CN102653548A - 一种靶向性抗肿瘤的化合物及其制备方法和用途 - Google Patents
一种靶向性抗肿瘤的化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种靶向性抗肿瘤活性的化合物及其制备方法和用途,所述化合物的结构式为式I所示。体外或体内实验证明,本发明化合物具有良好的靶向抗肿瘤活性,能将其制备成预防或治疗肿瘤的各种临床制剂。
Description
技术领域
本发明涉及具有抗肿瘤活性的化合物及其制备方法;尤其涉及具有靶向性抗肿瘤活性的铂配合物及其制备方法,本发明还涉及该化合物在制备预防或治疗各类肿瘤药物中的用途,本发明属于铂配合物领域。
背景技术
当前临床抗癌药物大多具有高毒副作用,毒副作用产生的根本原因:(1)抗癌药物的非特异性,肿瘤与正常细胞均被杀伤,引起毒副作用;(2)抗癌高疗效,要求药物高剂量,导致高毒副作用。毒副作用制约了药物抗肿瘤能力的发挥,极大影响了肿瘤的治疗。临床用于治疗的药物较多,但大多数药物由于在肝脏分布少、对其他脏器毒副作用大或在体内不稳定等,其临床应用受到很大限制,因此,探索治疗肿瘤的有效方法是当今世界面临的一个重要课题。
而随着对肿瘤发治疗研究的不断深入,众多学者认为靶向性治疗是未来肿瘤治疗的主要方向。靶向制剂亦称靶向给药系统(Targeting drug deliverysystem,TDDS),是通过载体使药物选择性的浓集于病变部位的给药系统,病变部位常被形象的称为靶部位,它可以是靶组织、靶器官,也可以是靶细胞或细胞内的某靶点。由于靶向制剂可以提高药效、降低毒性,可以提高药品的安全性、有效性、可靠性和病人用药的顺应性,所以日益受到国内外医药界的广泛重视。
现有的具有抗肿瘤活性的铂配合物均不同程度的存在着抗肿瘤活性较低、靶向性差等缺陷,有待改进。
发明内容
本发明的目的克服现有技术的不足,提供一种抗肿瘤活性高、靶向性好的新的铂配合物化合物及其衍生产品,所述化合物或其衍生产品不仅能单独用于治疗癌症,而且可以与其它抗肿瘤药物合用。
本发明人经过深入的研究后发现,一种具有下述技术方案中的所列的特征的化合物可以达到上述目的。
一种能治疗癌症的化合物,其结构为式1所示:
其中R为小分子化合物;优选的,所述R是具有肝靶向作用、肿瘤靶向作用、肝和肿瘤双靶向作用的小分子;进一步优选的,所述的R是胆酸,更优选为熊脱氧胆酸。
本发明所要解决的另一个技术问题是提供一种制备所述化合物的方法,包括以下步骤:
(1)向双叔丁氧羰基保护的2-氨基-丙酸中加入二碳酸二叔丁酯,即形成双Boc保护的2-氨基-丙酸,纯化制备,备用;
(2)以乙二胺为起始原料,按1∶1的摩尔比例加入Boc酸酐,得到单Boc保护的乙二胺;再加入具有靶向作用的酸性小分子,所得化合物中间体依次经三氟乙酸脱保护、加入双Boc保护的2-氨基-丙酸、再经三氟乙酸脱保护,从而将双胺基引入到靶向分子,后者加入四氯二钾合铂,并以硫酸银和乙二酸处理该化合物,经沉淀,即得。
更具体的,一种制备上述式1化合物的方法,包括:
以乙二胺为起始原料,按1∶1的比例加入适量Boc酸酐,准备成单Boc保护的乙二胺;再加入适量所需要反应的具有靶向作用的酸性小分子,如5克肝靶向小分子熊脱氧胆酸,所得化合物中间体按步骤经三氟乙酸脱保护、加入双Boc保护的2-氨基-丙酸、再经三氟乙酸脱保护,从而将双胺基引入到靶向分子如熊脱氧胆酸上后者加入3克的四氯二钾合铂,并以适量的硫酸银和乙二酸处理该化合物,经沉淀制备得到所需要的具有靶向作用的铂类衍生物
体外或体内实验证明,本发明化合物具有良好的靶向抗肿瘤活性,能将其制备成预防或治疗肿瘤的各种临床制剂。
附图说明
图1本发明化合物的结构式。
图2本发明式1化合物的合成路线图。
具体实施方式
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
实施例1熊脱氧胆酸铂的合成
1)实验仪器与材料:
Fmoc保护的二氨基丙酸、二乙胺、熊脱氧胆酸、四氯合铂、草酸
2)实验过程:
以乙二胺为起始原料,按1∶1的比例加入适量Boc酸酐,准备成单Boc保护的乙二胺;再加入适量所需要反应的具有靶向作用的酸性小分子,如5克肝靶向小分子熊脱氧胆酸,所得化合物中间体按步骤经三氟乙酸脱保护、加入双Boc保护的2-氨基-丙酸、再经三氟乙酸脱保护,从而将双胺基引入到靶向分子如熊脱氧胆酸上后者加入3克的四氯二钾合铂,并以适量的硫酸银和乙二酸处理该化合物,合成的粗品经岛津LC-6AD制备型反相HPLC纯化制备得到所需要的具有靶向作用的铂类衍生物
具有靶向作用的铂类衍生物的全部化学合成反应式见图2。
合成的粗品使用岛津LC-6AD制备型反相HPLC纯化,使用HPLC检测纯度>95%。所得到的纯品使用质谱(MS,electrospray)鉴定,例如熊脱氧胆酸合铂的分子量为819,与理论值相符。
实施例2MTT法检测奥沙利铂、本发明熊脱氧胆酸铂分别对人肝癌细胞细胞株HepG2的抑制作用
将人肝癌细胞细胞株HepG2(购于中国科学院上海细胞库)悬浮于含10%热灭活胎牛血清的RPMI1640培养液中,以5000-10000个/孔的密度接种于96孔板。培养24小时后,分别加入奥沙利铂(购于Sigma公司,批号119K1228)、本发明熊脱氧胆酸铂(实施例1所合成),其中每种药物的浓度梯度均为90μmol/L、30μmol/L、10μmol/L、3.3μmol/L、1.1μmol/L、0.37μmol/L、0.12μmol/L、0μmol/L,每个浓度设3个复孔。继续培养24小时后每孔加入MTT(5mg/ml)20μl,4小时后吸去培养液,每孔加入DMSO 150μl,震荡10分钟使紫色结晶充分溶解。酶标仪570nm测定吸光度。
细胞抑制率按下式计算:
细胞抑制率=(空白对照组OD值-实验组OD值)/空白对照组OD值×100%
二、实验结果:
本发明熊脱氧胆酸铂和奥沙利铂对人肝癌细胞细胞株HepG2都有抑制作用,本发明熊脱氧胆酸铂的半数有效浓度(IC50)为15.03μmol/L,奥沙利铂的IC50为23.31μmol/L,本发明胆酸铂对人肝癌细胞细胞株HepG2的抑制作用要强于奥沙利铂对于人肝癌细胞细胞株HepG2的抑制作用。实验结果说明,本发明铂配合物对肿瘤细胞有显著的抑制作用,可以作为治疗癌症的药物。
Claims (8)
1.具有抗肿瘤活性的化合物,其特征在于:其结构式为式I所示:
式I
其中,R为小分子化合物。
2.根据权利要求1所述的化合物,其特征在于:所述R是具有靶向作用的小分子。
3.根据权利要求2所述的化合物,其特征在于:R是具有肝靶向作用、肿瘤靶向作用、肝和肿瘤双靶向作用的小分子。
4.根据权利要求1-4任何一项所述的化合物,其特征在于:所述的小分子是胆酸。
5.一种制备权利要求1所述的化合物的方法,包括以下步骤:
(1)向双叔丁氧羰基保护的2-氨基-丙酸中加入二碳酸二叔丁酯,即形成双Boc保护的2-氨基-丙酸,纯化制备,备用;
(2)以乙二胺为起始原料,按1∶1的摩尔比例加入Boc酸酐,得到单Boc保护的乙二胺;再加入具有靶向作用的酸性小分子,所得化合物中间体依次经三氟乙酸脱保护、加入双Boc保护的2-氨基-丙酸、再经三氟乙酸脱保护,从而将双胺基引入到靶向分子,后者加入四氯二钾合铂,并以硫酸银和乙二酸处理该化合物,经沉淀,即得。
6.一种治疗或预防癌症的药用组合物,其特征在于:由治疗或预防上有效量的权利要求1-5任何一项所述化合物和药学上可接受的载体或辅料组成。
7.权利要求1-6任何一项所述化合物在制备治疗癌症药物中的用途。
8.按照权利要求7的用途,其特征在于:所述癌症包括头颈部肿瘤、肺癌、结肠癌、直肠癌、胃癌、食管癌、乳腺癌、肝癌、白血病、膀胱癌或子宫颈癌。
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