CN108864203A - 含氮杂环的钌配合物及其制备方法和应用 - Google Patents
含氮杂环的钌配合物及其制备方法和应用 Download PDFInfo
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- CN108864203A CN108864203A CN201810962510.5A CN201810962510A CN108864203A CN 108864203 A CN108864203 A CN 108864203A CN 201810962510 A CN201810962510 A CN 201810962510A CN 108864203 A CN108864203 A CN 108864203A
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- ruthenium complex
- nitrogenous heterocyclic
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Classifications
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- C07F15/0046—Ruthenium compounds
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
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Abstract
本发明公开了一种含氮杂环的钌配合物,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,本发明涉及具有含氮杂环的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含氮杂环的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,提供了一种含氮杂环的钌配合物,其特征在于,其结构式为式(I):
本发明还提供了一种所述的含氮杂环的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1,3,4-噻二唑-2,5-二胺,制得式(I)结构的钌配合物。
优选的是,所述的含氮杂环的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,所述的含氮杂环的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1,3,4-噻二唑-2,5-二胺、式(II)结构的配合物、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)结构的含氮杂环的钌配合物。
本发明还提供了一种所述的含氮杂环的钌配合物的应用,用于制备治疗肝癌和胃癌的药物。
优选的是,所述的含氮杂环的钌配合物的应用,用于制备治疗高血压的药物。
优选的是,所述的含氮杂环的钌配合物的应用,用于制备治疗高脂血症、高甘油三酯血症、肥胖和/或糖尿病的药物。
一种植入材料,所述植入材料上修饰有含氮杂环的钌配合物。
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含氮杂环的钌配合物,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、本发明的含氮杂环的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含氮杂环的钌配合物,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、本发明的含氮杂环的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>
含氮杂环的钌配合物的名称为化学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-(1,3,4-噻二唑-2,5-二胺)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):δ7.96(s,1H),7.68(s,2H),7.30(s,1H),7.26–7.18(m,3H),7.14(dd,J=7.9,1.6Hz,2H),5.51(d,J=5.7Hz,1H),5.36(d,J=5.7Hz,1H),5.31(d,J=5.7Hz,1H),5.16(s,2H),4.76(s,3H),4.66(d,J=5.7Hz,1H),3.82(s,1H),3.51(s,1H),2.91-2.81(m,1H),2.33(s,3H),2.12(s,1H),1.60(s,1H),1.23-1.15(m,6H),1.02(s,3H)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;
一壶法制备含氮杂环的钌配合物:称取305mg的(2S,3R)-3,4-二氢-3-异丙基-2-苯基-2H-嘧啶并[2,1-b]苯并噻唑加入至容纳有15ml的二氯甲烷的三口瓶中,加热至42℃,边搅拌边向反应液逐滴加入3ml的液溴,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。将118mg 1,3,4-噻二唑-2,5-二胺和31.5mg的式(II)结构的配合物加入至上述三口瓶中,搅拌均匀后再依次向其中加入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-(1,3,4-噻二唑-2,5-二胺)一甲基异丙基苯合钌。
利用式(II)结构的含氮杂环的钌配合物与多肽小分子制备含氮杂环的钌聚合材料,该聚合材料能够作为植入材料使用;含氮杂环的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2063.22g/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:DDCQQHHVWQDMFSTW;所述小分子多肽的等电点为4.16;所述小分子多肽的的分子量为:2063.22g/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含氮杂环的钌配合物,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含氮杂环的钌的聚丙烯。
重复2)操作1~10次,可得到负载10~100mg含氮杂环的钌的聚丙烯。
使用多肽作为固化剂将含氮杂环的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,可以根据需要量将含氮杂环的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、含氮杂环的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含氮杂环的钌配合物与胃癌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含氮杂环的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) | 0.13±0.06 | 0.18±0.15 |
从表1以看出,本发明制备得到的含氮杂环的钌配合物经体外抗肿瘤实验表明,该含氮杂环的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、含氮杂环的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含氮杂环的钌配合物的ACE抑制率(%)
抑制剂 | ACE抑制率(%) |
含氮杂环的钌配合物 | 95.2 |
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、含氮杂环的钌配合物对db/db小鼠空腹血糖、胰岛素耐量(ITT)、甘油三酯(TG)、血清胰岛素的影响:
本发明通过测定口服含氮杂环的钌配合物后的2型糖尿病模型小鼠(db/db小鼠)的空腹血糖水平、胰岛素耐量、甘油三酯、血清胰岛素等糖尿病相关指标,来研究含氮杂环的钌配合物对2型糖尿病的治疗或改善作用。结果表明含氮杂环的钌配合物具有显著的降血糖、降甘油三酯、改善胰岛素耐量和提高血清胰岛素的作用。
3.1、实验原理:db/db小鼠(leptin受体缺乏)属于自发性II-型糖尿病动物模型,是由C57BL/KsJ近亲交配株常染色体隐性遗传衍化而来。本发明以该品系的小鼠作为评价含氮杂环的钌配合物抗2型糖尿病的动物模型。
3.2、实验材料与方法
1)动物来源:遗传型自发性糖尿病db/db小鼠购自美国Jackson公司。
2)动物培养条件:SPF级动物房饲养;温度:22-24℃;湿度:45-80%;光照:150-300Lx,12小时昼夜交替。其饲养,给药,血糖测定和处死均严格按照动物实验和福利的指导。
3)动物分组与给药:db/db小鼠饲养于SPF级动物房中,适应性驯养一周后。根据测定禁食6小时后空腹血糖结果的均值将小鼠分为空白对照组、阳性对照组和受试物组,每组9只。各组小鼠每日早上10:00-11:00分别灌胃给予溶剂(5%Tween 80,空白对照),10mg/kg阳性化合物[文迪雅(马来酸罗格列酮片),购自葛兰素史克,阳性对照组],40mg/kg含氮杂环的钌配合物(受试物组)。
4)观察指标:
A、对小鼠血糖的长期作用:给药期间每周监测空腹血糖一次,空腹血糖为小鼠禁食不禁水后6h(从上午9:30-10:30到下午3:30-4:30)后的血糖值,并统计各组平均血糖,结果详见表3:
表3各组小鼠的平均血糖值(mM)
时间(周) | 空白组 | 阳性对照组 | 受试物组 |
0 | 10 | 10 | 10 |
1 | 15 | 6 | 11 |
2 | 15 | 7 | 12 |
3 | 20 | 8 | 14 |
4 | 18 | 8 | 16 |
5 | 17 | 7 | 18 |
B、胰岛素耐量试验(ITT):各组小鼠于给药后第5周进行胰岛素耐量试验,小鼠禁食6h后腹腔注射1.5U/kg胰岛素(购自Eli Lilly(礼来公司),测定给胰岛素后15、30、45、60、90和120min血糖值,结果详见表4:
表4给胰岛素后每组小鼠的平均血糖值(mM)
时间(min) | 空白组 | 阳性对照组 | 受试物组 |
0 | 18 | 8 | 15 |
15 | 25 | 12 | 20 |
30 | 24 | 8 | 19 |
45 | 23 | 6 | 20 |
60 | 22 | 7 | 19 |
90 | 20 | 5 | 18 |
120 | 19 | 5 | 17 |
C、对血清甘油三酯和胰岛素含量影响分析:各组动物于给药后第5周处死小鼠,进行解剖,眼眶采血,离心,利用生化分析仪检测血清中甘油三脂(TG)的水平以及胰岛素检测试剂盒检测血清中胰岛素的水平,分别测定其中甘油三酯TG和胰岛素的含量,结果详见表5;
表5各组小鼠的平均甘油三酯(mM)和血清胰岛素含量(mM)
空白组 | 阳性对照组 | 受试物组 | |
甘油三酯(mM) | 0.9 | 0.6 | 0.4 |
胰岛素(mM) | 1.0 | 0.7 | 1.6 |
3.3、实验结果分析:
由表3可知,空白对照组小鼠实验期间空腹血糖一直维持在相对较高水平。阳性对照组的空腹血糖第一周就表现出明显的下降现象,这种现象一直持续到实验结束。受试物组从第一周也表现出明显的空腹血糖下降现象,这种现象一直持续到实验结束。由此可见受试物组空腹血糖与空白对照组相比有所下降,并具有显著性差异(*P<0.05)。
由表4可知,含氮杂环的钌配合物组小鼠在给胰岛素前和给胰岛素后15、30、45、60、90和120min的血糖值与空白对照组相比表现出明显的胰岛素敏感性并具有显著性差异(*P<0.05);
由表5可知,与空白对照组相比,含氮杂环的钌配合物给药对甘油三酯具有显著性降低作用(*P<0.05),含氮杂环的钌配合物能显著性的提高血浆中的胰岛素含量(*P<0.05,与空白对照组相比)。
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 | 96.2% |
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。
含氮杂环的钌的多肽聚合物的药物释放测试:
将负载含氮杂环的钌的聚丙烯放入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(%) | 5.3 | 10.6 | 25.8 | 46.9 |
由表6可知,负载含氮杂环的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.含氮杂环的钌配合物,其特征在于,其结构式为式(I):
2.如权利要求1所述的含氮杂环的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1,3,4-噻二唑-2,5-二胺,制得式(I)结构的钌配合物。
3.如权利要求2所述的含氮杂环的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所述的含氮杂环的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1,3,4-噻二唑-2,5-二胺、式(II)结构的配合物、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)结构的含氮杂环的钌配合物。
5.如权利要求1所述的含氮杂环的钌配合物的应用,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所述的含氮杂环的钌配合物的应用,其特征在于,用于制备治疗高血压的药物。
7.如权利要求1中所述的含氮杂环的钌配合物的应用,其特征在于,用于制备治疗高脂血症、高甘油三酯血症、肥胖和/或糖尿病的药物。
8.一种植入材料,其特征在于,所述植入材料上修饰有含氮杂环的钌配合物。
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含氮杂环的钌配合物,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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