酸衍生物浓度增大而逐渐增强；在pH值为3.86～8.85范围内，其荧光强度较为稳定；在10～80 ℃范围内，其荧光强度随温度的升高而逐渐减弱；在常见干扰离子存在下，Fe3+对其荧光强度有较为显著的影响，其荧光强度显著降低。这为探索透明质酸在生命机体内的药物载体机理及其靶向作用提供良好的实验基础。

关键词: 透明质酸, 间氨基苯酚, 荧光强度, Fe3+

Abstract: 4-Trifluoromethyl-7-amino coumarin obtained from m-aminophenol and ethyl trifluoroacetoacetate, further reacted with chloroacetic chloride to generate 4-trifluoromethyl-7-chloro-acetylamino coumarin. Then, the product was treated with sodium hyaluronate to give hyaluronic acid derivatives containing fluorinated coumarin. The influences of concentration, pH and temperature on fluorescence intensity of hyaluronic acid derivatives were studied. The influence of different metal ions on fluorescence intensity of hyaluronic acid derivatives was also investigated. The results show that the fluorescence intensity of hyaluronic acid derivatives is enhanced with increased concentration, kept stable when the pH ranges from 3.86 to 8.85, and decreased when temperature increased from 10 ℃ to 80 ℃. In addition, Fe3+ leads to significantly reduced fluorescence intensity of hyaluronic acid derivatives in the presence of other interfering metal ions. These provide good experimental basis to explore the mechanism as well as the targeting behavior of hyaluronic acid as drug carrier.

Key words: hyaluronic acid, m-aminophenol, fluorescence intensity, iron ion

中图分类号:

O621.3

周维杰, 孙小强, 席海涛. 含氟香豆素透明质酸衍生物的合成及其荧光性能[J]. 应用化学, DOI: 10.3724/SP.J.1095.2014.30493.

ZHOU Weijie, SUN Xiaoqiang, XI Haitao*. Synthesis and Fluorescence Properties of Hyaluronic Acid Derivatives Containing Fluorinated Coumarin[J]. Chinese Journal of Applied Chemistry, DOI: 10.3724/SP.J.1095.2014.30493.

参考文献

[1] ZHANG Wei,YAN Cuie. Progress in Hyaluronic Acid and Its Derivatives as Drug Carriers[J]. Prog Chem,2006,18(12):1684-1690(in Chinese).

张伟,闫翠娥. 透明质酸及其衍生物药物载体[J]. 化学进展,2006,18(12):1684-1690.

[2] Benedetti L M,Topp E M,Stella V J,et al. Microspheres of Hyaluronic Acid Esters-fabrication Methods and in vitro Hydrocortisone Release[J]. J Controlled Release,1990,13(1):33-41.

[3] Kyronen K,Hume L,Benedtti L,et al. Methylprednisolone Esters of Hyaluronic Acid in Ophthalmic Drug Delivery:in vitro and in vivo Release Studies[J]. Int J Phytorem,1992,80(1):161-169.

[4] Surendrakumar K,Martyn G P,Hodgers E C M,et al. Sustained Release of Insulin from Sodium Hyaluronate Based Dry Powder Formulations after Pulmonary Delivery to Beagle Dogs[J]. J Controlled Release,2003,91(3):385-394.

[5] Luo Y,Prestwich G D. Synthesis and Selective Cytotoxicity of a Hyaluronic Acid-Antitumor Bioconjugate[J]. Bioconjug Chem,1999,10(5):755-763.

[6] Luo Y,Ziebell M R,Prestwich G D. A Hyaluronic Acid-Taxol Antitumor Bioconjugate Targeted to Cancer Cells[J]. Biomacromolecules,2000,1(2):208-218.

[7] Choi K Y,Chung H,Min K H,et al. Self-assembled Hyaluronic Acid Nanoparticles for Active Tumor Targeting[J]. Biomaterials,2010,31(1):106-114.

[8] He M,Zhao Z,Yin L,et al. Hyaluronic Acid Coated Poly(butyl cyanoacrylate) Nanoparticles as Anticancer Drug Carriers[J]. Int J Pharm,2009,373(1/2):165-173.

[9] Liu C C,Chang K Y,Wang Y J. A Novel Biodegradable Amphiphilic Diblock Copolymers Based on Poly(lactic acid) and Hyaluronic Acid as Biomaterials for Drug Delivery[J]. J Polym Res,2010,17(4):459-469.

[10] YU Chenjie,ZHANG Li,LI Hongmei,et al. Research Advances on Hyaluronic Acid and Its Derivatives as Drug Carriers[J]. Prog Pharm Sci,2011,35(12):543-549(in Chinese).

俞晨洁,张莉,李红玫,等. 透明质酸及其衍生物用作药物载体的研究进展[J]. 药学进展,2011,35(12):543-549.

[11] Sato S,Suzuki M,Soma T,et al. Synthesis and Properties of Umbelliferone-nitroxide Radical Hybrid Compounds as Fluorescence and Spin-label Probes[J]. Spectrochim Acta,2008,70(4):799-804.

[12] Singh R K,Mandal T,Balasubramanian N,et al. Coumarin-suberoylanilide Hydroxamic Acid as a Fluorescent Probe for Determining Binding Affinities and Off-rates of Histone Deacetylase Inhibitors[J]. Anal Biochem,2011,408(2):309-315.

[13] Trkovnik M. Ivezic Z. Syntheses of Some New Coumarin-quinolone Carboxylic Acids[J]. J Heterocycl Chem,2000,37(1):137-142.

[14] Dalapati S,Jana S,Alam M A,et al. Multifunctional Fluorescent Probe Selective for Cu(Ⅱ) and Fe(Ⅲ) with Dual-mode of Binding Approach[J]. Sens Actuators,B,2011,160(1):1106-1111.

[15] ZHAO Defeng,ZHANG Lijun,YANG Lingxiao. The Progress of Organic Fluorescent Dyes[J]. Dyestuffs Color,1997,34(3):1-6(in Chinese).

赵德丰,张立军,杨凌霄. 荧光染料结构与性能关系的研究进展[J]. 染料与染色,1997,34(3):1-6.

[16] Touati D. Iron and Oxidative Stress in Bacteria[J]. Arch Bioehem Biophys,2000,373(1):1-6.

[17] Wang J,Ha C S. Fluorescent Logic Operations Based on Azobenzene-containing Compounds[J]. Sens Actuators,B,2010,146(1):373-380.

[18] Li Z X,Zhang L F,Li X Y,et al. A Fluorescent Color/intensity Changed Chemosensor for Fe3+ by Photo-induced Electron Transfer(PET) Inhibition of Fluoranthene Derivative[J]. Dyes Pigm,2012,94(1):60-65.

[19] Lee D Y,Singh N,Jang D O. Fine Tuning of a Solvatochromic Fluorophore for Selective Determination of Fe3+:A New Type of Benzimidazole-based Anthracene-coupled Receptor[J]. Tetrahedron Lett,2011,52(12):1368-1371.

[20] Zhang L Z,Wang J Y,Fan J L,et al. A Highly Selective, Fluorescent Chemosensor for Bioimaging of Fe3+[J]. Bioorg Med Chem Lett,2011,21(18):5413-5416.

[21] Dong L,Wu C,Zeng X,et al. The Synthesis of a Rhodamine B Schiff-base Chemosensor and Recognition Properties for Fe3+ in Neutral Ethanol Aqueous Solution[J]. Sens Actuators,B,2010,145(1):433-437.

[22] Lohani C R,Kim J M,Lee K H. Facile Synthesis of Anthracene-appended Amino Acids as Highly Selective and Sensitive Fluorescent Fe3+ Ion Sensors[J]. Bioorg Med Chem Lett,2009,19(21):6069-6073.

[23] Lee H,Lee K,Park T G. Hyaluronic Acid-paclitaxel Conjugate Micelles:Synthesis, Characterization, and Antitumor Activity[J]. Bioconjugate Chem,2008,19(6):1319-1325.

[24] Mlcochova P,Hajkova V,Steiner B,et al. Preparation and Characterization of Biodergradable Alkylether Derivatives of Hyaluronan[J]. Carbohydr Polym,2007,69(2):344-352.

[25] Schantéa C E,Zubera G,Herlinb C,et al. Chemical Modifications of Hyaluronic Acid for the Synthesis of Derivatives for a Broad Range of Biomedical Applications[J]. Carbohydr Polym,2011,85(3):469-489.

[26] Eugene I,Bissell D,Kristin L,et al. Some 7-Substituted 4-(Trifluoromethyl) Coumarins[J]. J Chem Eng Data,1981,26(3):348-350.

[27] Valeur B,Leray I. Design Principles of Fluorescent Molecular Sensors for Cation[J]. Coord Chem Rev,2000,205(1):3-40.

[28] Suratwala T,Gardlund Z,Davidson K,et al. Silylated Coumarin Dyes in Sol-Gel Hosts.1.Structure and Environmental Factors on Fluorescent Properties[J]. Chem Mater,1998,10(1):190-198.

[29] Fakih S,Podinovskaia M,Kong X,et al. Targeting the Lysosome: Fluorescent Iron(Ⅲ) Chelators to Selectively Monitor Endosomal/lysosomal Labile Iron Pools[J]. J Med Chem,2008,51(15):4539-4552.

[30] De Silva A P,Gunaratne H Q N,Gunnlaugsson T,et al. Signaling Recognition Events with Fluorescent Sensors and Switches[J] Chem Rev,1997,97(5):1515-1566.