CN108752391A - 治疗胃癌的芳基钌配合物及其制备方法和用途 - Google Patents
治疗胃癌的芳基钌配合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种治疗胃癌的芳基钌配合物及其制备方法和用途,该芳基钌配合物具有式(1)所示结构:
Description
技术领域
本发明涉及金属配合物领域。更具体地说,本发明一种治疗胃癌的芳基钌配合物及其制备方法和用途。
背景技术
癌症已逐渐取代心血管等疾病成为威胁人类生命健康的头号杀手,在世界各国政府药物开发策略中,研发新型的高效、低毒、高选择性的抗癌药物也成为重要的战略目标。顺铂在抗肿瘤方面取得的巨大成功及后期各种改造铂类化合物的上市,吸引了大量的研究工作者对过渡金属配合物抗癌作用机制的研究。由于顺铂类化合物对人体毒副作用较大,包括肾毒性、耳毒性、神经毒性及胃肠道毒性,易造成病人的肾毒、恶心、厌食和神经障碍,易获得耐药性且水溶性小等,大量的改构类化合物,尤其是金属配合物被设计研究。在具有抗癌活性的过渡金属配合物中,钌和钌的配合物由于其低毒性,易吸收并在体内很快排泄,普遍认为将成为最有前途的抗癌药物之一。
高血压是持续血压过高的疾病,会引起中风、心脏病、血管瘤、肾衰竭等疾病,高血压是一种以动脉压升高为特征,可伴有心脏、血管、脑和肾脏等器官功能性或器质性改变的全身性疾病,它有原发性高血压和继发性高血压之分。高血压发病的原因很多,可分为遗传和环境两个方面。在未用抗高血压药情况下,收缩压≥139mmHg和/或舒张压≥89mmHg,按血压水平将高血压分为1,2,3级。收缩压≥140mmHg和舒张压<90mmHg单列为单纯性收缩期高血压。患者既往有高血压史,目前正在用抗高血压药,血压虽然低于140/90mmHg,亦应该诊断为高血压,而一般的高血压药是必须每天按时服用,这对高血压人群的出行造成了极大的不便。
因此,制备新的金属配合物药物,为高血压和癌症的治疗可以提供更多更好的选择,特别是具有长效作用的新型配合物药物,已成为目前的研究热点。
发明内容
本发明的一个目的是解决至少上述问题,并提供至少后面将说明的优点。
本发明的一个目的是提供一种治疗胃癌的芳基钌配合物及其制备方法和用途,该芳基钌配合物具有极强的抗肿瘤活性和血管紧张素转化酶(ACE)抑制活性得作用,具有治疗高血压、胃癌和肝癌的作用,是一种新型的制备方法简单,成本低廉的有效药物。
为了实现根据本发明的目的和其它优点,提供了一种芳基钌配合物,其化学名称为一氯化二氯一(1-(3-甲基吲哚基)-4-(1-苯基-5-二乙二醇双(2-丙炔基)醚基)苯基)一甲基异丙基苯合钌,其具有式(1)所示结构:
本发明还提供了芳基钌配合物的制备方法,其特征在于,包括:
S1、利用0.366g钌质量分数为37%的RuCl3·xH2O和3ml质量分数为95%的γ-松油烯,加热回流6h后,静置析出二氯化二氯-二-甲基异丙基苯合二钌,其结构为式(2);
S2、利用2-(4-碘苯基)-1-苯基苯并咪唑、3-甲基吲唑和二氯化二氯-二-甲基异丙基苯合二钌制备式(1)所示结构的芳基钌配合物;
优选得是,所述得芳基钌配合物的制备方法,所述S1中在加热回流之前,将RuCl3·xH2O和γ-松油烯需共同溶于15ml的二氯甲烷中。
优选得是,所述得芳基钌配合物的制备方法,所述S2中,向202mg的2-(4-碘苯基)-1-苯基苯并咪唑中加入20mL四氯化碳、1mg偶氮二异丁腈和177mgN-溴代丁二酰亚胺后,加热回流反应24h,再旋蒸除去溶剂后,得固体物,将所述固体物与135mg的3-甲基吲唑和31.5mg二氯化二氯-二-甲基异丙基苯合二钌共同溶于15ml二氯甲烷后,搅拌并加入0.2mLNaOH溶液、0.1mL乙二胺、3mg碳酸铯和6mL三乙胺,混合反应30min后,然后加入15mg四(三苯基膦)钯,1.9mgCuI和62mg二乙二醇双(2-丙炔基)醚,再次加热至80℃反应24h后,析出棕色固体,即得。
优选得是,所述得芳基钌配合物的制备方法,所述混合反应30min中一直通N2。
优选得是,所述得芳基钌配合物的制备方法,所述S2中在加热至80℃下反应24h后,析出棕色固体前,还需加入1mg氯化锌和1mL盐酸。
本发明还提供了芳基钌配合物的用途,用于制备治疗胃癌或肝癌的药物。
本发明还提供了芳基钌配合物的用途,用于制备治疗高血压的药物。
本发明至少包括以下有益效果:
1、本发明的芳基钌配合物可用于制备治疗癌症和高血压的药物,可制成注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂的形式使用。
2、本发明制备芳基钌配合物的制备方法简单,具有成本低的优势,且反应过程无需分离提纯过程,减少原料损耗,符合绿色化学的要求。
3、本发明的芳基钌配合物含有苯并咪唑和吲哚杂环,得到的钌配合物具相比于单一环有良好的生物活性,有大共轭体系,分子更稳定。
4、本发明的芳基钌配合物具有乙二醇结构,增强其疏水作用,有利于穿透癌细胞细胞膜,增强其抗肿瘤活性。
本发明的其它优点、目标和特征将部分通过下面的说明体现,部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
具体实施方式
下面结合实施例对本发明做进一步的详细说明,以令本领域技术人员参照说明书文字能够据以实施。
需要说明的是,下述实施例中所述实验方法,如无特殊说明,均为常规方法,所述试剂和材料,如无特殊说明,均可从商业途径获得。
芳基钌配合物,其化学名称为一氯化二氯一(1-(3-甲基吲哚基)-4-(1-苯基-5-二乙二醇双(2-丙炔基)醚基)苯基)一甲基异丙基苯合钌,其具有式(1)所示结构:
理化性质:为红色晶体,易溶于水和有机溶剂,其核磁共振氢谱数据为1H NMR(CDCl3溶剂):δ8.39(dd,J=7.5,1.4Hz,1H),8.10–8.02(m,4H),7.95(dd,J=7.5,1.4Hz,1H),7.90(dd,J=7.5,1.4Hz,1H),7.81–7.60(m,7H),7.41(s,1H),7.32(s,1H),5.33(d,1H,J=5.7Hz),4.91(d,1H,J=5.7Hz),4.90(d,1H,J=5.7Hz),5.01(s,2H),4.88(d,J=2.9Hz,2H),4.63–3.99(m,8H),3.98(d,1H,J=5.7Hz),3.01(s,1H),2.85(s,3H),2.75-2.66(m,1H),2.35(s,3H),1.23-1.17(m,6H)ppm。
芳基钌配合物的制备方法:
S1、将0.366g钌质量分数为37%的RuCl3·xH2O和3ml质量分数为95%的γ-松油溶于10ml无水乙醇中,加热回流6h后,静置析出二氯化二氯-二-甲基异丙基苯合二钌,其为具有式(2)结构的配合物;
S2、向202mg的2-(4-碘苯基)-1-苯基苯并咪唑中加入20mL四氯化碳、1mg偶氮二异丁腈和177mgN-溴代丁二酰亚胺后,加热回流反应24h,再旋蒸除去溶剂后,得固体物,将所述固体物与135mg的3-甲基吲唑和31.5mg二氯化二氯-二-甲基异丙基苯合二钌共同溶于15ml二氯甲烷后,搅拌并加入0.2mLNaOH溶液、0.1mL乙二胺、3mg碳酸铯和6mL三乙胺,通N2并混合反应30min后,然后加入15mg四(三苯基膦)钯,1.9mgCuI和62mg二乙二醇双(2-丙炔基)醚,再次加热至80℃反应24h后,加入1mg氯化锌和1mL盐酸,析出棕色固体,即为产物一氯化二氯一(1-(3-甲基吲哚基)-4-(1-苯基-5-二乙二醇双(2-丙炔基)醚基)苯基)一甲基异丙基苯合钌。
体外抗肿瘤活性实验:
采用MTT方法,进行体外细胞毒性测定。将得到得芳基钌配合物与胃癌SGC7901细胞株和肝癌BEL-7404细胞株分别作用时间72小时,结果如表1所示。
表1芳基钌配合物对肿瘤细胞株的半数有效浓度(IC50)
细胞株 | SGC-7901 | BEL-7404 |
IC50(umol/mL) | 0.51±0.45 | 0.38±0.29 |
从表1可以看出,本发明的芳基钌配合物经体外抗肿瘤实验表明,该钌配合物具有强的抗肿瘤活性,本发明为研究开发新的抗肿瘤药物提供了新的思路。
血管紧张素转化酶(ACE)抑制活性:
将底物马尿酸-组氨酸-亮氨酸溶解于0.1mol/L含0.2mol/LNaCl的硼酸盐缓冲液中(pH=8.3),配制成浓度为5.0mmol/L。取100μL上述马尿酸-组氨酸-亮氨酸溶液与100μL芳基钌配合物浓度为0.1g/L的水溶液混合,再加入150μL0.1U/mL血管紧张素转化酶溶液(溶于0.1mol/L含0.2mol/LNaCl底物的硼酸盐缓冲液中,pH=8.3),于37℃反应60min。加入250μL浓度为1.0mol/LHCl终止反应,然后加入乙酸乙酯1.5mL进行萃取,强烈振荡1min,在3000r/min下离心5min。取酯层0.5mL,加入1.0mL乙酸酐和2.0mL0.5%的二氨基联苯胺显色剂,40℃显色30min,在459nm处测定其吸光值。根据以下公式计算抑制率:
ACE抑制率=[(A-S)/(A-C)]×100%
其中A为以水代替抑制剂所测定的吸光值,S为添加抑制剂所测定的吸光值,C为加乙酸乙酯、乙酸酐和显色剂的参比吸光值。
表2芳基钌配合物的ACE抑制率(%)
抑制剂 | ACE抑制率(%) |
芳基钌配合物 | 91.2% |
从表2可知,本发明中芳基钌配合物具有很好的ACE抑制作用,为研究开发新的治疗高血压的药物提供了新的思路。
释放率实验:
将负载芳基钌的聚甲基丙烯酸甲酯放入100mLPBS溶液中,磁力搅拌.每隔一段时间,吸取缓释液,在紫外分光光度计下测定其吸光度;经测定后的液体倒人烧杯中继续搅拌,使其保持缓释液的体积不变;最后,根据吸光度计算质量浓度,进而得到药物随时间变化的释放量,表3为不同时间的药物释放率。
表3不同时间的药物释放率
时间 | 7d | 30d |
释放率(%) | 19.8 | 37.9 |
从表3可见,负载芳基钌的聚甲基丙烯酸甲酯具有缓慢释放的效果,可作为植入材料达到长效作用。说明本发明制备得芳基钌配合物不仅有极强的抗肿瘤活性和血管紧张素转化酶(ACE)抑制活性,而且通过有效得结合作用,含有芳基钌配合物的药物还可以维持良好得药效时间,呈现良好得药效。
尽管本发明的实施方案已公开如上,但其并不仅仅限于说明书和实施方式中所列运用,它完全可以被适用于各种适合本发明的领域,对于熟悉本领域的人员而言,可容易地实现另外的修改,因此在不背离权利要求及等同范围所限定的一般概念下,本发明并不限于特定的细节。
Claims (8)
1.芳基钌配合物,其特征在于,其化学名称为一氯化二氯一(1-(3-甲基吲哚基)-4-(1-苯基-5-二乙二醇双(2-丙炔基)醚基)苯基)一甲基异丙基苯合钌,其具有式(1)所示结构:
2.如权利要求1所述的芳基钌配合物的制备方法,其特征在于,包括:
S1、利用0.366g钌质量分数为37%的RuCl3·xH2O和3ml质量分数为95%的γ-松油烯,加热回流6h后,静置析出二氯化二氯-二-甲基异丙基苯合二钌,其结构为式(2);
S2、利用2-(4-碘苯基)-1-苯基苯并咪唑、3-甲基吲唑和二氯化二氯-二-甲基异丙基苯合二钌制备式(1)所示结构的芳基钌配合物;
3.如权利要求2所述的芳基钌配合物的制备方法,其特征在于,所述S1中在加热回流之前,将RuCl3·xH2O和γ-松油烯需共同溶于15ml的二氯甲烷中。
4.如权利要求2所述的芳基钌配合物的制备方法,其特征在于,所述S2中,向202mg的2-(4-碘苯基)-1-苯基苯并咪唑中加入20mL四氯化碳、1mg偶氮二异丁腈和177mgN-溴代丁二酰亚胺后,加热回流反应24h,再旋蒸除去溶剂后,得固体物,将所述固体物与135mg的3-甲基吲唑和31.5mg二氯化二氯-二-甲基异丙基苯合二钌共同溶于15ml二氯甲烷后,搅拌并加入0.2mLNaOH溶液、0.1mL乙二胺、3mg碳酸铯和6mL三乙胺,混合反应30min后,然后加入15mg四(三苯基膦)钯,1.9mgCuI和62mg二乙二醇双(2-丙炔基)醚,再次加热至80℃反应24h后,析出棕色固体,即得。
5.如权利要求4所述的芳基钌配合物的制备方法,其特征在于,所述混合反应30min中一直通N2。
6.如权利要求4所述的芳基钌配合物的制备方法,其特征在于,所述S2中在加热至80℃下反应24h后,析出棕色固体前,还需加入1mg氯化锌和1mL盐酸。
7.如权利要求1所述的芳基钌配合物的用途,其特征在于,用于制备治疗胃癌或肝癌的药物。
8.如权利要求1所述的芳基钌配合物的用途,其特征在于,用于制备治疗高血压的药物。
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