CN108641009A - 二氢卟吩e6-香菇多糖酯及其制备方法 - Google Patents

二氢卟吩e6-香菇多糖酯及其制备方法 Download PDF

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CN108641009A
CN108641009A CN201810495237.XA CN201810495237A CN108641009A CN 108641009 A CN108641009 A CN 108641009A CN 201810495237 A CN201810495237 A CN 201810495237A CN 108641009 A CN108641009 A CN 108641009A
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陈志强
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Guilin Xingda Photoelectric Medical Instrument Co Ltd
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Abstract

本发明的二氢卟吩e6‑香菇多糖酯由香菇多糖与二氢卟吩e6发生酯化反应制备得到，香菇多糖作为溶于水的极性端，使得二氢卟吩e6‑香菇多糖酯溶于水，解决了Ce6水溶性差的问题，具有二氢卟吩e6和香菇多糖双重抗肿瘤作用，属于光、声动力治疗药物，可用于制备治疗皮肤病、恶性肿瘤或癌性胸腹水的药物。

Description

二氢卟吩e6-香菇多糖酯及其制备方法
技术领域
本发明涉及光、声动力治疗药物，具体是二氢卟吩e6-香菇多糖酯。
背景技术
二氢卟吩e6(Chlorin e6, Ce6)，墨绿色粉末，极具吸湿性和易氧化性。不溶于水，溶于丙酮、四氢呋喃、乙醇。
二氢卟吩e6具有一定的光敏性和热敏性，因而二氢卟吩e6既是一种光敏剂，也是一种很有潜力的声敏剂。它具备663nm的吸收波长，能够产生更多的ROS（活性氧簇），而且无毒、肿瘤组织高选择性及非肿瘤组织清除率高，对皮肤的副反应也较小，因此适合用于肿瘤光、声动力治疗。但是Ce6水溶性差，因此限制了其在临床的开发应用。
香菇多糖(lentinan，LNT) 是从优质香菇子实体中提取的有效活性成分，是具有分支的β- (1-3)-D-葡聚糖，主链由β-(1-3)-连接的葡萄糖基组成，沿主链随机分布着由β-(1-6)连接的葡萄糖基，呈梳状结构。
临床与药理研究表明，香菇多糖是一种宿主免疫增强剂(host defensepotentiator，HDP)，具有抗病毒、抗肿瘤、调节免疫功能和刺激干扰素形成等作用。功能主治：不能手术或复发性胃癌、肝癌、膀胱癌，使用本品能缓解症状，提高病人免疫功能，纠正微量元素失调。香菇多糖加放疗、化疗治疗小细胞肺癌、乳癌、恶性淋巴瘤等。也可用于癌性胸腹水的治疗。
香菇多糖为灰白色粉末，大多为酸性多糖，溶于水、稀碱，尤其易溶于热水，不溶于乙醇、丙酮、乙酸乙酯、乙醚等有机溶剂，其水溶液呈透明黏稠状。香菇多糖对正常机体并无免疫促进作用，但能使荷瘤式或感染后的机体的免疫应答得以提高。香菇多糖具有抗肿瘤作用，它没有化疗药物的毒副作用。香菇多糖与化疗剂联合使用，有减毒、增效的作用。香菇多糖还能使肿瘤部位的血管扩张和出血，导致肿瘤出血坏死和完全退化。
未见香菇多糖与二氢卟吩e6结合的报道。
发明内容
为了综合香菇多糖与二氢卟吩e6的优点，开发更好的用于光、声动力治疗的药物，本发明提供二氢卟吩e6-香菇多糖酯。
二氢卟吩e6-香菇多糖酯的结构如下式：
由香菇多糖与二氢卟吩e6发生酯化反应制备得到。
二氢卟吩e6-香菇多糖酯的制备方法，包括下述步骤：
1）、在保护气体和避光条件下，香菇多糖与二氢卟吩e6发生酯化；
2）、离心，上清液以去离子水透析，冷冻干燥。
3）、干燥物用硅胶柱层析分离，洗脱剂是体积比为3/7~7/3的二氯甲烷/甲醇的混合溶液；
4）、挥去二氯甲烷/甲醇后，用甲醇或乙腈溶解，用反相柱层析精制纯化，洗脱剂为甲醇/水混合液或乙腈/水混合液；所述反相柱使用的填料为C18；所述甲醇/水混合液或乙腈/水混合液的体积比为3/7~7/3；
5）、所得纯化液浓缩至干，再将浓缩物真空干燥24~36h或冷冻干燥，得目标产物。
二氢卟吩e6-香菇多糖酯的应用，在于制备治疗皮肤病、恶性肿瘤或癌性胸腹水的药物，所述皮肤病包括：尖锐湿疣、扁平疣、痤疮、鲜红斑痣、毛细血管瘤，所述恶性肿瘤包括：食管癌、肺癌、脑瘤、头颈部肿瘤、眼肿瘤、咽癌、胸壁肿瘤、乳腺癌、胸膜间皮瘤、腹腔肉瘤、膀胱癌、妇科肿瘤、直肠癌、Kaposi肉瘤、皮肤癌、口腔癌、喉癌、宫颈癌、阴道癌、外阴癌、阴茎癌、肝癌、胆管癌、胃癌、小细胞肺癌、恶性淋巴瘤、白血病。
本发明的二氢卟吩e6-香菇多糖酯具有下述主要的优点：
1）、香菇多糖作为溶于水的极性端，使得二氢卟吩e6-香菇多糖酯溶于水，解决了Ce6水溶性差的问题。
2）、具有二氢卟吩e6和香菇多糖双重抗肿瘤作用。
3）、香菇多糖还能使肿瘤部位的血管扩张和出血，导致肿瘤出血坏死和完全退化。而在本发明中，这种血管扩张和出血恰好为二氢卟吩e6产生的ROS提供了二氢卟吩e6产生的ROS直接作用肿瘤细胞的有利途径，因而本发明的二氢卟吩e6-香菇多糖酯具有更好的抗肿瘤效果。
附图说明
图1是实施例1目标产物的H1-NMR图。
图2是实施例1目标产物的C13-NMR图。
具体实施方式
实施例1
在保护气体和避光条件下，二氢卟吩e6(Chlorin e6，Ce6)溶于乙醇中，为A。香菇多糖溶于50~80度热水后，加入A，室温条件搅拌下下反应32h；其中二氢卟吩e6(Chlorin e6,Ce6)与香菇多糖为等摩尔量。
离心，上清液以去离子水透析，冷冻干燥。
干燥物用硅胶柱层析分离，洗脱剂是体积比为3/7~7/3的二氯甲烷/甲醇的混合溶液；
挥去二氯甲烷/甲醇后，用甲醇或乙腈溶解，用反相柱层析精制纯化，洗脱剂为甲醇/水混合液或乙腈/水混合液；所述反相柱使用的填料为C18；所述甲醇/水混合液或乙腈/水混合液的体积比为3/7~7/3；
所得纯化液浓缩至干，再将浓缩物真空干燥24~36h或冷冻干燥，得目标产物二氢卟吩e6-香菇多糖酯。
纯度达到HPLC大于95%，产率大于63％。
二氢卟吩e6-香菇多糖酯的H1-NMR、C13-NMR如图1、2。分析可知结构得到确证。
二氢卟吩e6-香菇多糖酯的水溶性溶解度为：33.7。
应用例1
体外抗癌活性评价：
光动力活性：HepG2 肝癌细胞，663nm的吸收波长，光源高度为 20cm，测得IC50/μm：21.3。
声动力活性：HepG2 肝癌细胞，距超声发声探头2cm，超声激发(2MHz，2W)2min，测得IC50/μm：75.9。

Claims (3)

1.如下式的二氢卟吩e6-香菇多糖酯：
由香菇多糖与二氢卟吩e6发生酯化反应制备得到。
2.权利要求1所述的二氢卟吩e6-香菇多糖酯的制备方法，包括下述步骤：
1）、在保护气体和避光条件下，香菇多糖与二氢卟吩e6发生酯化；
2）、离心，上清液以去离子水透析，冷冻干燥；
3）、干燥物用硅胶柱层析分离，洗脱剂是体积比为3/7～7/3的二氯甲烷/甲醇的混合溶液；
4）、挥去二氯甲烷/甲醇后，用甲醇或乙腈溶解，用反相柱层析精制纯化，洗脱剂为甲醇/水混合液或乙腈/水混合液；所述反相柱使用的填料为C18；所述甲醇/水混合液或乙腈/水混合液的体积比为3/7～7/3；
5）、所得纯化液浓缩至干，再将浓缩物真空干燥24～36h或冷冻干燥，得目标产物。
3.权利要求1所述的二氢卟吩e6-香菇多糖酯的应用，在于制备治疗皮肤病、恶性肿瘤或癌性胸腹水的药物，所述皮肤病包括：尖锐湿疣、扁平疣、痤疮、鲜红斑痣、毛细血管瘤，所述恶性肿瘤包括：食管癌、肺癌、脑瘤、头颈部肿瘤、眼肿瘤、咽癌、胸壁肿瘤、乳腺癌、胸膜间皮瘤、腹腔肉瘤、膀胱癌、妇科肿瘤、直肠癌、Kaposi肉瘤、皮肤癌、口腔癌、喉癌、宫颈癌、阴道癌、外阴癌、阴茎癌、肝癌、胆管癌、胃癌、小细胞肺癌、恶性淋巴瘤、白血病。
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