CN107236055A - 一种新型葡聚糖衍生物及其应用 - Google Patents
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Abstract
本发明公开了一种新型葡聚糖衍生物，在葡聚糖骨架上连接有马来酰亚胺,具有下式结构，能够与巯基底物高效拼接，同时该葡聚糖衍生物具有良好的水溶性，可以用作给药载体。
Description
技术领域
本发明涉及药物制剂领域，尤其涉及一种葡聚糖衍生物及其应用，该衍生物是将马来酰亚胺链接到葡聚糖的羟基上，得到马来酰亚胺化的葡聚糖，保持了葡聚糖的水溶性和生物兼容性，其中的马来酰亚胺结构能够与巯基化合物发生高效拼接反应。
背景技术
高分子药物偶联物是近年来研究的一个热点，它具有延长药物循环时间，增强稳定性，增强溶解度以及靶向性等优点。在高分子药物偶联物的结构中，高分子载体是至关重要的部分。良好的药物载体必须具备生物兼容性好，水溶性强，一定的稳定性以及可修饰性强等特点。
葡聚糖是一种发酵得到的多糖分子，每个葡萄糖单元通过1,6-糖苷键连接，其分子量从几千到几万不等。葡聚糖具有良好的水溶性，生物兼容性，在临床上当作血浆替代品使用。葡聚糖的每个链节有3个游离的仲羟基，可以进行化学修饰，同时葡聚糖的糖苷键在体内有一定的稳定性，是一种良好的药物载体。
近年来，利用葡聚糖作为载体的研究越来越多，药物与葡聚糖的拼接需要对葡聚糖进行修饰，一般的方法有醚化法，氯甲酸对硝基苯酚酯活化法，以及酯化法等，这些修饰往往涉及苛刻的反应条件，不利于一些药物分子拼接，如紫杉醇，喜树碱等含有不稳定结构，往往不能承受这些反应条件。此外，这些修饰方法往往重现性较差。马来酰亚胺结构是一种常用的生物正交反应连接体，常常被用于蛋白修饰，马来酰亚胺与巯基的反应是一种高效的生物正交反应，即可以在生理条件下进行，而且重现性好。虽然已有文献报道葡聚糖的马来酰亚胺修饰，但是其结构中含有苯环，影响载体的理化性质，同时存在潜在的毒性。
发明内容
本发明的目的是提供一种可以用于高分子载药的新型葡聚糖衍生物，该衍生物具有良好的水溶性，生物兼容性，且能与巯基底物高效拼接，非常适合用作药物载体。
实现本发明目的的具体技术方案是：
一种新型葡聚糖衍生物，特点是具有以下结构通式：
其中，D代表葡聚糖，L代表连接片段；所述连接片段选自C2-C4的烷基链或2到12个链接的聚乙二醇链。
所述新型葡聚糖衍生物用作给药载体的应用。
本发明提供了一种结构更为简单，理化性质更好的马来酰亚胺化的葡聚糖载体，用于给药系统。本发明的葡聚糖衍生物(化合物I)具有较好的水溶性，而且通过一定的方式将抗肿瘤药物SN-38连接到化合物I上得到的化合物II具有与上市药物伊立替康盐酸盐相当的水溶性以及抗肿瘤细胞增殖效果，该新型葡聚糖衍生物可以很好地用作给药载体。
附图说明
图1为本发明化合物I的1H-NMR局部谱图；
图2为化合物II与伊立替康盐酸盐水溶液紫外可见吸收光谱图。
具体实施例方式
本发明的新型葡聚糖衍生物制备方法将在如下实施例中更详细叙述，但实施例不构成对本发明的限制。化合物I的合成路线如下。
实施例1
化合物I的制备
1.1化合物2的制备
将马来酸酐(10g，0.102mol)与3-氨基丙酸(9.9g，0.112mol)溶于冰乙酸(150mL)中，加热回流反应5h，反应完毕减压蒸馏除去溶剂，残渣在乙醚中重结晶得白色固体(9.5g,收率55％)。熔点105-107℃。1H-NMR(400MHz,DMSO–d6)δ12.4(s,1H),7.02(d,J＝4.4Hz,2H),3.62(t,J＝7.3Hz,2H),2.53-2.45(m,4H)。
1.2化合物 4的制备
将化合物2(1g,5.91mmol)溶于30mL无水丙酮中，降温至—5℃，加入三乙胺(0.902mL，6.50mmol)，氯甲酸乙酯(0.619mL，6.50mmol)，反应1h后加入叠氮化钠(384mg，5.91mmol)，继续反应1h。反应完毕将体系倒入冰水中，加甲苯萃取，无水硫酸镁干燥12h以上。将化合物3的甲苯溶液加热到100℃，反应2h。反应完毕减压蒸馏除去甲苯，得固体，直接用于下一步反应。
1.3化合物I的制备
将化合物 4(982mg，5.91mmol)溶于无水20mL无水DMSO中，加入葡聚糖(T20，1.91g，11.8mmol)，加热到45℃反应过夜。反应完毕将体系倒入300mL冰冷的乙醇中，析出固体，过滤，滤饼用冰冷的乙醇反复洗涤，干燥后得略带粉红色固体，进一步透析后冻干得白色固体。
1.5化合物I接枝比例的确定
在以D2O为溶剂的情况下，1H-NMR谱图中只出现葡聚糖骨架上的非活泼氢，以及马来酰亚胺结构的氢(图1)。化学位移6-7附近为马来酰亚胺双键的Ha和Hb，化学位移4.9处为葡萄糖单元的缩醛Hi，根据Ha/Hi的比例可以确定马来酰亚胺亚胺的接枝比GR。定义为：
GR＝马来酰亚胺数/葡萄糖单元数×100
如图中的GR＝9％。通过调节化合物4与葡聚糖的投料比，以及加入催化剂二月桂酸二丁基锡，可以得到不同接枝比例的葡聚糖-马来酰亚胺衍生物，满足各种需求。
实施例2
化合物I在给药系统中的应用
将喜树碱化合物SN-38通过一定的连接片段拼接到化合物I上，得到化合物II，提高了药物的水溶性，并表现出与上市药物伊立替康相似的抗肿瘤活性。化合物II的合成路线如下。
2.1化合物7的制备
化合物6参照文献《Zheng Y,Duanmu C,Gao Y.A magnetic biomimeticnanocatalyst for cleaving phosphoester and carboxylic ester bonds under mildconditions[J].Organic letters,2006,8(15):3215-3217.》合成得到，将化合物6(1g,2.47mmol)溶于无水DMF中，加入HATU(0.939g,2.47mmol)，DIEA(0.856mL,4.93mmol)室温反应 1h，加入6-氨基己酸(0.486g,3.71mmol)，室温反应过夜。旋干DMF，粗品经柱层析纯化得白色粉末0.625g，收率49％。熔点149-150℃。1H-NMR(400MHz,DMSO-d6)δ11.93(s,1H),8.05(d,J＝8.3Hz,1H),7.89(s,1H),7.41–7.14(m,15H),4.31(d,J＝7.5Hz,1H),3.11-2.85(m,2H),2.37-2.21(m,2H),2.14(t,J＝7.4Hz,2H),1.81(s,3H),1.49-1.30(m,4H),1.28-1.15(m,2H)；13C-NMR(100MHz,DMSO-d6)δ174.3,169.5,168.9,144.3,129.0,128.0,126.7,65.8,51.5,38.3,34.1,33.6,28.5,25.8,24.1,22.4.MS(ESI)m/z＝541.3[M+Na]+。
2.2化合物9的制备
首先，参照文献《Zhang X,Tang K,Wang H,et al.Design,Synthesis,andBiological Evaluation of New Cathepsin B-Sensitive Camptothecin NanoparticlesEquipped with a Novel Multifuctional Linker[J].Bioconjugate chemistry,2016,27(5):1267-1275.》合成得到化合物8，然后将化合物8(300mg，0.278mmol)溶解在20mL 10％的TFA/DCM溶液中，室温反应1h，旋干备用。将化合物7(159mg,0.306mmol)溶于无水DMF中，加入HATU(116mg,0.306mmol)，DIEA(0.053mL,0.306mmol)，室温反应1h，将之前旋干得到的粗品溶解于5mL无水DMF中并加入到该反应体系，并补充足量DIEA至体系为碱性。室温反应过夜。旋干DMF后，粗品经柱层析纯化得略带淡黄色固体62mg，收率15％。熔点151-152℃。1H-NMR(400MHz,DMSO-d6,D2O)δ8.30–8.10(m,2H),8.02–7.84(m,2H),7.70-7.49(m,3H),7.46–7.26(m,15H),5.58–5.32(m,4H),5.21–5.06(m,2H),4.70–4.54(m,2H),4.45-4.27(m,2H),4.25-4.15(m,3H),3.56(s,2H),3.47-3.40(m,2H),3.27–2.88(m,11H),2.43–2.29(m,3H),2.25-2.13(m,2H),2.08–1.91(m,3H),1.88(s,3H),1.81–1.58(m,3H),1.57–1.20(m,12H),0.99-0.85(m,9H).HR-MS(ESI)calcd for C80H94N11O15S[M+H]+1480.6652,found1480.7810。
2.3化合物II的制备
将化合物9(15mg,0.013mmol)溶于 2mL无水DCM中，加入TFA(0.1mL)，三乙基硅烷(0.05mL)，室温反应1h，加入饱和NaHCO3溶液调pH为8左右，将化合物I(GR＝9％)加入，按照巯基与马来酰亚胺摩尔比为1:1，室温反应5小时，体系经过凝胶柱(LH-20)纯化后冻干得纯品。
2.4化合物II溶解度测定
化合物II与伊立替康盐酸盐分别配制饱和水溶液，稀释相同的倍数，并通过紫外吸收光谱进行定量分析。如图2所示，SN-38连接载体后得到的化合物II与伊立替康盐酸盐溶液的紫外吸收峰位置与强度接近，表明溶解度相近，从而说明化合物I对药物具有较好的增溶效果。
2.5化合物II抗肿瘤细胞增殖活性评价
将化合物II与伊立替康盐酸盐在人结肠癌细胞HCT-116，人宫颈癌细胞Hela，人肝癌细胞HepG2三种细胞株上孵育72h，用MTT法测定细胞相对活力。结果如下表所示，化合物II表现出与伊立替康相当的抗肿瘤细胞增殖活性。
表1化合物抗肿瘤细胞增殖活性评价
Claims (2)
1.一种新型葡聚糖衍生物，其特征在于，具有以下结构通式：
其中，D代表葡聚糖，L代表连接片段；所述连接片段选自C2-C4的烷基链或2到12个链接的聚乙二醇链。
2.一种权利要求1所述新型葡聚糖衍生物用作给药载体的应用。
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