CN109970812A - 一种多吡啶钌配合物及其制备方法和应用 - Google Patents
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Abstract
本发明公开了一种多吡啶钌配合物,该配合物具有如下式I所述的结构:其中,X‑表示平衡电荷的一价阴离子。该配合物具有高光毒性、低暗毒性,可较好的用于制备光活化抗肿瘤药物中,能克服传统化疗药物毒副作用大的缺陷。本发明还公开了该多吡啶钌配合物的制备方法和应用。
Description
技术领域
本发明涉及抗肿瘤药物领域,特别涉及光活化抗肿瘤药物领域。更具体地,涉及一种多吡啶钌配合物及其制备方法和应用。
背景技术
虽然以顺铂为代表的铂类化疗药物在临床上广泛使用,但其毒副作用大以及肿瘤细胞耐药性等缺点,限制了其临床治疗效果。因此积极寻求新型非铂类抗肿瘤药物以及新型肿瘤治疗方式,是目前药物研发的一个重要方向。
光活化化学疗法(photoactivated chemotherapy,PACT)是一种新型的肿瘤治疗方法,即通过设计合成黑暗条件下没有活性的前药分子,该前药在光照条件下能转变成活性药物分子。利用光照在时间和空间上的可控性,将药物活性限域在肿瘤组织。与传统化疗相比,具有选择性好,毒副作用低等优点。与传统光动力疗法(photodynamic therapy,PDT)相比,光活化化学疗法在抗肿瘤机制上不依赖氧气,因此对通常处于乏氧微环境的大型实体瘤亦有较好的杀灭活性,故拥有更广阔的应用前景。
除了铂类药物以外,金属钌配合物的抗肿瘤活性也引起了广泛关注。金属钌与铁同族,通常认为钌配合物拥有低的毒副作用,因此钌配合物也被认为是一类很有前途的抗肿瘤药物。目前为止,已有三种基于钌配合物的化疗药物(NAMI–A,KP1019 and NKP1339)进入了临床研究。但目前报道的钌光活化化疗药物存在光毒性较小或者暗毒性较大等缺点。
发明内容
基于以上事实,本发明的第一个目的在于提供一种多吡啶钌配合物,该配合物具有高光毒性、低暗毒性,可用于制备光活化抗肿瘤药物中,能克服传统化疗药物毒副作用大的缺陷。
本发明的第二个目的在于提供一种多吡啶钌配合物的制备方法。
本发明的第三个目的在于提供一种多吡啶钌配合物在制备抗肿瘤药物中的应用。
为达到上述第一个目的,本发明采用下述技术方案:
一种多吡啶钌配合物,具有如下式I所述的结构:
其中,X-表示平衡电荷的一价阴离子。
可选地,所述一价阴离子选自Cl-、(PF6)-、(ClO4)-中的一种。
为达到上述第二个目的,本发明采用下述技术方案:
一种多吡啶钌配合物的制备方法,包括如下步骤:
1)将4,5-二氟-1,2-苯二胺与1,10-邻二氮杂菲-5,6-二酮在溶剂中回流、重结晶,得11,12-二氟代二吡啶并[3,2-a:2’,3’-c]吩嗪;
2)将制备得到的11,12-二氟代二吡啶并[3,2-a:2’,3’-c]吩嗪与二氯苯基钌(II)二聚体在溶剂中搅拌至溶液澄清,经去除溶剂后,将所得物溶解于水中;
3)向步骤2)所得物中加入吡啶,于惰性气氛下加热回流反应,待反应完全后,提纯、净化,得所述多吡啶钌配合物。
可选地,步骤1)中,所述溶剂为乙醇。
可选地,步骤2)中,所述溶剂为甲醇。
可选地该制备方法还包括:在步骤3)提纯后,向得到的物质中加入一价阴离子的水溶性盐,得难溶于水的沉淀的步骤。
可选地,所述一价阴离子的水溶性盐选自NH4PF6或NaClO4。此时,制备得到的配合物中阴离子分别为(PF6)-或(ClO4)-。
可选地,步骤3)中,所述提纯的条件为:在硅胶层析柱上用乙腈:饱和氯化钾水溶液=10:1的洗脱剂洗脱提纯,再利用氯化钾在乙醇中的低溶解度去除过柱产物中多余的氯化钾。
为达到上述第三个目的,本发明还提供上述第一个目的提供的多吡啶钌配合物在制备抗肿瘤药物中的应用。
可选地,所述抗肿瘤药物属于光活化化疗药物。
可选地,将所述多吡啶钌配合物用于制备治疗顺铂耐药性抗肿瘤药物。
可选地,将所述多吡啶钌配合物用于制备在乏氧环境中作用的抗肿瘤药物。
可选地,所述肿瘤包括宫颈癌、卵巢癌、人宫颈癌细胞株、人卵巢癌细胞株和人卵巢癌细胞株顺铂耐药细胞株中的一种或几种。
本发明的有益效果如下:
根据本发明的一个目的,本发明中提供的多吡啶钌配合物的结构中首次将氟代修饰引入[Ru(dppz)(py)4]2+体系中的dppz大环平面配体,使得具备有该特定结构的配合物具有高光毒性,低暗毒性,可用于制备光活化抗肿瘤药物中,对顺铂耐药系癌细胞具有较好的杀伤效果且在乏氧条件下保持抗癌活性。根据本发明的又一个目的,本发明中提供的多吡啶钌配合物在制备抗肿瘤药物中的应用中,因为具有该多吡啶钌配合物,故该应用具有如前所述的配合物能带来的效果。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1示出实施例4中Annexin V-FITC/PI染色的激光扫描共聚焦显微镜结果。
具体实施方式
为了更清楚地说明本发明,下面结合优选实施例和附图对本发明做进一步的说明。附图中相似的部件以相同的附图标记进行表示。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
实施例1
多吡啶钌配合物的制备方法,包括如下步骤:
将210mg(1mmol)4,5-二氟-1,2-苯二胺与126mg(1mmol)1,10-邻二氮杂菲-5,6-二酮在乙醇中回流三小时并在乙醇中重结晶制得11,12-二氟代二吡啶并[3,2-a:2’,3’-c]吩嗪。再将90mg(0.3mmol)11,12-二氟代二吡啶并[3,2-a:2’,3’-c]吩嗪与75mg(0.15mmol)二氯苯基钌(II)二聚体在40mL甲醇中搅拌过夜至形成澄清红色液体,再将溶剂去除,并重新溶解于40mL水中。加入1mL过量吡啶,氮气除气30分钟,加热回流2小时并接通氮气冷却。产物在硅胶层析柱上用乙腈:饱和氯化钾水溶液=10:1的洗脱剂洗脱提纯,再利用氯化钾在乙醇中的低溶解度去除过柱产物中多余的氯化钾。再将得到产物用丙酮,乙醚及正己烷清洗,得到纯的多吡啶钌配合物,其结构式如下式所示,
制备得到的该多吡啶钌配合物核磁数据为:1H NMR(400 MHz,Deuterium Oxide)δ9.16(d,J=8.3Hz,2H),9.08(d,J=5.6Hz,2H),8.55(d,J=5.8Hz,4H),8.05(t,J=7.8Hz,2H),8.02–7.94(m,2H),7.90(d,J=5.8Hz,4H),7.71(t,J=7.6Hz,4H),7.53(t,J=6.8Hz,4H),7.10(t,J=6.8Hz,4H).高分辨质谱得到阳离子的离子峰:HR ESI–MS:[C38H28F2N8Ru]2+,理论值:368.07238,实测值:368.07230
实施例2
重复实施例1,区别在于,在提纯完毕后,加入入NH4PF6或NaClO4,通过离子交换得到一价阴离子为(PF6)-或(ClO4)-具有式I所述结构的多吡啶钌配合物。
实施例3
所制备的配合物的抗肿瘤活性实验及结果。
细胞及培养条件:HeLa(人宫颈癌细胞株),SKOV-3(人卵巢癌细胞株),SKOV-3-ddp(人卵巢癌细胞株顺铂耐药细胞株),由中国医学科学院肿瘤医院提供。细胞用DMEM培养基培养,附加10%胎牛血清和100单位的青霉素与链霉素。
细胞毒性测试:
对于所述配合物的细胞毒性用经典MTT法测定。将细胞以5000-10000细胞/孔的密度种于96孔板上,在37摄氏度,5%二氧化碳的环境中培养24小时后,再分别加以含有不同浓度梯度的实施例1制备得到的配合物培养4小时,以(470nm,22.5mW/cm2)的光强光照20分钟,再继续培养20小时。添加5毫克/毫升的MTT(噻唑蓝溴化四唑)并继续培养4小时后,以甲醇:二甲基亚砜=1:1溶解,并于酶标仪上检测570nm处的吸收值。乏氧环境为3%氧气,5%二氧化碳的环境。实验同时设定暗对照组及空白组。实验结果如下表1所示。
表1配合物的抗肿瘤活性IC50值与顺铂比较
由表1数据可以看出,本发明提供的配合物具有良好的抗肿瘤活性和较高的光暗毒性比值,并且对顺铂耐药细胞在470nm光照条件下也具有一定的抑制活性,在乏氧环境下保持了细胞杀伤能力。
实施例4
Annexin V-FITC/PI染色用来鉴别药物抗癌作用中的引起细胞死亡的机制。Annexin V-FITC能够使早期凋亡细胞染色为绿色,而PI能够使晚期凋亡和坏死细胞染色为红色。SKOV-3细胞与10μM的实施例1制备得到的配合物共培养4小时后光照(470nm,22.5mW/cm2,20分钟)或不光照,再继续培养6小时,用商业Annexin V-FITC/PI试剂盒染色,可以观察得配合物光照能引发细胞以凋亡为主的死亡机制,而不光照条件下无明显的毒性,结果如图1所示。
显然,本发明的上述实施例仅仅是为清楚地说明本发明所作的举例,而并非是对本发明的实施方式的限定,对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动,这里无法对所有的实施方式予以穷举,凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。
Claims (10)
1.一种多吡啶钌配合物,其特征在于,具有如下式I所述的结构:
其中,X-表示平衡电荷的一价阴离子。
2.根据权利要求1所述的多吡啶钌配合物,其特征在于,所述一价阴离子选自Cl-、(PF6)-、(ClO4)-中的一种。
3.如权利要求1或2所述的多吡啶钌配合物的制备方法,其特征在于,包括如下步骤:
1)将4,5-二氟-1,2-苯二胺与1,10-邻二氮杂菲-5,6-二酮在溶剂中回流、重结晶,得11,12-二氟代二吡啶并[3,2-a:2’,3’-c]吩嗪;
2)将制备得到的11,12-二氟代二吡啶并[3,2-a:2’,3’-c]吩嗪与二氯苯基钌(II)二聚体在溶剂中搅拌至溶液澄清,经去除溶剂后,将所得物溶解于水中;
3)向步骤2)所得物中加入吡啶,于惰性气氛下加热回流反应,待反应完全后,提纯、净化,得所述多吡啶钌配合物。
4.根据权利要求3所述的制备方法,其特征在于,步骤1)中,所述溶剂为乙醇;优选地,步骤2)中,所述溶剂为甲醇。
5.根据权利要求3所述的制备方法,其特征在于,该制备方法还包括:在步骤3)提纯后,向得到的物质中加入一价阴离子的水溶性盐,得难溶于水的沉淀的步骤;优选地,所述一价阴离子的水溶性盐选自NH4PF6或NaClO4。
6.根据权利要求3所述的制备方法,其特征在于,步骤3)中,所述提纯的条件为:在硅胶层析柱上用乙腈:饱和氯化钾水溶液=10:1的洗脱剂洗脱提纯,再利用氯化钾在乙醇中的低溶解度去除过柱产物中多余的氯化钾。
7.如权利要求1或2所述的多吡啶钌配合物在制备抗肿瘤药物中的应用。
8.根据权利要求4所述的应用,其特征在于,所述抗肿瘤药物属于光活化化疗药物。
9.根据权利要求7或8所述的应用,其特征在于,将所述多吡啶钌配合物用于制备治疗顺铂耐药性抗肿瘤药物;或,
将所述多吡啶钌配合物用于制备在乏氧环境中作用的抗肿瘤药物。
10.根据权利要求7或8所述的应用,其特征在于,所述肿瘤包括宫颈癌、卵巢癌、人宫颈癌细胞株、人卵巢癌细胞株和人卵巢癌细胞株顺铂耐药细胞株中的一种或几种。
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