CN107266478A - 一种铈配合物及其制备方法和应用 - Google Patents
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
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Abstract
本发明提供了一种铈配合物及其制备方法和应用,所述配合物分子式为:[Ce(C24H19N8O2)(NO3)Br]·H2O或[Ce(HL)(L)(NO3)Br]·H2O,其中HL=N'‑(吡啶‑2‑亚甲基)皮考啉酰肼,化学式C12H10N4O)。此配合物的制备方法是将硝酸铈水溶液、配体HL的甲醇溶液以及溴化钠水溶液混合搅拌过夜;过滤收集黄绿色沉淀,依次用水、甲醇、乙醚洗涤,真空干燥,产率为75%。这种配合物对蛋白酪氨酸磷酸酶(SHP‑2,SHP‑1,PTP1B和TCPTP)的活性有较强的抑制作用,抑制能力依次为SHP‑2>TCPTP>PTP1B>SHP‑1,是一种SHP‑2的高效选择性抑制剂。
Description
技术领域
本发明涉及金属配合物领域,具体涉及一种铈配合物及其制备方法,以及铈配合物在制备蛋白酪氨酸磷酸酶活性抑制剂中的应用。
背景技术
蛋白酪氨酸磷酸酶(PTPs)是广泛存在于生物体内的一类不含金属的酶,与蛋白激酶共同调控蛋白酪氨酸磷酸化这一可逆的动态过程,调控细胞周期和信号转导等生命过程。PTPs活性异常可导致包括癌症、糖尿病和风湿性关节炎等在内的许多疾病的发生。由于PTPs在许多疾病发生发展方面发挥重要作用,因此作为药物靶标受到人们的高度关注。其抑制剂研究也受到人们的高度重视。目前人们研究发现的PTPs的种类已有107种,如PTP1B、TCPTP、SHP-1、SHP-2、PTP-MEG2等。
研究表明SHP-2调节Ras-Erk1/2MAP激酶通路以及SFKs和FAK,与肿瘤的生长和转移密切相关。乳腺癌和白血病等细胞中蛋白酪氨酸磷酸酶SHP-2明显升高。因此SHP-2成为理想的抗癌药物靶标,其抑制剂的研究受到广泛关注,可望筛选出高效低毒的抗癌新药物。
发明内容
本发明的目的在于提供一种铈配合物及其制备方法。
本发明的目的在于提供所述铈配合物在抑制蛋白酪氨酸磷酸酶活性中的应用,尤其在抑制蛋白酪氨酸磷酸酶SHP-2中的应用。
本发明提供的一种铈配合物,其分子式为:[Ce(C24H19N8O2)(NO3)Br]·H2O或[Ce(HL)(L)(NO3)Br]·H2O,其中HL=N'-(吡啶-2-亚甲基)皮考啉酰肼,即(N'-(pyridin-2-ylmethylene)picolino-hydrazide,化学式为:C12H10N4O);结构式为:
本发明提供的铈配合物的制备方法,包括如下步骤:
(1)将硝酸铈和溴化钠分别溶于水,将N'-(吡啶-2-亚甲基)皮考啉酰肼溶于甲醇;
(2)于反应器中将上述三种反应溶液混合,室温搅拌过夜,有沉淀析出;
(3)过滤收集沉淀,依次用水、甲醇、乙醚洗涤,真空干燥,得黄绿色粉末。
所述硝酸铈、溴化钠与N'-(吡啶-2-亚甲基)皮考啉酰肼的摩尔比为2:4:1。
本发明制备的铈配合物产率为75%,具有红外吸收(cm-1):3415ν(O-H,N-H),1639ν(C=O),1605ν(C=N),1475ν(NO3 - ),425ν(Ce-N),558ν(Ce-O)。元素分析按C24H21BrN9O6Ce计算:理论值(%)C 38.36,H 2.82,N 16.77;实验值(%)C 37.94,H 2.18,N 16.71。
该配合物中铈离子与三种配体(HL,NO3 -,Br-)形成1:2:1:1的摩尔比,两个有机配体均以三齿螯合配位到铈离子,其中一个具有中性形式,一个为阴离子形式。此外铈离子还与一个硝酸根离子及一个溴离子配位达到电中性。从水与甲醇混合溶剂得到的本发明配合物含有一个水分子。本发明的铈配合物可以应用到蛋白酪氨酸磷酸酶(SHP-2,SHP-1,PTP1B和TCPTP)的抑制剂。
所述配合物对SHP-2的半数抑制浓度(IC50)范围为:0.52~0.69μM。
所述配合物对TCPTP的半数抑制浓度(IC50)范围为:2.51~2.97μM。
所述配合物对PTP1B的半数抑制浓度(IC50)范围为:3.19~3.73μM。
所述配合物对SHP-1的半数抑制浓度(IC50)范围为:8.42~12.78μM。
与现有技术相比,本发明的优点和效果:
本发明的铈配合物是稀土铈盐与配体在室温反应得到,制备方法方便简单,产物纯度高,产率高。
本发明提供的稀土铈配合物通过半数抑制浓度(IC50)的测定获得其对蛋白酪氨酸磷酸酶的活性有较强的抑制作用,对不同PTPs的抑制能力显示差异,配合物抑制SHP-2的IC50值高达10-7M,其抑制SHP-2的IC50值是PTP1B的5倍、TCPTP的4倍、SHP-1的17倍,对SHP-2的抑制能力最强,是SHP-2的高效选择性抑制剂。
附图说明
图1本发明稀土铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O的红外光谱(KBr压片)。
图2本发明稀土铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O的电喷雾质谱(甲醇溶液,正离子模式)。
图3本发明稀土铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O抑制SHP-2活性的IC50值测定曲线。
图4本发明稀土铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O抑制TCPTP活性的IC50值测定曲线。
图5本发明稀土铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O抑制PTP1B活性的IC50值测定曲线。
图6本发明稀土铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O抑制SHP-1活性的IC50值测定曲线。
具体实施方式
实施例1.铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O的制备方法
1)分别将0.4342g Ce(NO3)3·6H2O(1.00mmol)和0.20587g NaBr(2.00mmol)溶解于2~4mL水中。
2)将0.1130g N'-(吡啶-2-亚甲基)皮考啉酰肼(0.50mmol)溶解于45~55mL甲醇中。
3)搅拌中缓慢混合上两种溶液,得到黄绿色悬浊液,继续搅拌过夜,抽滤得到黄绿色粉末,用水、甲醇、乙醚三次洗涤,真空干燥。收集样品重0.5636g,产率75%。
该铈配合物元素分析结果:按C24H21BrN9O6Ce计算,理论值(%)C 38.36,H 2.82,N16.77;实验值(%)C 37.94,H 2.18,N 16.71。
实施例2.本发明铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O的红外光谱
取微量[Ce(C24H19N8O2)(NO3)Br]·H2O固体粉末,KBr压片,在红外光谱仪记录4000-400cm-1吸收,见图1。配合物特征吸收峰(cm-1)与相应的振动模式为:3415ν(O-H,N-H),1639ν(C=O),1605ν(C=N),1475ν(NO3 - ),425ν(Ce-N),558ν(Ce-O)。
实施例3.本发明铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O的电喷雾质谱
将少量的[Ce(C24H19N8O2)(NO3)Br]·H2O固体粉末溶于甲醇,离心取上清液,进样到电喷雾质谱仪,以正离子方式检测并记录数据,见图2。该稀土铈配合物在电喷雾质谱中离子峰:[Ce(C24H19N8O2)(OCH3)]+(m/z)理论值622.09,实验值,622.06。
实施例4.本发明铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O对蛋白酪氨酸磷酸酶(SHP-2,SHP-1,PTP1B和TCPTP)抑制效果检测
1)抑制效果检测原理:蛋白酪氨酸磷酸酶能使反应底物对硝基苯磷酸二钠盐(pNPP)分解成黄色的对硝基苯酚(pNP),后者在405nm处有很强的可见光吸收。当蛋白酪氨酸磷酸酶与配合物作用后,可通过检测405nm处吸光度值的变化计算出酶活性的变化情况。
2)抑制效果检测指标,半数抑制率(IC50)。当被检测酶的活性受抑制降低为原酶活性的一半时的抑制剂浓度定义为半数抑制率,用IC50表示。该指标用来衡量抑制剂的抑制效果,当IC50数值越小,说明抑制剂抑制蛋白酪氨酸磷酸酶活性的效果就越好。
3)铈配合物对蛋白酪氨酸磷酸酶(SHP-2,SHP-1,PTP1B和TCPTP)抑制效果测定步骤:
(1)配制MOPS缓冲溶液(50mM NaCl 20mM MOPS,pH=6.0;MOPS为吗啉代丙烷磺酸)。
(2)配制100mM对硝基苯磷酸二钠盐(pNPP)溶液,现配现用。
(3)配制抑制剂溶液,现配现用。将配合物用二甲基亚砜(DMSO)溶解,配成10-2M的母液,再用DMSO稀释成不同浓度梯度(10-3~10-10M)的溶液。
(4)配制终止反应液2.0M NaOH溶液。
(5)用MOPS缓冲溶液将所要用的蛋白酪氨酸磷酸酶稀释至一定浓度,现用现配。
(6)酶活性抑制实验的测定。在96孔板中,每孔依次加入83μL含酶缓冲溶液,10μL不同浓度的配合物溶液,水浴37℃中恒温30min后,用2μL的pNPP启动反应,30min后,加5μL的NaOH溶液终止反应,通过酶标仪测定底物的分解产物(对硝基苯酚,pNP)在波长λmax=405nm处的吸收强度,计算抑制率。
(7)重复三次以上平行实验,所有测定必须设有空白及对照实验。
(8)数据处理。以配合物浓度的对数作为横坐标,抑制率作为纵坐标,利用Origin程序作图,拟合得到配合物对酶抑制能力的曲线,求得抑制率在50%时相应的配合物浓度,即IC50值。
(9)检测结果1:本发明稀土铈配合物对蛋白酪氨酸磷酸酶SHP-2半数抑制浓度(IC50)范围为:0.52~0.69μM。(见图3)。
(10)检测结果2:本发明稀土铈配合物对蛋白酪氨酸磷酸酶TCPTP的半数抑制浓度(IC50)范围为:2.51~2.97μM。(见图4)。
(11)检测结果3:本发明稀土铈配合物对蛋白酪氨酸磷酸酶PTP1B的半数抑制浓度(IC50)范围为:3.19~3.73μM。(见图5)。
(12)检测结果4:本发明稀土铈配合物对蛋白酪氨酸磷酸酶SHP-1的半数抑制浓度(IC50)范围为:8.42~12.78μM。(见图6)。
综上分析,本发明成功实施了一种简单的稀土铈配合物[Ce(C24H19N8O2)(NO3)Br]·H2O的合成,方法简单,无特殊限制。通过半数抑制浓度(IC50)的测定分析得出本发明稀土铈配合物对四种蛋白酪氨酸磷酸酶的活性有较强的抑制作用,且抑制能力显示较大差异。本发明稀土铈配合物抑制SHP-2的IC50值高达10-7M,其抑制SHP-2的IC50值是PTP1B的5倍、TCPTP的4倍、SHP-1的17倍,对SHP-2的抑制能力最强,可作为SHP-2的高效选择性抑制剂应用。
Claims (5)
1.一种铈配合物,其特征在于,分子式为:[Ce(HL)(L)(NO3)Br]·H2O,结构式为:
2.根据权利要求1所述的铈配合物的制备方法,其特征在于,包括如下步骤:
(1)将硝酸铈和溴化钠分别溶于水,将N'-(吡啶-2-亚甲基)皮考啉酰肼溶于甲醇;
(2)于反应器中将上述三种反应溶液混合,室温搅拌过夜,有沉淀析出;
(3)过滤收集沉淀,依次用水、甲醇、乙醚洗涤,真空干燥,得黄绿色粉末。
3.如权利要求2所述的一种铈配合物的制备方法,其特征在于,所述硝酸铈、溴化钠与N'-(吡啶-2-亚甲基)皮考啉酰肼的摩尔比为2:4:1。
4.如权利要求1所述的一种铈配合物在制备蛋白酪氨酸磷酸酶活性抑制剂中的应用。
5.如权利要求1所述的一种铈配合物在制备蛋白酪氨酸磷酸酶SHP-2活性抑制剂中的应用。
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