Thiol-ene click chemistry based preparation and characterization of fatty acid modified heparin

Abstract

The invention discloses thiol-ene click chemistry based preparation and characterization of fatty acid modified heparin. A preparation method comprises steps as follows: two compounds including sulfhydrylated fatty acid and a double-bond heparin-allyl conjugate are synthesized respectively, sulfydryl in the sulfhydrylated fatty acid and double bonds in the heparin-allyl conjugate are enabled to be subjected to a reaction with thiol-ene click chemistry, and then fatty acid is linked to a heparin structure, so that a fatty acid modified heparin conjugate modified with different long-chain saturated fatty acids is prepared. The invention further discloses characterization for fatty acid modified heparin on the basis of nuclear magnetic resonance hydrogen spectrum detection, anti-Xa activity determination, elemental analysis, grain-size analysis and gel permeation chromatography molecular-weight determination. According to advantages and characteristics of the thiol-ene click chemistry reaction, the long-chain saturated fatty acids are applied to heparin structure modification for the first time, anticoagulant activity of heparin is reserved, so that a new idea is provided for heparin modification, and the preparation and the characterization have great significance in research and development of novel long-acting heparin anticoagulant drugs.

Description

technical field [0001] The invention relates to the preparation and characterization of fatty acidated heparin based on thiol-ene click chemistry, and belongs to the field of biomedicine. Background technique [0002] Fatty acidation of drugs refers to the modification of drugs with fatty acids (saturated / unsaturated) to improve certain properties of drugs and better meet clinical needs. At present, there are not many studies on fatty acid modification drugs, and some existing studies mainly focus on the modification of protein and polypeptide drugs. The use of fatty acids to modify protein polypeptide drugs can effectively prolong their half-life in the body. In addition, compared with other modifiers, fatty acids are important components of cell membrane phospholipids and human fats and lipids, and directly participate in the composition of cell membranes and protein ligands. Combination with membrane receptors, so fatty acid modification is more helpful to improve the fa...

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Problems solved by technology

[0010] Low-molecular-weight heparin and chemically synthesized heparin drugs have been used in more and more therapeutic fields as new anticoagulant drugs, and they all overcome the short half-life and low bioavailability of unfractionated heparin to varying degrees.

However, low-molecular-weight heparin still needs to be injected twice a day, and patient compliance is poor; in addition, the production technology of low-molecular-weight heparin needs to be strictly controlled to avoid introducing foreign matter during the separation and depolymerization process or changing or even disappearing the anticoagulant active site of heparin ;The products obtained by different degradation methods have different characteristics and unstable quality, and they cannot be substituted for each other in clinical practice, and different research tests are required【Fareed J, Jeske W, Fareed D, et al.Are all low molecularweight heparins equivalent in the management of venous thromboembolism? [J].Clinical&Applied Thrombosis / hemostasis Official Journal of the International Academy of Clinical&Applied Thrombosis / hemostasis, 2008,14(4):385-392], so there are still many problems to be solved and overcome in the research and application of low molecular weight heparin

Although the half-life of fondaparinux is significantly prolonged with lower molecular weight heparin and unfractionated heparin, and the bioavailability has reached 100%, but because it is a fully chemically synthesized drug, the synthesis steps are complicated, making it the most expensive heparin anticoagulant In addition, there is no antidote for fondaparinux currently in clinical use, and these shortcomings limit the application of fondaparinux to a certain extent

[0011] Although it has been proven feasible to obtain anticoagulant drugs with extended half-life and improved bioavailability by degrading heparin or chemically synthesizing heparin-specific pentasaccharide analogues, and there are corresponding products approved for clinical use, but due to their Due to their own problems, these low molecular weight heparins and fondaparinux have not become the ideal "more effective and convenient" anticoagulant and antithrombotic drugs, and unfractionated heparin is still the drug of choice in some therapeutic areas

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