CN108707183A - 酪丝亮肽-二氢卟吩e6单酯及其制备方法 - Google Patents
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Abstract
本发明的酪丝亮肽‑二氢卟吩e6单酯由酪丝亮肽与二氢卟吩e6发生酯化反应制备得到。酪丝亮肽作为溶于水的极性端，使得酪丝亮肽‑二氢卟吩e6单酯溶于水，解决了Ce6水溶性差的问题，具有二氢卟吩e6和酪丝亮肽双重抗肿瘤作用，属于光、声动力治疗药物，可用于制备治疗皮肤病和恶性肿瘤的药物。
Description
技术领域
本发明涉及光、声动力治疗药物，具体是酪丝亮肽-二氢卟吩e6单酯。
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。
酪丝亮肽(Tyrosyl-seryl-leucine，YSL)，是一种三肽化合物，其化学结构组成为L-酪氨酰-L-丝氨酰-L-亮氨酸，分子式为C18H27N306，分子量为381.42，易溶于冰醋酸，溶解于水。
动物实验结果显示，酪丝亮肽显示出一定的抑制肿瘤细胞生长的作用。该药在剂量为40～80μg/kg时，可使腹水型肝癌H22小鼠生命延长率达60％～90％。经四次重复实验结果稳定。在体外实验中酪丝亮肽显示出对人肝癌BEL-7402细胞增殖的抑制作用，最佳抑瘤率可达36.29％。在裸鼠移植瘤实验中，给药剂量为160～320μg/kg时，酪丝亮肽可以显著抑制人肝癌BEL-7402裸鼠移植瘤的生长，经五次重复实验，抑瘤率达40～50％。酪丝亮肽在临床实验中也显示出良好的药效，能够明显延长肝癌病人的生存时间。但在临床研究中也发现，酪丝亮肽的抗肝癌作用在不同病人的个体之间存在差异，即不同的个体对酪丝亮肽的敏感度存在差异。有些病人在给予酪丝亮肽治疗后，肿瘤生长发生了明显抑制；而有些病人在注射酪丝亮肽后肿瘤生长未受到明显影响。
未见酪丝亮肽与二氢卟吩e6结合的报道。
发明内容
为了综合酪丝亮肽与二氢卟吩e6的优点，克服各自的缺点，开发更好的用于光、声动力治疗的药物，本发明提供酪丝亮肽-二氢卟吩e6单酯。
酪丝亮肽-二氢卟吩e6单酯的结构如下式：
由酪丝亮肽与二氢卟吩e6发生酯化反应制备得到。
酪丝亮肽-二氢卟吩e6单酯的制备方法，包括下述步骤：
1）、在保护气体和避光条件下，酪丝亮肽与二氢卟吩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。
酪丝亮肽-二氢卟吩e6单酯的应用，在于制备治疗皮肤病和恶性肿瘤的药物，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、白血病。
本发明的酪丝亮肽-二氢卟吩e6单酯具有下述主要的优点：
1）、酪丝亮肽作为溶于水的极性端，使得酪丝亮肽-二氢卟吩e6单酯溶于水，解决了Ce6水溶性差的问题。
2）、具有二氢卟吩e6和酪丝亮肽双重抗肿瘤作用，通过效果互补解决了酪丝亮肽的抗肝癌作用在不同病人的个体之间存在差异的问题。
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。酪丝亮肽溶于冰醋酸后，加入A，36℃条件搅拌下下反应28h；其中二氢卟吩e6(Chlorin e6, Ce6)与酪丝亮肽为等摩尔量。
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，得目标产物酪丝亮肽-二氢卟吩e6单酯。
纯度达到HPLC大于95%，产率大于65％。
酪丝亮肽-二氢卟吩e6单酯的H1-NMR、C13-NMR如图1、2。分析可知结构得到确证。
酪丝亮肽-二氢卟吩e6单酯在50 mmol/L pH4.0的醋酸盐缓冲液中的溶解度最大为16.6mg/ml，在pH5.0～7.5范围内溶解度为12.3mg/ml。
应用例1
体外抗癌活性评价：
光动力活性：BEL-7402肝癌细胞，663nm的吸收波长，光源高度为20cm，抑瘤率可达58.37％。
声动力活性：BEL-7402肝癌细胞，距超声发声探头2cm，超声激发(2MHz，2W)2min，抑瘤率可达46.69％。
Claims (3)
1.如下式的酪丝亮肽-二氢卟吩e6单酯：
由酪丝亮肽与二氢卟吩e6发生酯化反应制备得到。
2.权利要求1所述的酪丝亮肽-二氢卟吩e6单酯的制备方法，包括下述步骤：
1）、在保护气体和避光条件下，酪丝亮肽与二氢卟吩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所述的酪丝亮肽-二氢卟吩e6单酯的应用，在于制备治疗皮肤病和恶性肿瘤的药物，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、白血病。
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Cited By (3)
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| CN110028513A (zh) * | 2019-04-30 | 2019-07-19 | 北京太阳升高科医药研究股份有限公司 | 卟啉衍生物及声敏剂 |
| CN110478326A (zh) * | 2019-09-12 | 2019-11-22 | 嘉兴星创科技有限公司 | 二氢卟吩e6单酯脂质体冻干制剂及其制备方法 |
| CN115581633A (zh) * | 2022-10-14 | 2023-01-10 | 深圳市维琪医药研发有限公司 | 肽类化合物在制备用于皮肤延衰修复的组合物中的新用途 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028513A (zh) * | 2019-04-30 | 2019-07-19 | 北京太阳升高科医药研究股份有限公司 | 卟啉衍生物及声敏剂 |
| CN110478326A (zh) * | 2019-09-12 | 2019-11-22 | 嘉兴星创科技有限公司 | 二氢卟吩e6单酯脂质体冻干制剂及其制备方法 |
| CN115581633A (zh) * | 2022-10-14 | 2023-01-10 | 深圳市维琪医药研发有限公司 | 肽类化合物在制备用于皮肤延衰修复的组合物中的新用途 |
| CN115581633B (zh) * | 2022-10-14 | 2023-09-12 | 深圳市维琪科技股份有限公司 | 肽类化合物在制备用于皮肤延衰修复的组合物中的新用途 |
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