CN104693219B - 具有抑制脲酶活性的双氯芬酸铜配合物及其制备方法 - Google Patents
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Abstract
本发明涉及三种具有抑制脲酶活性的双氯芬酸铜配合物及其制备方法,属于配合物合成及药物化学技术领域。本发明提供的三种配合物均以铜离子为中心离子:配合物1以双氯芬酸和1,3‑丙二胺为配体,是一个双核结构;配合物2以双氯芬酸和咪唑为配体,是一个结构;配合物3以双氯芬酸和2,2'‑联吡啶为配体,是一个单核结构。经测试发现,本发明所述配合物1、2、3抑制脲酶的IC50值分别为0.132、0.25、0.448μmol/L,对脲酶活性的抑制率达到50%,阳性对照N‑羟基乙酰胺IC50值为12.5μmol/L,本发明所述配合物抑制脲酶活性均优于阳性对照,是一种很好的脲酶抑制剂。
Description
技术领域
本发明涉及三种具有抑制脲酶活性的双氯芬酸铜配合物及其制备方法,属于配合物合成及药物化学技术领域。
背景技术
本发明涉及一种具有抑制脲酶活性的金属配合物及其制备方法和用途,属于有机合成技术领域。
幽门螺杆菌(Helicobacter pylori ,Hp)能诱发人类的慢性胃炎、消化性溃疡、胃黏膜相关性淋巴样组织淋巴瘤、肠性胃癌。世界卫生组织WHO已将Hp列为人类胃癌的I类致癌原。Hp能在胃内存活,得益于它有高活性脲酶,脲酶可以将尿素催化水解为氨和二氧化碳,形成的氨云保护层可以使幽门螺旋杆菌在胃酸环境下生存,能抑制脲酶的物质对Hp在胃中定植是不利的,因此开发脲酶抑制剂具有重要意义。
目前常用的脲酶抑制剂都是有机物小分子,大多存在有效抑制时间短,效率低,有普遍耐药性等缺点。脲酶对金属离子非常敏感,但金属离子毒性较大,吸收差,使其应用受到了一定的限制。如果以具有生物活性的有机小分子和金属离子反应,合成配合物,可以提高大大降低金属离子的毒性,改善其吸收性。
配合物的合成中,第二配体的引进,能改变配合物的结构及其生物活性,为寻找高效低毒的配合物提供了更多可能,是药物开发的重要手段。
因此引入不同的有机小分子,和金属盐反应从而制备配合物,是获得高效、低毒及吸收性能好的脲酶抑制剂的重要手段。
发明内容
本发明的目的在于提供三种具有抑制脲酶活性的金属配合物及其制备方法和用途。
本发明以具有抗炎活性的双氯芬酸为配体,分别以含氮的小分子1,3-丙二胺、咪唑和2,2'-联吡啶为第二配体,和铜盐反应,制备了三种配合物,培养了其单晶,利用单晶X射线衍射仪对其结构进行了表征,三种配合物均以铜离子为中心离子,配合物1以双氯芬酸和1,3-丙二胺为配体,配合物2以双氯芬酸和咪唑为配体,配合物3以双氯芬酸和2,2'-联吡啶为配体。经测试,配体双氯芬酸没有抑制脲酶的活性,本发明的三种配合物均具有很强的抑制脲酶的活性,可以用于制备脲酶抑制剂。
本发明技术方案如下:
步骤1.分别配置0.1mmol/mL的双氯芬酸钠和高氯酸铜溶液,1mmol/mL的1,3-丙二胺、咪唑和2,2'-联吡啶溶液。
步骤2.准确量取一定体积的双氯芬酸钠溶液和一定体积的高氯酸铜溶液于烧杯中,添加溶剂至一定体积,室温搅拌5分钟,往烧杯中滴加一定体积的1,3-丙二胺或咪唑溶液,室温搅拌5分钟。
步骤3. 准确量取一定体积的双氯芬酸钠溶液和一定体积的2,2'-联吡啶溶液于试管中,然后向试管中添加一定体积的不含溶质的溶剂,之后向试管中添加一定体积的高氯酸铜溶液。
步骤4.上述步骤2和3中烧杯或试管用封口膜封口,封口膜用牙签扎眼,置室温静止缓慢挥发,几天后有晶体析出。
步骤5.上述步骤2和3中烧杯或试管中溶液过滤,弃滤液,所得无色针状透明晶体用冷甲醇或乙醇冲洗,置真空干燥箱干燥。
步骤6. 上述步骤所得晶体,用单晶X衍射仪进行结构测试,用酚红法测试其抑制脲酶活性。
附图说明
图1是本发明实施例1所述配合物1的X-衍射单晶结构图。
图2是本发明实施例2所述配合物2的X-衍射单晶结构图。
图3是本发明实施例3所述配合物3的X-衍射单晶结构图。
具体实施方式
通过以下实施例进一步详细说明本发明,但本发明的范围并不受这些实施例的任何限制。
实施例一:以双氯芬酸及1,3-丙二胺为配体的铜配合物(配合物1)的制备。
双氯芬酸钠溶液(0.1mmol/ML 甲醇)的配制:准确称取双氯芬酸钠0.318g(1mmol)溶于10mL甲醇。高氯酸铜溶液(0.1mmol/mL 甲醇)的配制:准确称取高氯酸铜[Cu(ClO4)2.6H2O] 0.37g(1mmol)溶于10mL甲醇。1,3-丙二胺溶液(1mmol/mL 甲醇)的配制:准确称取1,3-丙二胺0.74g(10mmol)溶于10mL甲醇。准确量取双氯芬酸钠溶液(0.1mmol/mL甲醇)10mL和高氯酸铜溶液(0.1mmol/mL甲醇) 5mL于烧杯中,添加甲醇至60mL,室温搅拌5分钟,再滴加1,3-丙二胺溶液(1mmol/mL甲醇)0.1mL, 用封口膜封口,封口膜用牙签扎眼,置室温静止缓慢挥发,几天后有绿色块状晶体析出,溶液过滤,弃滤液,所得晶体用冷甲醇冲洗,置真空干燥箱干燥得到配合物1的晶体。经X-射线单晶衍射进行结构测试,晶体结构图如附图图1所示,晶体数据见表1,分子式为C62N8O10H60Cl8Cu2,结构式如下:
经测试,配合物1是一个双核结构,每个配合物分子含有4分子去质子化的双氯芬酸、2分子1,3-丙二胺和2个铜离子。
实施例二:以双氯芬酸和咪唑为配体的铜配合物 (配合物2)的制备。
双氯芬酸钠溶液(0.1mmol/mL)的配制:准确称取双氯芬酸钠0.318g(1mmol)溶于10mL甲醇和二氯甲烷的混合溶剂(甲醇二氯甲烷体积比为1:3)。高氯酸铜溶液(0.1mmol/mL)的配制:准确称取高氯酸铜[Cu(ClO4)2.6H2O] 0.37g(1mmol) 溶于10mL甲醇。咪唑溶液(1mmol/mL)的配制:准确称取咪唑0.68g(10mmol)溶于10mL甲醇。准确量取双氯芬酸钠溶液(0.1mmol/mL甲醇:二氯甲烷体积比为1:3)2mL和高氯酸铜溶液(0.1mmol/mL甲醇)1mL于烧杯中,再滴加咪唑溶液(1mmol/mL甲醇) 0.1mL,添加甲醇和二氯甲烷的混合溶剂(甲醇:二氯甲烷体积比为1:3)至总体积10mL,用封口膜封口,封口膜用牙签扎眼,置室温静止缓慢挥发,几天后有紫色块状晶体析出,溶液过滤,弃滤液,所得晶体用冷甲醇冲洗,置真空干燥箱干燥得到配合物2的晶体。经X-射线单晶衍射进行结构测试,晶体结构图如附图图2所示,晶体数据见表1,分子式为C38H28Cl4N4O4Zn,结构式如下:
经测试,配合物2是一个6配位的单核结构,每个配合物分子含有2分子去质子化的双氯芬酸、2分子咪唑和1个铜离子。
实施例三:以双氯芬酸及2,2’-联吡啶为配体的铜配合物 (配合物3)的制备。
双氯芬酸钠溶液(0.1mmol/mL)和高氯酸铜溶液(0.1mmol/mL)配制方法同实施例2。配制1mmol/mL的2,2’-联吡啶溶液:准确称取2,2’-联吡啶1.56g(10mmol)溶于10mL甲醇。准确量取双氯芬酸钠溶液(0.1mmol/mL,甲醇二氯甲烷体积比为1:3)2mL和2,2’-联吡啶溶液(1mmol/mL甲醇)0.1mL于试管中并混匀,向试管中添加4mL甲醇和二氯甲烷的混合溶液(甲醇二氯甲烷体积比为1:1)4mL,再向试管中添加高氯酸铜溶液(0.1mmol/mL 甲醇)1 mL,用封口膜封口,封口膜用牙签扎眼,置室温静止缓慢挥发,几天后有绿色块状晶体析出,溶液过滤,弃滤液,所得晶体用冷甲醇冲洗,置真空干燥箱干燥得到配合物3的晶体。经X-射线单晶衍射进行结构测试,晶体结构图如附图图3所示,晶体数据见表1,分子式为C38H28Cl4CuN4O4,结构式如下:
经测试,配合物3是一个6配位的单核结构,每个配合物分子含有2分子去质子化的双氯芬酸、1分子2,2’-联吡啶、一个铜离子。
表1 本发明所述列配合物主要晶体结构数据
实施例三:双氯芬酸铜配合物抑制脲酶活性测试
(1)配药液:
称取一定量的本发明3种配合物,分别用10mL的溶剂(二甲基亚砜:水=1:1 v:v)溶解,配置100μmol/L的药液。将配好的药液(100μmol/L)倍比稀释得到50、25、12.5、6.25、3.125、1.56、0.781μmol/L浓度的药液。
阳性对照药采用脲酶抑制剂N-羟基乙酰胺(CAS号:546-88-3),配置方法同上,配置浓度为200、100、50、25、12.5、6.25、3.125μmol/L。
(2)配制缓冲液:
pH6.8的磷酸缓冲液100mL:0.2mol/L磷酸二氢钠51mL,0.2mol/L磷酸氢二钠49mL,500mmol/L尿素,0.002g/100mL酚红。
pH7.7的磷酸缓冲液 100mL:0.2mol/L磷酸二氢钠10.5mL,0.2mol/L磷酸氢二钠89.5mL,0.002g/100mL酚红,0.45μm的滤膜过滤。
(3)配浓度为(10kU/L)的脲酶溶液:
根据脲酶活力单位数,称取一定量的脲酶,溶解于去离子水中,得到10kU/L的脲酶溶液。
(4) pH7.7的缓冲液OD值测定:
96孔板中加上述(2)中pH7.7的磷酸缓冲液200μL,设5个重复,测OD值,平均值记为OD7.7。
(5)空白对照测试:
96孔板中加25 µL脲酶溶液 (10kU/L)、25μL配制上述(1)药液所用溶剂,每个药物浓度设5个重复,放入37℃恒温培养箱中培养一个小时。一小时后取出,再加上述(2)中pH6.8的磷酸缓冲液200μL,开始计时,并每隔1分钟测试其OD值,随着时间的延长,缓冲液中尿素被脲酶分解产氨,体系pH值升高,在酚红指示剂的作用下,OD值上升。记录OD值达到上述(4)OD7.7所用的时间,记为T空白。
(6)样品测试:
96孔板中加25 µL脲酶溶液(10kU/L)、25μL上述(1)配置的各种浓度配合物和N-羟基乙酰胺药液,每个药物浓度设5个重复,放入37℃恒温培养箱中培养一个小时。一小时后取出,再加上述(2)中pH6.8的磷酸缓冲液200μL,开始计时,并每隔1分钟测试其OD值,记录OD值达到上述(4)OD7.7所用的时间,记为T样品。
(7)数据计算:
抑制率=(T样品-T空白)/T样品,用Origin75或SPSS软件计算IC50。
实验时抑制率应超过50%,保证量-效曲线跨越足够的范围,不可外推计算IC50值。
本发明所述配合物1、2、3抑制脲酶的IC50值分别为0.132、0.25、0.448 μmol/L,即配合物1、2、3浓度分别为0.132、0.25、0.448 μmol/L时,对脲酶活性的抑制率达到50%,阳性对照N-羟基乙酰胺IC50值为12.5 μmol/L, 本发明所述配合物抑制脲酶活性均优于阳性对照,是一种很好的脲酶抑制剂。
Claims (5)
1.三种具有抑制脲酶活性的双氯芬酸铜配合物,其结构如下:
。
2.一种权利要求1所述的具有抑制脲酶活性的配合物1的制备方法,其特征在于:双氯芬酸钠、高氯酸铜和1,3-丙二胺按照摩尔比2:1:1,溶于甲醇反应,置室温静止缓慢挥发制得。
3.一种权利要求1所述的具有抑制脲酶活性的配合物2的制备方法,其特征在于:双氯芬酸钠、高氯酸铜和咪唑按照摩尔比2:1:1,溶于甲醇和二氯甲烷的混合溶液反应,置室温静止缓慢挥发制得。
4.一种权利要求1所述的具有抑制脲酶活性的配合物3的制备方法,其特征在于:双氯芬酸钠、高氯酸铜和2,2’-联吡啶按照摩尔比2:1:1,分别溶于溶剂,在试管中用分层扩撒法制得,所述分层扩散法步骤为:双氯芬酸钠和2,2’-联吡啶溶解于甲醇和二氯甲烷的混合溶液,置于试管中为下层,加入不含溶质的甲醇和二氯甲烷的混合溶液为中间层,再加入高氯酸铜的甲醇溶液为上层,置室温静止缓慢扩散制得。
5.一种权利要求1所述的具有抑制脲酶活性的配合物的用途,其特征在于:配合物具有很好的抑制脲酶的活性,可以用于制备脲酶抑制剂。
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