CN117531021A - 一种刺五加苷e-靶向肽偶联物及其应用 - Google Patents
一种刺五加苷e-靶向肽偶联物及其应用 Download PDFInfo
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- CN117531021A CN117531021A CN202410032634.9A CN202410032634A CN117531021A CN 117531021 A CN117531021 A CN 117531021A CN 202410032634 A CN202410032634 A CN 202410032634A CN 117531021 A CN117531021 A CN 117531021A
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- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
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Abstract
一种刺五加苷E‑靶向肽偶联物及其应用,属于药物合成技术领域。本发明为了解决刺五加苷E水溶性较差、靶向性较弱、安全性和生物利用度较低的技术问题,提供一种刺五加苷E‑靶向肽偶联物,并提供该偶联物在制备抗肿瘤药物中的应用。本发明通过将刺五加苷E与靶向肽连接获得刺五加苷E‑靶向肽偶联物,能够精准释放,达到了提高肿瘤治疗效果的目的,由于提高了刺五加苷E化合物的水溶性,因此避免了助溶剂的添加;提高了偶联药物靶向性和药物吸收利用度,降低了对正常细胞的损伤和毒副作用,提高了安全性。本发明的靶向肽肽序较短,易于通过固相合成获得,具有低成本、安全高效的优点,可适用于大规模工业生产。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种刺五加苷E-靶向肽偶联物及其应用。
背景技术
刺五加(Acanthopanax senticosus)为五加科植物,主要分布于黑龙江、吉林、辽宁、河北以及山西等地,生于森林或灌丛中,喜温暖湿润气候,耐寒、耐荫蔽;药理上,刺五加具有兴奋神经系统、提高免疫力、抗衰老、修复受损细胞等多种生物活性,并且具有木质素结构;相关研究表明,木质素结构具有抗癌、抗氧化和抗炎活性等功能。在临床上,刺五加注射液已被广泛应用于短暂性脑缺血、脑动脉硬化、脑血栓和脑栓塞等疾病的治疗,但现有技术中临床应用的刺五加注射液均为混合物,除刺五加苷E成分以外,还含有刺五加苷A、刺五加苷B、刺五加苷C和刺五加苷D等成分,导致因为药物成分复杂而出现不明原因的不良反应。刺五加苷E(Eleutheroside E)在稀甲醇中为无色针状结晶,其水溶性较差、靶向性较弱、安全性和生物利用度较低,现有技术中关于刺五加苷E药理作用的相关报道较少,其药理学研究报道主要为降低血糖、抗中枢疲劳、降低心肌梗塞发生的率,临床主要应用于防治心脑血管疾病方面,关于刺五加苷E在抗肿瘤方面的应用还未见报道。
发明内容
本发明的目的是为了解决刺五加苷E水溶性较差、靶向性较弱、安全性和生物利用度较低的技术问题,本发明一种刺五加苷E-靶向肽偶联物及其应用。
本发明的目的之一在于提供一种刺五加苷E-靶向肽偶联物,所述刺五加苷E-靶向肽偶联物是由刺五加苷E通过连接键与靶向肽连接获得。
在本发明的一个优选实施例中,所述刺五加苷E的结构为:
。
在本发明的一个优选实施例中,所述连接键为可断裂的二硫键。
在本发明的一个优选实施例中,所述可断裂二硫键的结构为
。
在本发明的一个优选实施例中,所述靶向肽为
[Cys-Asp-Gly-Arg-Arg-Gly-Asp-Cys]-NH2。
在本发明的一个优选实施例中,所述靶向肽的缩写为[CDGRRGDC]-NH2。
在本发明的一个优选实施例中,所述靶向肽的结构为
。
在本发明的一个优选实施例中,所述刺五加苷E-靶向肽偶联物为刺五加苷E-Mpa-S-S-Mpa-[CDGRRGDC]-NH2。
在本发明的一个优选实施例中,所述刺五加苷E-靶向肽偶联物的结构为:
。
本发明的目的之二在于提供一种上述刺五加苷E-靶向肽偶联物在制备抗肿瘤药物中的应用。
有益效果
本发明通过将刺五加苷E与靶向肽连接获得刺五加苷E-靶向肽偶联物,能够精准释放,达到了提高肿瘤治疗效果的目的,具体效果包括:由于提高了刺五加苷E化合物的水溶性,因此避免了助溶剂的添加;同时提高了偶联药物的靶向性,提高了药物吸收利用度,降低了对正常细胞的损伤,降低毒副作用,提高了安全性。
本发明的靶向肽肽序较短,易于通过固相合成获得,具有低成本、安全高效的优点,可适用于大规模工业生产。
附图说明
图1为实施例1-2中工艺制备流程图;
图2为实施例2中Mpa-[CDGRRGDC]-NH2质谱检测结果;
图3为实施例3中刺五加苷E-Mpa(Trt)反应液检测结果;
图4为实施例3中刺五加苷E-Mpa(Trt)液相纯化结果;
图5为实施例3中刺五加苷E-Mpa(Trt)质谱检测结果;
图6为实施例4中刺五加苷E-Mpa-S-S-Mpa-[CDGRRGDC]-NH2反应液检测结果;
图7为实施例4中刺五加苷E-Mpa-S-S-Mpa-[CDGRRGDC]-NH2液相纯化结果;
图8为实施例4中刺五加苷E-Mpa-S-S-Mpa-[CDGRRGDC]-NH2质谱检测结果。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,下面结合具体的实施方式及说明书附图对本发明进行进一步详细说明。下述实施例中所使用的实验方法如无特殊说明均为常规方法,所用材料、试剂、方法和仪器,未经特殊说明,均为本领域常规材料、试剂、方法和仪器,本领域技术人员均可通过商业渠道获得。
在本发明中使用的缩写具有下面的含义:
RA Resin:混合树脂;
Fmoc:9-芴甲氧羰基;
Arg:精氨酸;
Asp:天冬氨酸;
Gly:甘氨酸;
Mpa:巯基丙酸;
Cys:半胱氨酸;
OtBu:叔丁基酯;
Trt:三苯甲基;
Pbf:2,2,4 ,6,7-五甲基二氢苯并呋喃-5-磺酰;
tBu:叔丁基;
DIC:N ,N '-二异丙基碳二亚胺;
HOBt:1-羟基苯并三唑;
TFA:三氟乙酸;
EDT:1 ,2-乙二硫醇;
DMF:N ,N-二甲基甲酰胺。
实施例1:靶向肽树脂的制备
S1:取10 g替代度为0.8 mmol/g 的RA Resin树脂为固相载体,加入反应柱中,再加入10 ml DMF溶胀1 h;加入150 ml 25%的哌啶/DMF(体积比)脱保护液,反应5 min后排液,再次加入脱保护液反应15 min,反应结束后,加入200ml DMF洗涤,共洗涤6次,取树脂用茚三酮检测为阳性;然后称取14.1 g Fmoc-Cys(Trt)-OH(3eq)氨基酸、3.3 g HOBT加入到150 ml DMF溶液中搅拌溶解,搅拌的同时加入3.7 ml DIC(3eq)缩合剂,获得氨基酸混合液;最后将上述氨基酸混合液倒入反应柱中,在20-30 ℃条件下反应2 h,反应结束后进行抽滤,加入200 ml DMF洗涤2次,获得Fmoc-Cys(Trt)-RA Resin,使用茚三酮检测上述树脂为阴性;
S2:以25%哌啶/DMF为脱保护液、DIC/HOBT为缩合剂,重复S1中脱保护和缩合的步骤,依次偶联氨基酸Fmoc-Asp(OtBu)-OH、Fmoc-Gly-OH、Fmoc-Arg(pbf)-OH、Fmoc-Arg(pbf)-OH、Fmoc-Gly-OH、Fmoc-Asp(OtBu)-OH、Fmoc-Cys(Trt)-OH,获得NH2-Cys(Trt)-Asp(OtBu)-Gly-Arg(pbf)-Arg(pbf)-Gly-Asp(OtBu)-Cys(Trt)-RA resin直链肽树脂;
S3:向S2中获得的直链肽树脂中加入碘/DMF溶液进行环化反应2 h,反应结束后加入抗坏血酸钠溶液洗涤2次,DMF溶液洗涤6次,获得NH2-[Cys-Asp(OtBu)-Arg(pbf)-Arg(pbf)-Gly-Asp(OtBu)-Cys]-RA resin;
S4:向S3中获得的物质中加入8.4 g Mpa(Trt)、3.3 g HOBT和150 ml DMF搅拌溶解,再加入3.7 ml DIC,将氨基酸混合液倒入反应柱中,20-30℃条件下反应2 h,反应结束后进行抽滤,加入200 ml DMF洗涤6次,最终获得28.5 g 靶向肽树脂(Mpa(Trt)-[Cys-Asp(OtBu)-Gly-Arg(pbf)-Arg(pbf)-Gly-Asp(OtBu)-Cys]-RA resin)。
实施例2:靶向肽的制备
本实施例取20 g 实施例1中获得的靶向肽树脂加入200 ml裂解液,其中1 g肽树脂对应10 ml裂解液,配比为TFA:EDT:H2O(95:2.5:2.5),20-30℃反应2 h后过滤,用适量三氟乙酸洗涤树脂,合并滤液,然后加入5倍体积的甲基叔丁醚中析出肽,过滤除去液体,滤饼用甲基叔丁基醚洗涤5次,甲基叔丁基醚每次用量约100 ml,将洗涤后的滤饼干燥,得到12.1 g靶向肽(Mpa-[Cys-Asp-Arg-Arg-Gly-Asp-Cys]-NH2);通过制备型高效液相使用乙腈和0.1%的三氟乙酸水溶液纯化,收集含有产物纯品的流份,冻干得4.7 g 靶向肽(Mpa-[Cys-Asp-Arg-Arg-Gly-Asp-Cys]-NH2),收率为87.03%,质谱检测结果如图2所示,理论分子量966.08,实测分子量966.4,质谱确认正确。
图1为实施例1-2中以RA Resin树脂为原材料制备靶向肽树脂,再以靶向肽树脂为原材料制备靶向肽的工艺流程图。
实施例3:刺五加苷E-Mpa(Trt)的制备
本实施例取5 g刺五加苷E(6.73mmol,1eq,MW742.72)溶解在50 ml DMF中,冷却至0℃,加入3.2 g EDCI(16.82mmol,2.5eq)搅拌溶解反应5 min,加入2.8 g Mpa(Trt)(8.07mmol,1.2eq)搅拌溶解,加入3.3 ml DIEA(20.19mmol,3eq)搅拌反应2h,取样HPLC检测,当Mpa(Trt)完全反应完,停止搅拌并将反应液加入300 ml 30%乙腈/水中稀释,通过制备型高效液相使用乙腈和0.1%的三氟乙酸水溶液纯化,收集含有产物纯品的流份,冻干,获得刺五加苷E-Mpa(Trt)。
经检测,本实施例获得1.2 g刺五加苷E-Mpa(Trt),收率为16.3%,液相色谱结果如图3-4所示,反应液检测结果41.768,纯化结果41.758,质谱检测结果如图5所示,理论分子量1091.16,实测分子量1092.7,质谱确认正确。
实施例4:刺五加苷E-靶向肽偶联物的制备
取1.17 g 实施例2中获得的Mpa-[Cys-Asp-Arg-Arg-Gly-Asp-Cys]-NH2(1.2eq)靶向肽,使用120 ml甲醇溶解,再加入1.08 g实施例3中获得的刺五加苷E-Mpa(Trt)(1eq)溶解,再滴加碘/MeOH(25 g/L)溶液,待反应溶液颜色变淡黄色,停止滴加,搅拌反应1h,然后将反应液加入到500 ml纯化水中,通过可断裂二硫键连接靶向肽和刺五加苷E-Mpa(Trt),初步获得刺五加苷E-靶向肽偶联物;然后再通过制备型高效液相,使用乙腈和0.1%的三氟乙酸水溶液纯化,收集含有产物纯品的流份,冻干,获得纯化后的刺五加苷E-靶向肽偶联物(刺五加苷E-Mpa-S-S-Mpa-[CDGRRGDC]-NH2)。
经检测,本实施例获得刺五加苷E-Mpa-S-S-Mpa-[CDGRRGDC]-NH2产物400 mg,收率为22.5%;液相色谱结果如图6-7所示,反应液检测结果为19.258,纯化结果为19.253,质谱检测结果如图8所示,其一理论分子量1795.91,实测分子量1795.9;其二理论分子量898.45,实测分子量898.5,质谱正确。
实施例5:刺五加苷E-靶向肽偶联物在制备抗肿瘤药物中的应用
一、急性毒性试验
1、目的:确认由刺五加苷E-靶向肽(JC-001-E001)与刺五加苷E进行毒性对比。
2、实验原理:医学上通常以半数致死量(LD50)来衡量;通过对实验动物进行动物静脉或腹腔注射试验材料或其浸提液来观察实验动物体重在1周内的变化、运动、呼吸状态以及死亡情况作为评价的指标,判定供试材料的急性毒性作用;刺五加苷E最大给药剂量45mg/kg,将刺五加苷E-靶向肽药物换算成刺五加苷E的给药剂量给药,按小鼠体重20 mg计算给药量,详见下表1:
表1
样品名称 | 20 mg小鼠给药量 |
刺五加苷E-靶向肽 | 229.7 ug |
刺五加苷E | 95 ug |
3、实验对象:小鼠。
4、实验器材和药品:蒸馏水,灭菌注射用水,注射器(1 ml),量筒(10 ml),小烧杯(50 ml、100 ml),刺五加苷E,刺五加苷E-靶向肽。
5、实验步骤:
(1)将称重后的健康、未做过其他实验的小鼠随机分为实验组和对照组,每组雌鼠各3只;
(2)将不同浓度的供试品溶液腹腔注射于实验组小鼠;
(3)记录药物注射后7天各组小鼠的体重,观察其各种生物学反应情况。
6、评价方法:
注射后的动物反应观察指标如表2所示:
表2 注射后的动物反应观察指标表
7、实验结果
供试品配制:
刺五加苷E:95 mg,用生理盐水配制成9.5 mg/ml;
刺五加苷E-靶向肽(JC-001-E001):229.7 mg,用生理盐水配制成22.97 mg/ml。
实验结果如表3所示:
表3 药物注射后动物反应观察表
结果证明:刺五加苷E-靶向肽的毒性明显小于刺五加苷E,230 mg/kg无死亡,初期小鼠受影响,体重增长缓慢,一周后恢复。
二、药效试验
1、组别:
实验组:药物分别为盐酸吉西他滨、刺五加苷E-靶向肽(JC-001-E001);
对照组:不加药物的溶媒。
2、本次试验所用细胞系:
PANC-1:人胰腺癌细胞(胰头癌原发肿瘤)。
3、实验步骤:
(1)雌性裸鼠(无胸腺)皮下注射肿瘤细胞,构建异种肿瘤移植模型;
(2)将已构建模型的小鼠随机分为试验组和对照组,每组雌鼠各8只,分别给药注射用盐酸吉西他滨 50 mg/kg、JC-001-E001 150mg/kg,对照组注射溶媒;
(3)于0、4、7、11、14、18、21天测各组雌鼠肿瘤体积。
试验结果如表4所示:
表4 小鼠肿瘤体积测量表
结果证明:通过与空白对照组数据进行比对,发现刺五加苷E-靶向肽能够明显抑制肿瘤细胞增长,药效与盐酸吉西他滨相当。
本发明说明书中未详细描述内容为本领域技术人员公知技术。虽然本发明已以较佳的实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可以做各种改动和修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (10)
1.一种刺五加苷E-靶向肽偶联物,其特征在于,所述刺五加苷E-靶向肽偶联物是由刺五加苷E通过连接键与靶向肽连接获得。
2.根据权利要求1所述的刺五加苷E-靶向肽偶联物,其特征在于,所述刺五加苷E的结构为:
。
3.根据权利要求1所述的刺五加苷E-靶向肽偶联物,其特征在于,所述连接键为可断裂的二硫键。
4.根据权利要求3所述的刺五加苷E-靶向肽偶联物,其特征在于,所述可断裂二硫键的结构为。
5.根据权利要求1所述的刺五加苷E-靶向肽偶联物,其特征在于,所述靶向肽为[Cys-Asp-Gly-Arg-Arg-Gly-Asp-Cys]-NH2。
6.根据权利要求5所述的刺五加苷E-靶向肽偶联物,其特征在于,所述靶向肽的缩写为[CDGRRGDC]-NH2。
7.根据权利要求5所述的刺五加苷E-靶向肽偶联物,所述靶向肽的结构为
。
8.根据权利要求1所述的刺五加苷E-靶向肽偶联物,其特征在于,所述刺五加苷E-靶向肽偶联物为刺五加苷E-Mpa-S-S-Mpa-[CDGRRGDC]-NH2。
9.根据权利要求1所述的刺五加苷E-靶向肽偶联物,其特征在于,所述刺五加苷E-靶向肽偶联物的结构为:
。
10.权利要求1-9任一项所述的刺五加苷E-靶向肽偶联物在制备抗肿瘤药物中的应用。
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