CN104829635B - 丝氨酸n衍生物的金属铜配合物及其制备方法和应用 - Google Patents
丝氨酸n衍生物的金属铜配合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了丝氨酸N衍生物的金属铜配合物,其分子式分别为:[CuL1Cl(H2O)](1)、[Cu(L2)2]·H2O(2),其中HL1为N‑(2‑吡啶甲基)‑L‑丝氨酸;HL2为N‑(4‑羟基苯基)‑L‑丝氨酸。配合物的制备方法是将铜盐的水溶液滴加到置于圆底烧瓶的配体水溶液中,室温搅拌5~9h,过滤,滤液缓慢挥发析出蓝色块状晶体,产率大于50%。这两种配合物对蛋白酪氨酸磷酸酶(PTPs)的活性有高效抑制作用,配合物2对PTP1B显示出较好的选择性。
Description
技术领域
本发明涉及铜配合物,具体涉及丝氨酸N衍生物的金属铜配合物及其制备方法和应用。
背景技术
蛋白酪氨酸磷酸酶(PTPs)是一个庞大的酶家族,与蛋白酪氨酸激酶(PTKs)共同调节生物体内蛋白酪氨酸的磷酸化水平。如果酪氨酸磷酸化水平紊乱,就会引发多种疾病,如癌症、免疫紊乱、糖尿病和肥胖等。由于PTPs及PTKs在疾病控制方面发挥关键作用,因此它们都可作为药物靶标。将PTKs作为药物靶标的研究已趋于成熟,而PTPs作为药物靶标的化合物还处在探索阶段。人类基因组分析发现的PTPs大约有130种,它们都具有一个由200-250个氨基酸残基组成的催化结构域,并且在其活性中心含有一段保守的氨基酸序列。这段高度保守序列具有磷酸结合和催化的作用,因此开发出针对某一种PTP高效、专一的抑制剂是相关疾病治疗与预防中最理想的。
蛋白酪氨酸磷酸酶1B(PTP1B)是PTPs家族中的一员,它通过使胰岛素受体去磷酸化,负向调节胰岛素信号转导。生物化学研究表明,PTP1B基因敲除鼠不仅发育正常,而且对胰岛素的敏感度增高,癌症发病率和发胖的概率为零。因此,PTP1B是治疗Ⅱ型糖尿病和肥胖病的有效靶点。PTP1B抑制剂的研究可望筛选出高效低毒的抗糖尿病和抗肥胖症的新药物。为了进一步筛选配合物类抗糖尿病药物,发明人探讨了各种不同结构的铜配合物对PTP1B抑制的选择性,以期筛选以PTP1B为靶标的高效低毒的潜在铜配合物抗糖尿病药物。研究显示并非所有的铜配合物都对PTP1B具有好的抑制作用和选择性,其配体结构能够明显影响其对PTP1B的抑制强度和选择性。在此基础上,我们研究了丝氨酸N衍生物与铜离子结合形成的铜配合物对PTPs的抑制作用和选择性,为糖尿病的治疗提供一种新的药物开发途径。
发明内容
本发明的目的在于提供一种可以作为PTP1B特异性抑制剂的金属铜配合物及其制备方法。
本发明提供的丝氨酸N衍生物的金属铜配合物,其分子式分别为:[CuL1Cl(H2O)](1)、[Cu(L2)2]·H2O(2),其中HL1为N-(2-吡啶甲基)-L-丝氨酸;HL2为N-(4-羟基苯基)-L-丝氨酸。结构式分别为:
上述配合物(1)、(2)对PTP1B的半数抑制浓度(IC50)分别为:0.12~2.49、0.02~1.39μM;对TCPTP的半数抑制浓度(IC50)分别为:0.27~2.52、0.05~2.83μM。
所述的金属铜配合物(1)的制备方法,包括如下步骤:
将配体N-(2-吡啶甲基)-L-丝氨酸溶于蒸馏水,滴加CuCl2水溶液,配体与CuCl2的摩尔比为1︰1,室温反应5~9h,过滤得蓝色滤液,室温缓慢挥发,两周后析出蓝色粉末或块状晶体。
所述的金属铜配合物(2)的制备方法,包括如下步骤:
将配体N-(4-羟基苯基)-L-丝氨酸溶于蒸馏水,滴加Cu(Ac)2水溶液,配体与Cu(Ac)2的摩尔比为1︰1,室温反应5~9h,过滤得蓝色滤液,室温缓慢挥发,一周后析出蓝色粉末或块状晶体。
本发明的优点和效果:
本发明的铜配合物是铜离子与手性分子丝氨酸N衍生物在室温条件下反应得到,制备方法方便简单,产物纯度高,产率高。电喷雾质谱表明两种配合物在溶液中能够稳定存在,其组分与固体一致。热分析表明两种配合物在室温能够稳定存在,并且都是以合成得到的形式存在的。
本发明提供的铜配合物通过半数抑制浓度(IC50)的测定得知它们对蛋白酪氨酸磷酸酶(PTPs)的活性有明显抑制作用,对不同PTPs的抑制能力不同,配合物2对PTP1B显示出较好的选择性。
附图说明
图1本发明铜配合物(1)的晶体结构图
图2本发明铜配合物(2)的晶体结构图
图3-1本发明铜配合物(1)的电喷雾质谱图
图3-2本发明铜配合物(2)的电喷雾质谱图
图4-1本发明铜配合物(1)的热分析图
图4-2本发明铜配合物(2)的热分析图
图5本发明铜配合物(1)、(2)抑制PTP1B活性的IC50值测定曲线
图6本发明铜配合物(1)、(2)抑制TCPTP活性的IC50值测定曲线
具体实施方式
实施例1.本发明铜配合物[CuL1Cl(H2O)](1)的制备及晶体培养方法。
将配体N-(2-吡啶甲基)-L-丝氨酸溶于蒸馏水,滴加CuCl2水溶液,配体与CuCl2的摩尔比为1︰1,室温反应5~9h,过滤得蓝色滤液,室温缓慢挥发,两周后析出蓝色块状晶体,抽滤,分别用水、甲醇和乙醚各洗涤三次,真空干燥,产率为51~65%。元素分析:理论值:C 34.62,H 4.20,N 8.97;实验值:C 34.87,H 4.13,N 8.82。
实施例2.本发明铜配合物[Cu(L2)2]·H2O(2)的制备及晶体培养方法。
将配体N-(4-羟基苯基)-L-丝氨酸溶于蒸馏水,滴加Cu(Ac)2水溶液,配体与Cu(Ac)2的摩尔比为1︰1,室温反应5~9h,过滤得蓝色滤液,室温缓慢挥发,一周后析出蓝色块状晶体。抽滤,分别用水、甲醇和乙醚各洗涤三次,真空干燥,产率为50~63%。元素分析:理论值:C 47.85,H 5.22,N 5.58;实验值:C 47.97,H 5.07,N 5.49。
配合物的晶体结构测定:
晶体结构测定采用北京同步辐射源,使用MARCCD-165探测器收集衍射数据 数据经HKL2000还原后,用SHELXL-97直接法解得晶体结构,并经Lorentz和极化效应修正。C/O原子采用理论加氢详细的晶体测定数据见表1。晶体结构见图1、图2。
表1配合物的晶体学数据
配合物的电喷雾质谱:
为了研究配合物在溶液中的存在形式,将少量的配合物(1)和(2)固体粉末溶于水,取上清液,上样到电喷雾质谱仪,采用电喷雾离子源,以正离子方式检测并记录数据。图3-1和图3-2是配合物(1)和(2)的正离子电喷雾质谱图。所有图谱中都能观察到相应配合物的分子离子峰。表2是配合物(1)和(2)的正离子电喷雾质谱归属。结果表明,实验值与理论值一致,配合物(1)和(2)在溶液中是以合成得到的形式稳定存在。
表2配合物(1)和(2)的正离子电喷雾质谱归属
配合物的热分析:
热分析结果表明铜配合物在170℃以上才开始分解,说明它们具有较高的热稳定性,在室温能够稳定存在,见图4-1、图4-2。
实施例3.本发明铜配合物对PTP1B、TCPTP抑制效果检测。
IC50测定原理:
蛋白酪氨酸磷酸酶(PTPs)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,该产物在405nm处有很强的吸收。PTPs与配合物作用后,通过检测405nm处吸光度值的变化来间接检测酶活性的变化情况。
IC50值的意义:
IC50指的是酶的活性降低为原活性的一半时,此时的抑制剂浓度,以此来衡量抑制剂的抑制效果,IC50数值越小,说明抑制剂抑制PTPs活性的效果就越好,以此为依据来检测抑制率。
IC50的测定方法:
酶活性抑制实验的测定是以0.1M对硝基苯磷酸二钠盐(pNPP)为反应底物在pH为7.20的MOPS缓冲体系[20mM吗啉代丙烷磺酸(MOPS),50mM NaCl]中进行的。
将配合物用二甲基亚砜(DMSO)或水溶解,配成10-2M的母液,再用DMSO或水稀释成不同浓度的溶液(10-3M、10-4M、10-5M、10-6M、10-7M、10-8M、10-9M)。用MOPS缓冲溶液将所要用的PTPs稀释至一定浓度(现用现配)。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,37℃水浴恒温30min后,用2μl(0.1M)的pNPP启动反应,30min后,加5μl(2M)的NaOH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λ=405nm处的吸收强度。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,也就是IC50值。
所有测定过程都设空白及对照实验,以排除溶剂和配合物本身颜色的干扰。每次都用新配制的配合物溶液,并且重复三次以上平行实验。实验结果:配合物(1)、(2)对PTP1B的半数抑制浓度(IC50)分别为:0.12~2.49、0.02~1.39μM(见图5);对TCPTP的半数抑制浓度(IC50)分别为:0.27~2.52、0.05~2.83μM(见图6)。
Claims (5)
1.丝氨酸N衍生物的金属铜配合物,特征在于,其结构式为:
其晶体学数据:分子式C9H13ClCuN2O4;分子量312.21;温度(K)100(2);波长0.71;晶系四方;空间群P43212;晶胞参数:a=6.3687(4),b=6.3687(18),c=57.028(7),α=90.00,β=90.00,γ=90.00,晶胞体积2313.1(4);晶胞中重复单元数8;计算密度(g/cm3)1.793;吸收系数(mm-1)2.123;晶体大小(mm3)0.10x 0.10x 0.10;吸收校正半经验;精修方法最小二乘法;数据/限制/参数1981/18/156;基于F2的吻合度1.240;最终R因子[I>2σ(I)]R1=0.1000;R因子(所有数据)R1=0.1020。
2.丝氨酸N衍生物的金属铜配合物,特征在于,其结构式为:
其晶体学数据:分子式C20H26CuN2O9;分子量501.98;温度(K)100(2);波长0.71;晶系正交;空间群P212121;晶胞参数:a=8.9040(18),b=9.1530(18),c=24.891(5),α=90.00,β=90.00,γ=90.00,晶胞体积2028.6(7);晶胞中重复单元数4;计算密度(g/cm3)1.644;吸收系数(mm-1)1.135;晶体大小(mm3)0.25x 0.22x 0.20;吸收校正半经验;精修方法最小二乘法;数据/限制/参数6251/0/291;基于F2的吻合度1.194;最终R因子[I>2σ(I)]R1=0.0484;R因子(所有数据)R1=0.0489。
3.根据权利要求1所述的金属铜配合物的制备方法,其特征在于,包括如下步骤:
将配体N-(2-吡啶甲基)-L-丝氨酸溶于蒸馏水,滴加CuCl2水溶液,配体与CuCl2的摩尔比为1︰1,室温反应5~9h,过滤得蓝色滤液,室温缓慢挥发,两周后析出蓝色粉末或块状晶体。
4.根据权利要求2所述的金属铜配合物的制备方法,其特征在于,包括如下步骤:
将配体N-(4-羟基苯甲基)-L-丝氨酸溶于蒸馏水,滴加Cu(Ac)2水溶液,配体与Cu(Ac)2的摩尔比为1︰1,室温反应5~9h,过滤得蓝色滤液,室温缓慢挥发,一周后析出蓝色粉末或块状晶体。
5.如权利要求1或2所述的金属铜配合物用作蛋白酪氨酸磷酸酶的抑制剂;所述的蛋白酪氨酸磷酸酶是PTP1B或TCPTP。
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