CN110305147B - 一种苯甲酸衍生物锌配合物及其制备方法和应用 - Google Patents
一种苯甲酸衍生物锌配合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了一种苯甲酸衍生物锌配合物及其制备方法和应用。所述锌配合物的分子式为：[Zn(HL)Br2]，其中配体HL为2‑(3‑(吡啶‑2‑基)‑1H‑吡唑‑1‑基)苯甲酸；配合物的制备方法：将硝酸锌、溴化钾的甲醇溶液滴加到置于圆底烧瓶的配体甲醇溶液中，60～80℃加热冷凝回流4～6h，得无色澄清溶液，过滤，在室温下静置一个星期后滤液中析出无色块状晶体，产率为60％以上。锌配合物属于单斜晶系，空间群为P21/n，其不对称单元由一个Zn2+，一个配体和两个Br‑组成，中心金属Zn2+与两个N、两个Br‑和一个O配位形成变形的四方锥构型，同时Zn2+与另一分子中的配体上的羧基O桥连形成一维链状结构。该配合物对蛋白酪氨酸磷酸酶PTP1B显示出较好的选择性，可在制备治疗糖尿病的药物中应用。
Description
技术领域
本发明涉及金属配合物领域，具体涉及一种苯甲酸衍生物锌配合物及其制备方法和应用。
背景领域
蛋白酪氨酸磷酸酶(PTPs)是细胞内广泛存在的非金属酶类，与蛋白酪氨酸激酶共同调控细胞内酪氨酸的磷酸化水平，在细胞信号传导和调节过程中发挥重要作用。研究表明，PTPs活性紊乱能够引起蛋白酪氨酸磷酸化水平异常，从而引起包括癌症、糖尿病、肥胖、免疫紊乱等在内的多种人类疾病。
在一百多种已经被发现的蛋白酪氨酸磷酸酶中，蛋白酪氨酸磷酸酶1B(PTP1B)是第一个被分离纯化出来的由PTPN1基因编码的非受体PTP，研究显示，PTP1B在胰岛素和瘦素信号中起负调节作用，所以当PTP1B过量表达时，胰岛素受体、胰岛素受体底物以及瘦素等大量去磷酸化，使得胰岛素受体不能与胰岛素结合，导致了胰岛素抵抗，从而引发Ⅱ型糖尿病。PTP1B基因敲除小鼠实验表明，小鼠对胰岛素的敏感性明显增强，并对肥胖具有一定的抵抗性，所以PTP1B被认为是治疗Ⅱ型糖尿病和肥胖的有效靶点，高效、特异、低毒的PTP1B抑制剂也将有望成为潜在的治疗糖尿病和肥胖的候选药物。
考虑到PTPs催化活性位点的保守性，某些PTPs抑制剂的选择性研究仍具有一定的挑战，对于PTP1B来说，由于另外一种酪氨酸磷酸酶T细胞PTP(TCPTP)与其同源性高达80％以上，所以寻找高选择性的PTP1B抑制剂就显得尤为困难，PTP1B抑制剂的选择性也逐渐成为人们研究的热点。
锌作为人体必需的过渡金属元素，基于锌配合物的PTP1B抑制剂相对于目前已进入临床的抗糖尿病钒配合物，其毒副作用明显降低，所以设计合成能够有效且选择性抑制PTP1B活性的锌配合物，将有望开发出高效、特异、低毒的抗疗糖尿病锌配合物药物。
发明内容
本发明的目的在于提供一种苯甲酸衍生物锌配合物及其制备方法，以及将该配合物用作PTP1B抑制剂，进而在制备治疗糖尿病药物中应用。
本发明提供的一种苯甲酸衍生物锌配合物，其分子式为[Zn(HL)Br2]，其中HL为2-(3-(吡啶-2-基)-1H-吡唑-1-基)苯甲酸，结构式为：
本发明提供的苯甲酸衍生物锌配合物的制备方法，制备步骤如下：
(1)将Zn(NO3)2·6H2O、KBr、2-(3-(吡啶-2-基)-1H-吡唑-1-基)苯甲酸分别溶于甲醇；
(2)将上述三种溶液置于一个反应容器中，60～80℃加热回流4～6h，得无色澄清溶液，过滤，一周后滤液中析出无色块状晶体。
所述的步骤(1)中Zn(NO3)2·6H2O、KBr、2-(3-(吡啶-2-基)-1H-吡唑-1-基)苯甲酸物质的量比为2：1：1。
所述反应温度优选为70℃加热回流；所述反应时间优选为5h。
本发明制备的锌配合物属于单斜晶系，空间群为P21/n，晶胞参数：
α＝90°，β＝101.266(3)°，γ＝90°。其不对称单元由一个Zn2+，一个配体和两个Br-组成，中心金属Zn2+与两个N、两个Br-和一个O配位形成变形的四方锥构型，同时Zn2+又通过羧基上的羰基氧桥连形成一维链状结构。
本发明的苯甲酸衍生物锌配合物对PTP1B的半数抑制浓度(IC50)为：0.29μM，对TCPTP的半数抑制浓度(IC50)为：1.6μM，对PTP1B活性的抑制具有较好的选择性，并通过荧光光谱分析，推测锌配合物作用于PTP1B的活性位点。
与现有技术相比本发明的有益效果：本发明的锌配合物是过渡金属锌Zn(NO3)2·6H2O、KBr、苯甲酸配体在加热条件下反应得到，制备的方法简单，产物纯度高，产率高，可达70％。
本发明提供的锌配合物能够有效抑制PTP1B和TCPTP活性，且抑制PTP1B活性的能力明显强于TCPTP，所以该配合物对PTP1B活性的抑制具有高效性和选择性；本发明的锌配合物也将用作治疗Ⅱ型糖尿病的潜在药物候选物。
附图说明
图1本发明锌配合物[Zn(HL)Br2]的配位环境图
图2本发明锌配合物[Zn(HL)Br2]的一维链状图
图3本发明锌配合物[Zn(HL)Br2]抑制PTP1B活性的IC50值测定曲线
图4本发明锌配合物[Zn(HL)Br2]抑制TCPTP活性的IC50值测定曲线
图5本发明锌配合物[Zn(HL)Br2]对PTP1B的荧光滴定光谱图
图6本发明中依次用Na3VO4和配合物[Zn(HL)Br2]滴定PTP1B的荧光谱图
具体实施方式
实施例1.本发明锌配合物[Zn(HL)Br2]的制备及晶体培养方法。
称取0.0594g Zn(NO3)2·6H2O溶于5mL甲醇，0.0238g溶于5mL甲醇，0.0265g(2-(3-(吡啶-2-基)-1H-吡唑-1-基)苯甲酸溶于10ml甲醇，将上述三种溶液置于圆底烧瓶中，70℃加热回流5h，得无色澄清溶液，过滤，一周后滤液在室温下析出无色块状晶体。收集晶体分别用水、甲醇各洗涤三次，真空干燥，产率为70％。元素分析C15H11Br2N3O2Zn：理论值：C,36.73，H,2.26N,8.57；实验值：C,36.86，H,2.23，N,8.74。
实施例2.本发明配合物[Zn(HL)Br2]的单晶X-ray衍射试验条件和晶体结构分析。
尝试了各种结晶的方法，通过常温挥发我们得到配合物的单晶。配合物晶体结构的测试是在显微镜下挑选形状规则、比较透明的块状单晶黏于玻璃丝上，用BrukerAPEX-ⅡCCD衍射仪在北京同步辐射(BSRF)3W1A线站上进行测试。选用石墨单色器
以ω-2θ扫描方式，在室温下收集X-ray衍射数据，晶胞参数通过SMART程序确定，并通过SAINTPLUS程序对原始数据还原、校正。最终数据使用SHELXS-97程序包通过直接法进行解析。最后用SHELXL197(Sheldrick，2008)程序包对其精修，得到的晶胞参数、键长、键角见表如表1和表2，从晶体解析结果可以看出，本发明制备的锌配合物属于单斜晶系，空间群为P21/n，晶胞参数：
α＝90°，β＝101.266(3)°，γ＝90°。其不对称单元由一个Zn2+，一个配体和两个Br-组成，中心金属Zn2+与两个N、两个Br-和一个O配位形成变形的四方锥构型(如图1)，同时Zn2+又通过羧基上的羰基氧桥连形成一维链状结构(如图2)。
表1锌配合物的晶体学数据
表2锌配合物的部分主要键长
和键角数据(°)
实施例3.本发明锌配合物对PTP1B和TCPTP活性抑制的IC50值测定
IC50测定原理：
蛋白酪氨酸磷酸酶(PTPs)能够将其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)，pNP在405nm处有很强的紫外吸收吸收，其摩尔消光系数ε＝1.78×104(mol-1·L·cm)-1，在PTPs抑制实验中，可通过检测405nm处吸光度值的变化来间接检测酶活性的变化情况。
在本实验中PTPs的活性抑制实验均以pNPP为反应底物，在(20mM MOPS,50mMNaCl,pH＝7.24)的MOPS缓冲液中进行，最后用2M的NaOH终止反应，将酶标仪所测数据用origin程序拟合即可得到配合物抑制酶的半数抑制浓度IC50值。通过IC50值的大小可以判断抑制剂抑制能力的强弱，IC50值越小，说明抑制剂的抑制效果越好。
IC50值测定的实验步骤：在96孔板中，前三排加入含酶的MOPS缓冲溶液(50mMNaCl,20mM MOPS,pH＝7.24)，为了扣除溶液体系本身吸收对测定结果的影响，在第四排中加入不含酶的MOPS缓冲溶液，作为空白组。然后在第一列中加入10μL DMSO溶液作为对照组，之后的每一列中，按照浓度递增的顺序依次加入10μL不同浓度的配合物溶液，将96孔板置于水浴锅中，37℃恒温反应30min后，用2μL pNPP启动反应，约半个小时后，96孔板中的溶液变黄，最后加5μL NaOH(2M)终止反应，然后用酶标仪测量反应体系在405nm处的紫外吸光度值，将数据用origin程序拟合处理后，即可得到配合物抑制PTPs活性的IC50值，为了尽可能减少实验误差，每个配合物的IC50值测定结果至少重复三次以上，而且每次配合物可用三天，含酶的MOPS缓冲溶液需要现配现用。实验结果显示，锌配合物[Zn(HL)Br2]能够有效抑制PTP1B活性，其IC50值为0.29μM(如图3)，同时该配合物也能抑制TCPTP活性，其IC50值为1.6μM(如图4)，比较锌配合物抑制两种酶活性的IC50值大小可以发现，该配合物抑制PTP1B活性的能力约是其抑制TCPTP活性能力的6倍，表明该锌配合物对PTP1B的抑制具有较好的选择性。
实施例4.本发明锌配合物对PTP1B的荧光增强作用
蛋白质分子中由于含有酪氨酸和色氨酸残而使其具有天然荧光，当向蛋白溶液中加入一些小分子后，小分子与蛋白分子的结合会影响到蛋白分子微环境的变化，从而引起蛋白分子的荧光变化，可以借助蛋白分子的荧光信号的变化来研究他们的作用模式和机理。所以我们研究了本发明配合物对PTP1B的荧光增强作用。图5所示为扣除了配合物本身的荧光强度之后，配合物滴定PTP1B的荧光光谱图，从图中可以看出随着配合物的浓度逐渐增加，PTP1B在351nm处的荧光强度逐渐增加，直至增加到一定程度后，荧光强度几乎不变，这可能是配合物与PTP1B结合形成的复合物的荧光峰，这个实验结果进一步证明了锌配合物与PTP1B之间的相互作用。
实施例5.本发明锌配合物与PTP1B可能结合位点的研究
众所周知，抑制剂对对酶活性的抑制作用方式有很多种，其中较为常见的就是竞争型抑制，该类抑制剂也称为竞争型抑制剂，它指的是抑制剂与底物在结构上有相似性，与底物竞争性的与酶的活性位点结合，为了证明配合物是否与PTP1B的活性位点结合，如图6所示，首先用钒酸钠滴定PTP1B至荧光强度不变，钒酸钠与PTP1B活性位点完全结合，继续向二者的混合溶液中滴加配合物，发现配合物的加入并没有改变溶液的荧光强度，表明钒酸钠“锁定”PTP1B的活性位点后配合物不能再与PTP1B结合，由此推测出配合物[Zn(HL)Br2]可能作用于PTP1B的活性位点。
Claims (7)
1.一种苯甲酸衍生物锌配合物，其特征在于结构式为：
其不对称单元由一个Zn2+，一个配体和两个Br-组成，中心金属Zn2+与两个N、两个Br-和一个O配位形成变形的四方锥构型，同时Zn2+又通过羧基上的羰基氧桥连形成一维链状结构。
2.如权利要求1所述的锌配合物的制备方法，其特征在于合成步骤如下：
（1）将Zn(NO3)2 ·6H2O、KBr与2-（3-（吡啶-2-基）-1H-吡唑-1-基）苯甲酸分别溶于甲醇溶液；
（2）将上述三种溶液置于一个反应容器中，60~80℃加热回流4~6 h，得无色澄清溶液，过滤，一周后滤液中析出无色块状晶体。
3.如权利要求2所述的一种锌配合物的制备方法，其特征在于，所述的步骤（1）中Zn(NO3)2 ·6H2O、KBr、2-（3-（吡啶-2-基）-1H-吡唑-1-基）苯甲酸物质的量比为2：1：1。
4.如权利要求2所述的一种锌配合物的制备方法，其特征在于，所述反应温度为70℃加热回流；所述反应时间为5 h。
5.如权利要求1所述的一种锌配合物在制备PTP1B抑制剂中的应用。
6.如权利要求1所述的一种锌配合物在制备TCPTP抑制剂中的应用。
7.如权利要求1所述的一种锌配合物在制备治疗糖尿病药物中的应用。
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