CN103804472B - 一种紫杉烷类药物前体 - Google Patents
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Abstract
本发明公开了一种紫杉烷类药物前体,所述紫杉烷类药物前体为紫杉烷类化合物的C-2’位或C-7位羟基与水溶性靶向肽通过连接桥结合形成的偶联物,所述连接桥中包含酯键、碳酸酯键、脲键和二硫键中的至少一种。与紫杉烷类化合物相比,该前药具有极好的水溶性,溶解度达2mg/ml,解决了现有技术中只能使用有机溶剂及吐温80等不安全物质来溶解紫杉烷类化合物的问题;共价偶联的方式保证了该紫杉烷类药物前体在体外保存时具有较高的稳定性,而进入细胞后能够迅速释放紫杉烷类化合物而发挥药效;靶向肽能够将紫杉烷类化合物运送到特定的肿瘤细胞,降低对正常细胞的杀伤力,靶向肽在细胞内的降解产物为氨基酸,因此具有较高的生物相容性。
Description
技术领域
本发明涉及一种紫杉烷类药物前体,具体涉及一种紫杉烷类药物前体。
背景技术
紫杉烷类药物主要包括紫杉醇和多烯紫杉醇,是目前临床上最有效的抗肿瘤药物之一。紫杉醇(paclitaxel)是从太平洋红豆杉树皮中分离得到的一种四环二萜类化合物,分子式为C47H51O14N,分子量为853.9,不溶于水。1992年美国FDA批准上市,其作用机制是与细胞微管蛋白结合,促进微管蛋白聚合,以对抗解聚、阻断有丝***,从而抑制肿瘤生长,诱导肿瘤细胞凋亡。临床研究已经证实了紫杉醇在治疗多种实体肿瘤,包括乳腺癌、晚期卵巢癌、肺癌、脑部和颈部肿瘤以及急性白血病等方面,都有显著的作用。多烯紫杉醇(docetaxel)是从欧洲红豆杉提取到的非细胞毒性前体化合物10-脱酰基浆果赤霉素Ⅱ经半合成得到的,1998年获美国FDA批准上市。多烯紫杉醇的作用机理与紫杉醇相似,但抗肿瘤活性是紫杉醇的很多倍,对乳腺癌、非小细胞肺癌等癌症具有明显的治疗效果。
由于紫杉烷类药物的水溶性较低(约1~10μg/mL),因此临床上所使用的紫杉醇注射液和多烯紫杉醇注射液均需要分别使用表面活性剂聚氧乙烯蓖麻油(CremophorEL)和聚山梨醇80(吐温80)以及助溶剂乙醇来达到溶解药物的目的。
现有上市的紫杉醇注射剂(商品名为“泰素”),以聚氧乙烯蓖麻油(CremophorEL)∶乙醇=1∶1为溶剂,浓度为6mg/mL,临床应用时用生理盐水或右旋糖苷稀释5~20倍,一次静注3h,用药剂量为135mg/m2。聚氧乙烯蓖麻油已被证明会导致严重的过敏反应、神经毒性、肾毒性和低血压等。此外,聚氧乙烯蓖麻油还可在血液中形成微小颗粒包裹紫杉醇分子,影响药物分子向组织间扩散,降低抗肿瘤效果。
同样地,目前上市的多烯紫杉醇注射剂(商品名为“泰索帝”),采用吐温80与无水乙醇的复合溶媒制备而成,但吐温80的使用易引发病人严重的过敏反应,在化疗前,病人往往需预先服用或注射抗过敏药物(皮质类激素和H2受体拮抗剂),在输液过程中,还需连接微孔过滤器以防止药物在稀释过程中产生的结晶微粒进入病人血液循环***,这些均给临床应用带来极大的风险和不便。
基于上述原因,近年来人们开发了一系列的紫杉烷类药物的衍生物或者新型制剂来克服其水溶性问题。如通过化学偶联法,在紫杉醇母核的C-2’位或者C-7位的羟基引入水溶性基团而得到水溶性较大的紫杉醇衍生物。此外,把紫杉醇导入到脂质体、胶束或者制成乳剂的方法也可以达到增溶的效果。但是目前的这些技术往往只能提高紫杉烷类药物的水溶性,药物的靶向性问题并不能得到有效的改善。通过偶联一些具备肿瘤细胞靶向性的水溶性小分子多肽来制备紫杉烷类药物的前药,不仅能够解决溶解性问题,而且能够赋予药物在体内对肿瘤细胞的靶向能力,具有非常良好的市场前景与临床应用价值。
发明内容
本发明提供了一种紫杉烷类药物前体,该紫杉烷类药物前体在紫杉烷类化合物分子中共价偶联小分子靶向肽,大大提高了药物的靶向性和水溶性。
一种紫杉烷类药物前体,所述紫杉烷类药物前体为紫杉烷类化合物的C-2’位或C-7位羟基与水溶性靶向肽通过连接桥结合形成的偶联物,所述连接桥中包含酯键、碳酸酯键、脲键和二硫键中的至少一种。
通过在C-2’位或C-7位羟基上连接水溶性靶向肽,使紫杉烷类化合物的水溶性和肿瘤靶向性大大提高,使用时只需用水溶解即可,不再需要有机助溶剂,大大降低了药物使用过程中产生的毒性。
作为优选,所述紫杉烷类药物前体为紫杉烷类化合物的C-2’位羟基与水溶性靶向肽通过连接桥结合形成的偶联物。与C-2’位相比,C-7位处的化学合成难度较大。
作为优选,所述共价键为酯键、碳酸酯键、脲键、二硫键中的至少一种。
作为优选,所述靶向肽为肝癌细胞靶向肽。作为进一步优选,所述肝癌细胞靶向肽的氨基酸序列为:SFSIIHTPILPL。偶联可发生在该氨基酸序列的N端,也可发生在C端。作为优选,在发生偶联的一端,所述靶向肽上还带有连接肽,连接肽优选由2~4个甘氨酸组成,连接肽可避免紫杉烷类化合物影响靶向肽与肿瘤细胞的结合。
本发明中,所述紫杉烷类化合物为紫杉醇或多烯紫杉醇。
作为优选,所述紫杉烷类药物前体的结构式如式(Ⅰ)或式(Ⅱ)所示:
或者,如式(Ⅲ)或式(Ⅳ)所示:
其中,X为水溶性氨基酸,水溶性氨基酸的个数n为0~5。
为进一步提高所述紫杉烷类药物前体的水溶性,在靶向肽与紫杉烷类化合物偶联的一端(N端或C端)引入水溶性氨基酸,作为优选,水溶性氨基酸的个数n为2~5。所述水溶性氨基酸优选为精氨酸、赖氨酸、天冬氨酸、或谷氨酸,更优选为精氨酸或赖氨酸。
并且,利用半胱氨酸的巯基与紫杉烷类化合物进行偶联,巯基不仅易于反应,制备条件温和,还能提供多个偶联位点,偶联可发生在靶向肽的C端(亮氨酸的羧基)、N端(半胱氨酸的氨基)或半胱氨酸的巯基,在巯基上发生偶联时,还能形成稳定的二硫键,保证所述紫杉烷类药物前体结构稳定。
式(Ⅰ)或式(Ⅱ)在紫杉醇或多烯紫杉醇C-2’位上的羟基与靶向肽的半胱氨酸巯基之间引入碳酸酯键和二硫键;式(Ⅲ)或式(Ⅳ)则在紫杉醇或多烯紫杉醇C-2’位上的羟基与靶向肽的半胱氨酸巯基之间引入酯键和脲键。
作为进一步优选,所述紫杉烷类药物前体的结构式如式(Ⅴ)或式(Ⅵ)所示:
或者,如式(Ⅶ)或式(Ⅷ)所示:
式(Ⅴ)、(Ⅵ)、(Ⅶ)、(Ⅷ)中,甘氨酸(Gm)作为连接肽,甘氨酸的个数m优选为2~4,更优选为2。
所述紫杉烷类药物前体的制备方法包括:先在紫杉烷类化合物的C-2’位或C-7位羟基引入相应基团,合成紫杉烷类化合物的衍生物;然后将该衍生物与靶向肽混合,室温搅拌下进行偶联,获得所述紫杉烷类药物前体。
本发明还提供了所述紫杉烷类药物前体在制备抗肝癌药物中的应用。所述紫杉烷类药物前体经冻干后可以单独使用,也可以加入不同的赋形剂后加工成任何一种剂型,包括片剂、丸剂、胶囊剂、颗粒剂、口服液及用于静脉注射的水针剂或粉针剂。
与现有技术相比,本发明的有益效果体现在:
(1)与紫杉烷类化合物相比,本发明的紫杉烷类药物前体具有极好的水溶性,溶解度可达1.8mg/ml,解决了现有技术中只能使用有机溶剂及吐温80等不安全物质来溶解紫杉烷类化合物的问题;获得的紫杉烷类药物前体,制备成本低,稳定性高,安全性好,符合临床用药的要求,符合大规模生产的要求,具备良好的市场前景;
(2)靶向肽能够将紫杉烷类化合物运送到特定的肿瘤细胞,降低对正常细胞的杀伤力,靶向肽在细胞内的降解产物为氨基酸,因此具有较高的生物相容性。
附图说明
图1为实施例1中SP94-紫杉醇的合成路线图;
图2为图1中紫杉醇C’-2位衍生物的1H-NMR核磁图谱;
图3为图1中紫杉醇马来酰亚胺衍生物的1H-NMR核磁图谱;
图4为图1中SP94-紫杉醇的ESI质谱图;
图5为实施例2中SP94-多烯紫杉醇的合成路线图;
图6为图5中多烯紫杉醇衍生物的1H-NMR核磁图谱;
图7为SP94-多烯紫杉醇的ESI质谱图;
图8为SP94-紫杉醇与紫杉醇的体外抗肿瘤活性MTT测定结果图。
具体实施方式
实施例1紫杉醇通过酯键与肝癌靶向肽SP94偶联前药的制备
利用紫杉醇与肝癌靶向肽SP94偶联制备紫杉烷类药物前体,其合成路线如图1所示,包括以下步骤:
(1)紫杉醇C’-2位衍生物2的合成
在干燥的反应瓶中加入紫杉醇1(300mg,0.35mmol),用无水吡啶2ml溶解;向反应液中加入丁二酸酐(105mg,1.05mmol)及4-二甲氨基吡啶DMAP(4.3mg,0.035mmol)。室温搅拌2小时,TLC显示反应结束后终止反应,减压旋蒸除去吡啶;正相硅胶柱(二氯甲烷:甲醇=20:1)分离得到白色固体,产物收率为91%。利用1H-NMR(图2)确认目标产物2。
(2)紫杉醇马来酰亚胺衍生物3的合成
取化合物2(100mg,0.105mmol)溶于2ml无水DMF,往反应液中加入N-(2-氨基乙基)马来酰亚胺三氟乙酸盐(28mg,0.11mmol)、HOBt(15.6mg,0.115mmol)、HBTU(43.7mg,0.115mmol)和DIPEA(69.3mg,0.42mmol);室温搅拌4小时,TLC检测显示反应结束后终止反应,减压旋蒸除去DMF;固体溶于二氯甲烷后依次用饱和碳酸氢钠水溶液、5%柠檬酸及饱和食盐水水洗,无水硫酸钠干燥后减压旋蒸除去二氯甲烷;正相硅胶柱(二氯甲烷:甲醇=20:1)分离得到固体,产物收率为80%。利用1H-NMR(图3)确认目标产物3。
(4)SP94多肽偶联紫杉醇的前药合成及高效液相分离
取化合物3(10mg,8.4μmol)及SP94多肽(13mg,8.4μmol)(氨基酸序列如SEQIDNo.1所示)溶于DMF和Tris缓冲液(pH8.0),室温搅拌2小时,TLC显示反应结束后终止反应,反应液用高效液相(CH3CN:H2O=10:90(0min)→90:10(30min))分离得到18mg白色固体。产物收率为78%,目标产物4的ESI质谱见如图4。目标产物4的水溶性约为2mg/ml。
实施例2多烯紫杉醇通过碳酸酯键及二硫键与肝癌靶向多肽SP94偶联前药的制备
利用多烯紫杉醇与肝癌靶向肽SP94偶联制备紫杉烷类药物前体,其合成路线如图5所示,包括以下步骤:
(1)化合物9的合成
根据文献(E.A.Dubikovskayaetal.,Overcomingmultidrugresistanceofsmall-moleculetherapeuticsthroughconjugationwithreleasableoctaargininetransporters,ProceedingsoftheNationalAcademyofSciences,2008,105(34):12128-12133.),合成化合物9。
(2)多烯紫杉醇衍生物11的合成
取多烯紫杉醇10(40mg,49.5μmol)溶于2ml无水DCM,往反应液中加入化合物9(22mg,59.4μmol)、DMAP(7.3mg,59.4μmol);室温搅拌4小时,TLC显示反应结束后终止反应;再往反应液中加入DCM50ml,然后依次用饱和碳酸氢钠水溶液、饱和食盐水水洗,无水硫酸钠干燥后减压旋蒸除去二氯甲烷;正相硅胶柱(二氯甲烷:甲醇=20:1)分离得到固体60mg,产物收率为85%。利用1H-NMR(图6)确认目标产物11。
(3)SP94多肽偶联多烯紫杉醇的前药合成及高效液相分离
取化合物11(10mg,9.7μmol)及SP94多肽(15mg,9.7μmol)溶于2mlDMF和Tris缓冲液(pH8.0),室温搅拌4小时,TLC显示反应结束后终止反应,反应液用高效液相分离得到15mg白色固体。产物收率为60%,目标产物12的ESI质谱见图7。目标产物12的水溶性约为1.8mg/ml。
实施例3抗肿瘤药效评价
为评价实施例1获得的目标产物4(SP94-PTX)对肿瘤细胞的杀伤能力,以肝癌细胞系7721为例,采用MTT法进行了药效评价,并以紫杉醇作为对照。SP94-PTX4对肝癌7721的细胞毒性结果见图8。由图8可见,溶于水的SP94-PTX与细胞共培养72小时后,其体外抗肝癌效果显示,SP94-PTX具有与PTX相同的细胞毒性。
Claims (3)
1.一种紫杉烷类药物前体,其特征在于,所述的紫杉烷类药物前体的结构式如式(Ⅰ)或式(Ⅱ)所示:
其中,X为水溶性氨基酸,水溶性氨基酸的个数n为2~5;
或者如式(Ⅲ)或式(Ⅳ)所示:
其中,X为水溶性氨基酸,水溶性氨基酸的个数n为2~5。
2.如权利要求1所述的紫杉烷类药物前体,其特征在于,所述水溶性氨基酸为精氨酸、赖氨酸、天冬氨酸或谷氨酸。
3.如权利要求2所述的紫杉烷类药物前体,其特征在于,所述水溶性氨基酸为精氨酸或赖氨酸。
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