CN108658849B - 一种Cr(III)配合物及其制备方法和应用 - Google Patents
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Abstract
本发明涉及一种联吡啶二羧酸衍生物的金属铬(III)配合物及其制备方法和生物应用，属于药物开发研究领域。本发明所述的Cr(III)配合物化学式为：{[Cr(Bpybc)1.5(H2O)3]}n，其制备方法：将铬盐(III)和浓硝酸用水溶解，加热回流，形成深紫色铬溶液；加入配体二氯化1,1’‑二(3‑苯甲酸)‑4,4’‑联吡啶(Bpybc)，搅拌加热回流，停止反应，静置，过滤，将所得滤液常温自然挥发，得到紫红色晶体。本发明Cr(III)配合物可在制备降糖减肥药物中应用。本发明对于研发推广有实际应用价值的铬营养剂和遏制目前不断增多的肥胖症及糖尿病具有重要的意义。
Description
技术领域
本发明涉及金属配合物，具体为一种Cr(III)配合物及其制备方法和应用。
背景技术
铬是人体一种必需微量元素，广泛分布于体内各个器官和体液中，铬的主要功能是参与糖的代谢，协助胰岛素分泌和发挥作用。相关研究表明，有机铬(III)水平可影响空腹血糖、循环胰岛素水平、胰岛素结合力、β细胞敏感性、受体数量及糖代谢中酶的活性。随着年龄的增长，人体内的Cr(III)含量会逐渐减少，Cr(III)的缺乏可能会导致组织对胰岛素的敏感性降低。目前，糖尿病发病率在全球呈年轻化趋势。
目前市售营养补铬剂其成分多为：富铬酵母、烟酸铬、氨基酸铬和吡啶铬等。但研究表明：这些配合物有的结构特别稳定，在转运过程中不会被铬转运蛋白分解，而是以完整结构由肠道经血液系统输运到细胞内部，在细胞内维生素C的作用下分解，释放出铬离子；有的在与维生素C作用的过程中会产生羟基自由基，引起DNA损伤；另外，其水溶性差，生物利用率低(2％)，其使用效果逐渐受到人们怀疑。因此人们试图从配体角度对铬配合物进行修饰，合成高效、低毒、易吸收的新型有机Cr(III)配合物具有重大意义。
发明内容
本发明的目的在于提供一种Cr(III)配合物及其制备方法，以及该配合物在制备降糖减肥药物中的应用。
根据本发明的一个方面，提供一种Cr(III)配合物，其分子结构式为：
该配合物化学式为：{[Cr(Bpybc)1.5(H2O)3]}n。
根据本发明的另一方面，本发明提供以上Cr(III)配合物的制备方法，反应式：
包括如下步骤：
1)将铬盐(III)和浓硝酸用水溶解，加热回流，形成了深蓝色溶液；
2)将深蓝色溶液转入反应器并加入固体二氯化1,1’-二(3-苯甲酸)-4,4’-联吡啶，搅拌加热回流4～5h，静置后过滤，除去杂质；
3)将得到的滤液静置，常温下自然挥发，得到紫红色晶体。一般而言，在三天到两周时间时间内可获得上述紫红色晶体。
进一步地，步骤1)中所述的铬盐(III)为硝酸铬。
进一步地，步骤1)中所述的铬盐(III)和浓硝酸的摩尔比为1:1。
进一步地，步骤2)中所述的二氯化1,1’-二(3-苯甲酸)-4,4’-联吡啶与铬盐(III)的摩尔比约为2～5:1。
本发明的另一方面，提供上述Cr(III)配合物在制备降糖减肥药物中应用。
与现有技术相比，本发明的Cr(III)配合物，可充分利用配体分子中联吡啶上N原子和羧酸根对三价铬离子的配合作用，同时结合配体二氯化1,1’-二(3-苯甲酸)-4,4’-联吡啶(Bpybc)自身特有的羧基基团，可改善吡啶甲酸铬配合物水溶性、稳定性以及生物利用率。本发明对于研发二代含铬营养剂、推广有实际应用价值的铬营养剂以及遏制目前不断增多的肥胖症及糖尿病病例具有十分重要的意义。
附图说明
图1本发明Cr(III)配合物中铬的配位环境图。
图2本发明Cr(III)配合物中铬的立体空间结构图。
图3本发明Cr(III)配合物的紫外光谱图。
图4本发明Cr(III)配合物的红外光谱图。
具体实施方式
实施例1
Cr(III)配合物的制备及结构表征
称取0.40g(1.0mmol)Cr(NO3)·9H2O和80μl(63％)浓HNO3置于100mL圆底烧瓶中，加入40mL蒸馏水，加热回流，形成深蓝色溶液；缓慢加入1.00g二氯化1,1’-二(3-苯甲酸)-4,4’-联吡啶(2.0mmol)，加热回流反应4h，停止反应，过滤，将所得滤液静置，常温自然挥发，两周后得到紫红色晶体，产率40％。
元素分析测定结果，由分子式C39H42CrN3O12理论值(％)：C,58.79；H,5.31；N,5.27；实验值(％):C,58.23；H,5.13；N,5.34。
晶体测定结果(见附图1)：结构简式为[Cr(Bpybc)1.5(H2O)3]·3H2O，其中配体为Bpybc＝1,1'-bis(4-carboxybenzyl)-4,4'-bipyridinium，分子式为C39H42CrN3O12分子量为796.75，三方晶系，空间点群为R-3，
α＝90°，β＝90°，γ＝120°，
Z＝6。
紫外-可见吸收光谱：配体二氯化1,1’-二(3-苯甲酸)-4,4’-联吡啶在276nm处有特征吸收峰(附图3，曲线a)，与Cr3+配位后其吡啶环的π-π*吸收峰红移到312nm(曲线b)，说明π共轭体系上的电子云向Cr3+的空d轨道发生转移；
配合物的红外图谱参见图4。
配合物[Cr(L)1.5(H2O)3]·3H2O易溶于水。
实施例2
称取1.0g(2.5mmol)Cr(NO3)·9H2O和200μl(63％)浓HNO3置于250mL圆底烧瓶中，加入80mL蒸馏水，加热回流，形成深蓝色溶液；缓慢加入5.0g二氯化1,1’-二(3-苯甲酸)-4,4’-联吡啶(10mmol)，加热回流反应5h，停止反应，过滤，将所得滤液静置，常温自然挥发，一周后得到紫红色晶体,产率42％。
实施例3
称取0.8g(2.0mmol)Cr(NO3)·9H2O和160μl(63％)浓HNO3置于250mL圆底烧瓶中，加入80mL蒸馏水，加热回流，形成深蓝色溶液；缓慢加入5.0g二氯化1,1’-二(3-苯甲酸)-4,4’-联吡啶(10.0mmol)，加热回流反应大约5h，停止反应，过滤，将所得滤液静置，常温自然挥发，两周后得到紫红色晶体，产率38％。
实施例4：Cr(III)配合物的降糖动物实验
Cr(III)配合物的降糖减肥活性在山西省中医药研究院实验动物中心测定。选取小鼠50只，雌雄各半，室温18～25℃，相对湿度30％～50％，自然光照，自由进食与饮水。高脂饲料配方：普食66.5％、猪油10％、蔗糖20％、胆酸钠1％、胆固醇2.5％。按体重随机分为4组，正常组10只，模型组10只，阳性对照Cr(Pic)3组10只，给药组20只。自实验开始，正常组小鼠给予普通饲料，其余各组均给予高脂饲料，历时2个月。造模成功后开始给药，阳性对照组Cr(Pic)3剂量为50mg/kg，给药组剂量分别为每天10和50mg/kg，模型组采用生理盐水作为对照，每天上午灌胃1次，实验持续8周。实验结束后，禁食18h，称体重，眼眶静脉丛取血，试剂盒测定相关生化指标。各组数据采用SPSS17.0进行统计分析，所有数据均以x±S表示，组间差异采用单因素方差分析，以P<0.05为有显著性差异。实验结果见表1。
表1各项生理生化指标
与正常组比较，▲P<0.05，▲▲P<0.01；与模型组比较，*P﹤0.05，**P﹤0.01
结果表明：
(1)模型组的各项生化指标与正常组相比差异显著，说明高脂食物会对小鼠的血糖血脂浓度升高，低密度脂蛋白浓度提高，高密度脂蛋白浓度降低，同时带来体重增加明显；
(2)与模型组相比，给药组的体重明显减少，血糖降低，总胆固醇和甘油三酯均降低，高密度脂蛋白升高；
(3)与模型组相比，配合物的减肥效果明显，尤其增大给药量对各项指标均产生明显差异性影响。
由此可见，相比与阳性对照组化合物Cr(Pic)3来说，本专利所合成的新型铬配合物[Cr(Bpybc)1.5(H2O)3]·3H2O具有较好的生理降糖减肥活性。这可能是由于：(1)该配合物结构中铬中心直接配位三个水分子，在代谢过程中配位水分子易于解离，导致配合物不稳定，铬离子容易被体内铬转运蛋白所转运；(2)该配合物结构中含有羧基，水溶性好，生物吸收利用率高。
Claims (5)
1.一种Cr(III)配合物，其特征在于，化学式为：[Cr(Bpybc)1.5(H2O)3]·3H2O，其中配体Bpybc=1,1’-二(4-羧苄基)-4,4’-联吡啶。
2.如权利要求1所述的Cr(III)配合物的制备方法，其特征在于，包括如下步骤：
1）将铬盐(III)和浓硝酸用水溶解，加热回流，形成了深紫色溶液；
2） 将深紫色溶液转入反应器并加入配体二氯化1,1’-二(4-羧苄基)-4,4’-联吡啶，搅拌加热回流4~5 h，静置后过滤，除去杂质；
3）将得到的滤液静置，常温下自然挥发，得到紫红色晶体。
3.根据权利要求2 所述的Cr(III)配合物的制备方法，其特征在于，步骤1) 所用铬盐(III)为硝酸铬。
4.根据权利要求2所述的Cr(III)配合物的制备方法， 其特征在于，步骤2)所述的二氯化1,1’-二(4-羧苄基)-4,4’-联吡啶与铬盐(III)的摩尔比约为（2~5）: 1。
5.如权利要求1所述的Cr(III)配合物在制备降糖减肥药物中的应用。
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