CN108794542A - 具有抗肿瘤活性的芳基钌配合及其制备方法和应用 - Google Patents
具有抗肿瘤活性的芳基钌配合及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种具有抗肿瘤活性的芳基钌配合物,其结构式为式(I):
Description
技术领域
本发明涉及金属配合物的技术领域。更具体地说,本发明涉及具有抗肿瘤活性的芳基钌配合物及其制备方法和应用。
背景技术
恶性肿瘤具有高致死率,是目前危害人类健康的最主要疾病之一,迄今为止尚缺乏有效的治疗措施。临床应用的抗肿瘤药物多数属于核苷类药物,这些药物存在着抗肿瘤谱的相似性,有很强的毒副作用。另一方面,某些肿瘤细胞株对临床应用的药物容易产生抗药性,肿瘤细胞株也容易发生变异,因此研制能克服抗药性或具有广谱活性的抗肿瘤药物受到关注。金属配合物的抗肿瘤谱及其抗肿瘤作用机制与核苷类药物有所不同,得到了广大科研工作者的广泛关注。但是,目前运用于临床化疗或辅助的数十种抗肿瘤药物,仅对部分肿瘤的治疗具有较好的治愈效果。因此,制备新的金属配合物抗肿瘤药物,为肿瘤疾病的治疗可以提供更多更好的选择,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。
本发明还有一个目的是提供一种具有抗肿瘤活性的芳基钌配合物及其制备方法和应用,本发明提供的钌配合物具有较强的抗肿瘤和ACE抑制活性,并且制备方法简单、成本低、原料损耗少。
为了实现根据本发明的这些目的和其它优点,提供了一种具有抗肿瘤活性的芳基钌配合物,其特征在于,其结构式为式(I):
本发明还提供了一种所述的具有抗肿瘤活性的芳基钌配合物的制备方法,其包括以下步骤:
步骤一、利用RuCl3·xH2O和γ-松油烯制备式(II)结构的配合物;
步骤二、利用(2S,3R)-3,4-二氢-3-异丙基-2-苯基-2H-嘧啶并[2,1-b]苯并噻唑、式(II)结构的配合物以及(5-巯基-1,3,4-噻二唑-2-基硫代)乙酸,制得式(I)结构的钌配合物;
优选的是,所述的具有抗肿瘤活性的芳基钌配合物的制备方法,步骤一具体为:将含钌重量百分数为37%的RuCl3·xH2O和体积分数为95%的γ-松油烯溶于10mL无水乙醇中,加热回流,搅拌6小时后静置析出,得到式(II)结构的配合物。
优选的是,所述的具有抗肿瘤活性的芳基钌配合物的制备方法,步骤二具体为:将(2S,3R)-3,4-二氢-3-异丙基-2-苯基-2H-嘧啶并[2,1-b]苯并噻唑溶于二氯甲烷中,加热至42℃,边搅拌边向反应液中逐滴加入液溴,反应24h后停止加热,通入氮气将液溴和二氯甲烷鼓出,随后向反应液中依次加入(5-巯基-1,3,4-噻二唑-2-基硫代)乙酸、式(II)结构的配合物、乙腈,、碳酸铯和三乙胺,加热至70℃,反应12小时后,加入氯化锌和盐酸,析出棕色固体,即为式(I)结构的芳基钌配合物。
本发明还提供了一种所述的具有抗肿瘤活性的芳基钌配合物的应用,用于制备治疗肝癌和胃癌的药物。
优选的是,所述的具有抗肿瘤活性的芳基钌配合物的应用,用于制备治疗高血压的药物。
优选的是,所述的具有抗肿瘤活性的芳基钌配合物的应用,用于制备重症肌无力的药物。
一种植入材料,所述植入材料上修饰有芳基钌配合物。
优选的是,所述的植入材料的制备方法,包括以下步骤:
S1、将3mg多肽分子加入至5mL水中,超声振荡后,加入0.5mg分子量为(S)-缩水甘油,超声振荡5min后,加入1~10mg芳基钌配合物,超声振荡5min,得到溶液一;
S2、取植入材料浸泡于溶液一中,取出后烘干,之后将剩余的溶液一滴于植入材料的表面,然后置于60℃下烘干,得到表面修饰有1mg的芳基钌配合物的植入材料。
优选的是,所述的植入材料的制备方法,所述植入材料为聚丙烯。
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、本发明用一壶法制备芳基钌配合物,制备方法简单,具有成本低的优势,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噻唑和噻二唑杂环,相比于单一单杂环或单一稠杂环,得到的钌配合物具有良好的生物活性,抗肿瘤活性更高,并且具有ACE抑制活性,脂肪链结构增强疏水作用,有利于穿透癌细胞细胞膜,进一步提高抗肿瘤活性;而且具有大共轭体系,分子更稳定。
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。
<实施例>
芳基钌配合物的名称为化学名称为一氯化二氯一(1-(3,4-二氢-3-异丙基-2H-嘧啶并
[2,1-b]苯并噻唑)-4-((5-巯基-1,3,4-噻二唑-2-基硫代)乙酸)一甲基异丙基苯合钌,其中钌的化合价为二价;
结构式:
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):δ7.92(dd,J=7.4,1.5Hz,1H),7.71(d,J=7.5Hz,2H),7.62(d,J=7.5Hz,2H),7.51–6.45(m,3H),5.59(d,1H,J=5.7Hz),5.53(d,1H,J=5.7Hz),5.36(d,J=7.9Hz,1H),4.96(d,1H,J=5.7Hz),4.25(s,2H),4.09(d,1H,J=5.7Hz),3.96(dd,J=7.5,1.6Hz,1H),3.89(dd,J=7.5,1.4Hz,1H),2.70-2.59(m,1H),2.65(s,1H),2.10(s,3H),1.79–1.66(m,1H),1.22-1.11(m,6H),1.08(d,J=6.4Hz,6H).ppm。
制备方法:
将0.366g钌重量含量37%的RuCl3·xH2O和3mL纯度体积分数为95%的γ-松油烯溶于10mL无水乙醇,加热回流搅拌6小时。静置析出得到二氯化二氯-二-甲基异丙基苯合二钌;如式(II)所示
一壶法制备芳基钌配合物:称取305mg的(2S,3R)-3,4-二氢-3-异丙基-2-苯基-2H-嘧啶并[2,1-b]苯并噻唑,加入至三口瓶的15mL的二氯甲烷中,加热至42℃,边搅拌边逐滴加入3mL液溴,恒温反应24小时后停止加热,通入氮气,将过量液溴和二氯甲烷鼓出。向上述三口瓶中加入152mg(5-巯基-1,3,4-噻二唑-2-基硫代)乙酸和31.5mg的式(II)结构的配合物,搅拌均匀后依次向其中加入10mL乙腈,3mg碳酸铯,1mL三乙胺,随后通氮气,加热至70℃,恒温反应12小时后,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-(3,4-二氢-3-异丙基-2H-嘧啶并[2,1-b]苯并噻唑)-4-((5-巯基-1,3,4-噻二唑-2-基硫代)乙酸)一甲基异丙基苯合钌。
利用式(II)结构的钌配合物与多肽小分子制备芳基钌聚合材料,该聚合材料能够作为植入材料使用;芳基钌聚合材料的制备方法具体为:
1)多肽小分子的制备:选用氨基酸-王树脂作为载体(树脂),用二氯甲烷将树脂充分溶胀,用二甲基甲酰胺清洗几遍,用DBLK(体积比哌啶:DMF=1:4),将Fmoc-保护基团脱出(Fmoc为9-芴甲氧羰基,其可用作氨基保护基),之后用二甲基甲酰胺清洗数遍,洗去DBLK,称取适合的缩合剂苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐和活化剂甲基吗啉以及C端第二个Fmoc-保护氨基酸(Fmoc-Pro-OH)进行偶联,通过茚三酮检测法进行检测确保连接比较完全,用二甲基甲酰胺清洗几遍,洗去残留的各种残基,活化剂和缩合剂,依氨基酸序列进行偶联,将所有的氨基酸连接结束后,脱去最后的Fmoc-保护基团,用切割液裂解,去除树脂和氨基酸保护基团,得到小分子多肽的粗品,送质谱确认产品分子量2100.45g/mol符合理论值;
其中,小分子多肽的氨基酸序列如SEQ ID No.1所示;SEQ ID No.1:DEGMPPSFPPMKLRRVDQ;所述小分子多肽的等电点为7.0;所述小分子多肽的的分子量为:2100.45g/mol;
2)植入材料的制备:将3mg多肽分子加入5mL水中,超声振荡5min,加入0.5mg(S)-缩水甘油,超声振荡5min,加入1-10mg芳基钌配合物,超声振荡5min。取聚丙烯浸泡于溶液中,取出后于60℃烘干,取出聚丙烯,将剩余溶液滴于聚丙烯表面,再于60℃烘干,得到负载1mg芳基钌的聚丙烯。
重复2)操作1~10次,可得到负载10~100mg芳基钌的聚丙烯。
使用多肽作为固化剂将芳基钌配合物引入聚丙烯表面,制备方法简单,无需复杂仪器,负载量易于调节,可以根据需要量将芳基钌配合物固定于聚乙烯基底表面;得到的多肽聚合物的产品具有缓释作用,多肽分子具有良好的生物相容性和无毒的优点,可作为植入材料使用。
<试验例>
1、芳基钌配合物的体外抗肿瘤活性实验:
采用MTT方法,进行体外细胞毒性测定。将本发明制备得到的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)
从表1以看出,本发明制备得到的芳基钌配合物经体外抗肿瘤实验表明,该芳基钌配合物具有强的抗肿瘤活性,为研究开发新的抗肿瘤药物提供了新的思路。
2、芳基钌配合物对血管紧张素转化酶(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/L NaCl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钌(II)配合物浓度为0.1g/L的水溶液混合,再加入150μL 0.1U/mL血管紧张素转化酶溶液(溶于0.1mol/L含0.2mo l/L NaCl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/L HCl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 | 90.5 |
从表2可知,本发明中钌(II)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。
3、芳基钌配合物在治疗重症肌无力中的应用
重症肌无力(myasthenia gravis,MG)是一种主要累及神经肌肉接头突触后膜上乙酰胆碱受体(acetylcholine receptor,AchR)的自身免疫性疾病。临床主要表现为部分或全身骨骼肌无力和易疲劳,活动后症状加重,经休息和胆碱酯酶抑制剂(cholinesteraseinhibitors,ChEI)治疗后症状减轻。患病率为77~150/100万,年发病率为4~11/100万。女性患病率大于男性,约3:2,各年龄段均有发病,儿童1~5岁居多。重症肌无力的发病原因分两大类,一类是先天遗传性,极少见,与自身免疫无关;第二类是自身免疫性疾病,最常见。发病原因尚不明确,普遍认为与感染、药物、环境因素有关。同时重症肌无力患者中有65~80%有胸腺增生,10~20%伴发胸腺瘤。
1、重症肌无力小鼠模型的建立
EAMG模型用AChR和福氏佐剂1:2混匀后免疫小鼠,初次致敏取AChR 15μg制成200μL抗原乳剂,于背部、肢体、尾基部多处皮内接种。4周后用含15μg AChR的抗原乳剂100μL再次接种。佐剂对照组用等量福氏佐剂免疫。末次免疫后7~14d对模型进行判定。
判定标准:
(1)临床表现:EAMG小鼠出现毛发干枯、隆背、食量下降、活动减少和跛足等不同程度的肌无力表现;
(2)游泳试验:EAMG小鼠游泳时间明显短于佐剂对照组。
芳基钌配合物在治疗实验性重症肌无力小鼠的临床疗效
60只体重为18~22g的重症肌无力昆明种小鼠,随机分成2组(每组30只),分别进行如下处理:
芳基钌配合物的处理组:将本发明制备得到的芳基钌配合物与氯化钠按照重量比为4:1进行混合,并溶解于注射用水中,过滤得注射剂;实验第1天,向小鼠腹腔中注射注射剂;实验第8天,再次腹腔注射注射剂;实验第22天,再次腹腔注射注射剂。每次注射剂量均为200μg芳基钌配合物/只;
对照组:实验第1天腹腔注射pH7.4、0.01mol/L PBS缓冲液,实验第8天,再次腹腔注射pH7.4、0.01mol/L PBS缓冲液;实验第22天,再次腹腔注射pH7.4、0.01mol/L PBS缓冲液。每次注射剂量均为100μL/只。
1)体重检测:芳基钌配合物治疗当日起每日称重小鼠。
2)临床评分:采用盲法由两个观察者对小鼠进行EAMG严重性的临床评估。0分:肌力正常;1分:活动轻度减少,抓握无力或低吟,易疲劳;2分:活动明显减少,体重明显减轻,休息时呈弓背、头低伏,前趾弯曲、周身发抖;3分:严重的周身无力,无低吟,无抓握动作,呈濒死状态或死亡。症状居中间者分别评分为0.5、1.5、2.5分。分别于治疗后第4周进行临床评分。
本发明提供的芳基钌配合物对小鼠体重影响的检测结果见表3。结果表明,与对照组小鼠相比,经本发明提供的芳基钌配合物免疫治疗后的小鼠的体重显著升高。
表3芳基钌配合物对小鼠体重的影响(平均值±sd值)
组别 | n | 治疗前 | 治疗后 |
对照组 | 30 | 13.21±1.3 | 14.76±0.88 |
处理组 | 30 | 13.15±1.5 | 16.56±0.64 |
芳基钌配合物对小鼠临床评分的影响检测结果见表4。结果表明,与对照组小鼠相比,经芳基钌配合物免疫小鼠的临床评分显著降低。
表4芳基钌配合物免疫治疗对小鼠临床评分的影响(平均值±sd值)
组别 | n | 治疗前 | 治疗后 |
对照组 | 30 | 1.92±0.47 | 2.09±0.28 |
处理组 | 30 | 2.06±0.45 | 0.78±0.34 |
上述结果表明,用芳基钌配合物免疫治疗小鼠,能够有效的治疗或减轻重症肌无力的症状。
4、小分子多肽的杀菌能力测试
在灭菌试管中加入1mL浓度为1×106个/mL的菌液,加入1mg本发明所提供的小分子多肽,37℃培养24小时后,培养基收集起来用倍比稀释,稀释倍数为10倍和涂布培养法检测活菌数。结果如表5所示:
表5小分子多肽的杀菌率(%)
细菌 | ATCC 6538 |
杀菌率 | 96.1% |
由表5可知,本发明所提供的小分子多肽,对金黄色葡萄球菌(ATCC 6538)有良好的杀菌能力。可见,本发明的小分子多肽可用于制备抗菌药物。
芳基钌的多肽聚合物的药物释放测试:
将负载芳基钌的聚丙烯放入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;经测定后的液体倒入烧杯中继续搅拌,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6为不同时间的药物释放率。
表6不同时间的药物释放率
时间 | 1天 | 4天 | 7天 | 30天 |
释放率(%) | 11.5 | 21.1 | 39.6 | 57.3 |
由表6可知,负载芳基钌的聚丙烯具有缓慢释放的效果,可作为植入材料达到长效作用。
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和这里示出与描述的实施例。
Claims (10)
1.具有抗肿瘤活性的芳基钌配合物,其特征在于,其结构式为式(I):
2.如权利要求1所述的具有抗肿瘤活性的芳基钌配合物的制备方法,其特征在于,其包括以下步骤:
步骤一、利用RuCl3·xH2O和γ-松油烯制备式(II)结构的配合物;
步骤二、利用(2S,3R)-3,4-二氢-3-异丙基-2-苯基-2H-嘧啶并[2,1-b]苯并噻唑、式(II)结构的配合物以及(5-巯基-1,3,4-噻二唑-2-基硫代)乙酸,制得式(I)结构的芳基钌配合物;
3.如权利要求2所述的具有抗肿瘤活性的芳基钌配合物的制备方法,其特征在于,步骤一具体为:将含钌重量百分数为37%的RuCl3·xH2O和体积分数为95%的γ-松油烯溶于10mL无水乙醇中,加热回流,搅拌6小时后静置析出,得到式(II)结构的配合物。
4.如权利要求2所述的具有抗肿瘤活性的芳基钌配合物的制备方法,其特征在于,步骤二具体为:将(2S,3R)-3,4-二氢-3-异丙基-2-苯基-2H-嘧啶并[2,1-b]苯并噻唑,与式(II)结构的配合物共溶于二氯甲烷中,加热至42℃,边搅拌边向反应液中逐滴加入液溴,反应24h后停止加热,通入氮气将液溴和二氯甲烷鼓出,随后向反应液中依次加入(5-巯基-1,3,4-噻二唑-2-基硫代)乙酸、乙腈,、碳酸铯和三乙胺,加热至70℃,12小时后,加入氯化锌和盐酸,析出棕色固体,即为式(I)结构的芳基钌配合物。
5.如权利要求1所述的具有抗肿瘤活性的芳基钌配合物的应用,其特征在于,用于制备治疗肝癌和胃癌的药物。
6.如权利要求1所述的具有抗肿瘤活性的芳基钌配合物的应用,其特征在于,用于制备治疗高血压的药物。
7.如权利要求1所述的具有抗肿瘤活性的芳基钌配合物的应用,其特征在于,用于制备重症肌无力的药物。
8.一种植入材料,其特征在于,所述植入材料上修饰有芳基钌配合物。
9.如权利要求8所述的植入材料的制备方法,其特征在于,包括以下步骤:
S1、将3mg多肽分子加入至5mL水中,超声振荡后,加入0.5mg分子量为(S)-缩水甘油,超声振荡5min后,加入1~10mg芳基钌配合物,超声振荡5min,得到溶液一;
S2、取植入材料浸泡于溶液一中,取出后烘干,之后将剩余的溶液一滴于植入材料的表面,然后置于60℃下烘干,得到表面修饰有1mg的芳基钌配合物的植入材料。
10.如权利要求9所述的植入材料的制备方法,其特征在于,所述植入材料为聚丙烯。
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US4471117A (en) * | 1979-06-21 | 1984-09-11 | Janssen Pharmaceutica N.V. | 3,4-Dihydro-2H-pyrimido(2,1-b)benzothiazoles |
CN101863925A (zh) * | 2010-05-21 | 2010-10-20 | 广东药学院 | 一种芳基钌(ⅱ)配合物及其制备方法和应用 |
CN102260296A (zh) * | 2011-06-07 | 2011-11-30 | 中山大学 | 一种单核钌配合物及其制备方法和在活细胞染色中的应用 |
CN105251054A (zh) * | 2015-11-17 | 2016-01-20 | 广西中医药大学 | 利用钌配合物制备具有抗菌抗癌的二氧化钛纳米管的方法 |
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CN101863925A (zh) * | 2010-05-21 | 2010-10-20 | 广东药学院 | 一种芳基钌(ⅱ)配合物及其制备方法和应用 |
CN102260296A (zh) * | 2011-06-07 | 2011-11-30 | 中山大学 | 一种单核钌配合物及其制备方法和在活细胞染色中的应用 |
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