CN114957294B - 一种n-杂环硫代氨基脲混价铜配合物的制备方法和应用 - Google Patents
一种n-杂环硫代氨基脲混价铜配合物的制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种N‑杂环硫代氨基脲混价铜配合物的制备方法和应用，铜配合物化学式为[CuII 2(L)2(Cl)2CuI(Cl)]，式中L为(1Z,2E)‑N‑甲基‑2‑(苯基(吡啶‑2‑基)亚甲基)肼硫代亚氨基。该铜配合物的合成条件温和，目标产率高。体外MTT活性研究发现该铜配合物的抗癌能力明显优于顺铂，表现出微摩尔级的抗癌活性。该铜配合物在三维A549球体模型中也表现出良好的细胞抑制作用。细胞划痕实验表明该铜配合物具有良好的抗癌细胞迁移的能力。通过蛋白组学实验发现，该铜配合物通过抑制癌细胞的能量代谢而执行其抗癌能力。本发明的铜配合物不仅可以用于癌症的治疗，而且具有抗癌细胞迁移的能力，具有广泛的应用前景。
Description
技术领域
本发明涉及铜配合物，具体是一种N-杂环硫代氨基脲混价铜(I/II)配合物的制备方法和应用。
背景技术
具有R1R2C=N-NH-(C=S)-NR3R4骨架的硫代氨基脲由于其广泛的生物活性，例如抗氧化剂，抗病毒，抗疟疾和抗增殖活性而受到了药物化学家的广泛关注。特别是，在侧链上具有含氮杂环的N杂环硫代氨基脲在体外和体内均表现出显着的抗癌活性。例如为癌症治疗而开发的Triapine®（3-氨基吡啶-2-甲醛硫代氨基脲）已进入多个临床研究了。通过它们的N-N-S供体系统，N-杂环硫代氨基脲可以作为三齿螯合配体，与多种过渡金属配位。有趣的是，早期研究表明，在体内和体外，多种金属（例如铜和锌）与N-杂环硫代氨基脲形成的配合物的抗癌活性均高于游离配体的抗癌活性。
作为所有生物的基本元素，铜不仅参与许多关键的生理过程，例如能量代谢，氧转运，酶活性，和细胞信号传导。而且，大量研究表明，癌细胞中铜水平的升高可以作为癌症治疗的靶标，因为肿瘤组织比正常组织需要更多的铜。此外，Cu 可以以氧化态 I 和 II 中的形成各种配位化合物。Cu(II) 可以与以 N、O、S 和卤化物为供体原子的配体配位，形成四坐标方平面、五坐标三角双锥体和六坐标八面体几何形状。相比之下，Cu(I) 化合物中的配位数在 2 和 4 之间变化，包括两坐标线性、三坐标三角形和四坐标四面体几何形状。最近的证据还证实了铜在癌症进展和发展中的重要性，因为它在促进血管生成、转移和癌症生长方面具有抑制活性。因此，铜配合物，特别是N-杂环硫代氨基脲铜配合物，的设计和开发作为抗癌剂具有巨大的价值，已显示出巨大的希望。
发明内容
本发明提供一种可以与2价铜离子配位的(E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼碳硫酰胺的配体，利用该配体，合成了一种混价（+1和+2）铜配合物。
实现本发明目的技术方案如下：
一种N-杂环硫代氨基脲混价铜配合物，它的化学式为[CuII 2(L)2(Cl)2CuI(Cl)]，其中L为(1Z, 2E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼硫代亚氨基；Cu(II)金属与HL配体配位，HL上的氢会脱去，配体变成阴离子，所以化学式中用L表示；同时，由于配体和Cl离子的还原，部分Cu(II)在溶液中还原为Cu(I)，并与2个N和一个Cl配位。
该混价Cu(I/II)配合物的结构式如下：
X-射线单晶衍射研究显示，该混价Cu(I/II)配合物属于具有C 2/c空间群的单斜晶系；晶胞参数为：a (Å) 22.3281(9), b (Å) 8.1420(4), c (Å) 18.5535(10), α (o)90.00, β(o) 111.551(5), γ (o) 90.00。在该配合物中存在三个Cl原子，三个Cu原子和两个单负三齿L配体；四配位的Cu中心显示+2氧化态，而三配位的Cu中心为+1氧化态。
上述式所示混价Cu(I/II)配合物的制备方法如下：
将CuCl2·2H2O加入到含有(E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼碳硫酰胺的甲醇溶液中，55-65℃回流1-2小时；然后，常温静置、析晶，收集晶体，即得到所述的混价Cu(I/II)配合物。
所述CuCl2·2H2O与(E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼碳硫酰胺的摩尔比为3:2；所述(E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼碳硫酰胺与甲醇溶液的配比为1mmol:10 mmol。制备时，可按上述配比的倍数添加原料。
本发明的另一目的在于，提供所述的混价Cu(I/II)配合物在制备抗癌（如肺癌）药物方面的应用。
本发明的另一目的在于，提供所述混价Cu(I/II)配合物可用于抗肺癌细胞（A549）转移。
本发明的另一目的在于，提供所述的混价Cu(I/II)配合物在制备抑制癌细胞能量代谢药物中的应用。
本发明的优点：
（1）实验步骤少，实验条件要求低，且可以高效合成所述的混价Cu(I/II)配合物；
（2）本发明制备了一种N-杂环硫代氨基脲混价铜配合物，该混价Cu(I/II)配合物不仅可以有效杀死癌细胞，还具有良好的抗癌活性和抗癌细胞转移能力。
附图说明
图1 为本发明N-杂环硫代氨基脲混价铜配合物的晶体结构分子图，为了简洁，分子结构中的H删除，对称代码i = – x, y, 0.5 – z。
图2 为用指定浓度的实施例2的混价铜配合物处理3D A549肿瘤球体的形态学变化图，比例尺：500 μm。
图3 为通过伤口愈合测定实施例2的混价铜配合物对A549细胞的抗迁移作用图。
图4为实施例2的混价铜配合物（0.2 μM）作用A549细胞24 h后，GO（geneontology）功能分类的差异累积蛋白图。
图5为实施例2的混价铜配合物（0.2 μM）作用A549细胞24 h后，GO（geneontology）富集分析差异表达的蛋白图。
图6为实施例2的混价铜配合物（0.2 μM）作用A549细胞24 h后，基于KEGG（KyotoEncyclopedia of Genes and Genomes）数据库的差异表达蛋白的通路分析图。
具体实施方式
下面结合实施例和附图对本发明内容作进一步的详细说明，但不是对本发明的限定。
实施例中，N-甲基肼甲硫酰胺，3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴化物（MTT），苯基（吡啶-2-基）甲酮和CuCl2·2H2O购自Sigma-Aldrich。其余所有试剂和溶剂均从商业来源获得，且无需进一步纯化即可使用。
实施例1
(E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼碳硫酰胺配体（HL）的合成与表征：
将N-甲基肼甲硫酰胺（0.51 g，5 mmol）和苯基（吡啶-2-基）甲酮（0.92 g，5 mmol）在60℃甲醇中回流1 h，得到含(E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼碳硫酰胺配体的黄色溶液；在4℃下缓慢蒸发溶剂并结晶，可生成HL的黄产物，产量0.92 g，产率74％；计算值 C14H14N4 (270.35): C, 62.20; H, 5.22; N, 20.72。实测值: C, 61.92; H, 5.61;N, 20.42。m/z: 269.08 [M – H]+。
实施例2
混价铜配合物的制备和结构表征：
将6 mmol 的CuCl2·2H2O加入到4 mmol 的HL配体的甲醇（40 mmol）溶液中，在55-65℃回流1-2小时；然后将混合溶液放置在常温环境，通过缓慢蒸发滤液溶剂而获得黑色的块状混价Cu(I/II)配合物，产率：61%，计算值C28H26Cl3Cu3N8S2 (835.66): C, 40.24; H,3.14; N, 13.41。实测值: C, 40.07; H, 3.51; N, 13.21。
混价Cu(I/II)配合物单晶结构表征：在Mo-Kα源（λ = 0.71073 Å）的Bruker SMARTApex II CCD衍射仪上收集混价Cu(I/II)配合物的结构数据。通过SHELXTL 5.1软件中的直接法（Direct methods）求解，并通过全矩阵最小二乘法进行结构优化。H原子放置在几何上理想的位置，并通过骑式模式约束在其母原子上。Cu(I/II)配合物的部分晶体参数和键合参数分别列于表1和表2中。
表1. Cu(I/II)配合物晶体参数
表2. Cu(I/II)配合物的键长（Å）和键角（º）
i = - x, y, 0.5 - z。
如图1所示，X-射线单晶衍射显示，该混价铜配合物中存在三个Cl原子，三个Cu原子和两个单负三齿L配体；四配位的Cu中心显示+2氧化态，而与一个Cl阴离子和来自两个L配体的两个N原子配位的Cu中心显示+1氧化态。
实施例2制备的混价Cu(I/II)配合物体外抗癌活性研究：
人肺癌细胞A549，耐顺铂肺癌细胞A549/DDP和人正常肾细胞HK-2，用含1%链霉素/青霉素和10%的胎牛血清的完全培养液置于培养箱中培养。由表3中可见，Cu(I/II)配合物的IC50值显著低于HL配体和CuCl2·2H2O的IC50值，这表明HL与CuII离子的螯合可能是导致混价铜配合物高细胞毒性的原因。进一步地，Cu(I/II)配合物显示出比顺铂更优异的体外抗癌能力。此外，Cu(I/II)配合物对A549和A549cisR表现出相当的抗癌活力，表明Cu(I/II)配合物可以克服耐药性。
表3. 混价铜配合物抑制人癌细胞系生长的IC50值（48 h，μM）。
通过3D A549肿瘤球评估实施例2制备的混价Cu(I/II)配合物的抗癌能力：
与单层肿瘤模型相比，多细胞三维（3D）肿瘤球体能够更准确地模拟实体瘤的一些要素，例如可溶性介质的生理反应、分泌、耐药机制以及空间结构。因此，使用多细胞3D 的A549肿瘤球体模型来评估混价Cu(I/II)配合物的抗肿瘤潜力。将含有600个A549细胞培养基加入到超低附着率的圆底96孔板（Corning®，Sigma-Aldrich）培养。温育2天后，将所选的球体用不同浓度（0-，0.4-和0.8- μM）的Cu(I/II)配合物处理7天，隔天观察并拍照（分别是第0天，第2天，第4天和第6天），如图2所示，分为对照组（0 μM）、0.4 μM组和0.8 μM组。图2显示用混价Cu(I/II)配合物处理后对A549肿瘤球体的抑制作用。对照组中的3D肿瘤球非常紧凑并且肿瘤球体的表面是光滑的。而用0.4 μM组和0.8 μM组的混价Cu(I/II)配合物，特别是0.8 μM组的混价Cu(I/II)配合物，处理3D球状体导致3D球体表面的崩解，发生细胞膜破裂和细胞渗漏，更多边缘细胞从球状体松散。
实施例2制备的混价铜配合物的伤口愈合实验：
为了评估混价Cu(I/II)配合物的抗转移活性，在A549细胞系中进行伤口愈合实验测定。对于伤口愈合测定，将2.5 mL的A549细胞的悬浮液加入到6孔板中并培养直至90％融合度。随后，使用移液管尖端（无菌）在单层细胞中划痕而形成伤口间隙。用PBS仔细冲洗细胞碎片，加入仅含0.8％v/v FBS的培养基中培养。伤口愈合24h测定实验结果如图3所示，分为对照组（0 μM）、0.2 μM和0.4 μM混价铜配合物组，分别观察各组在0 h和24 h，A549细胞的迁移情况，结果显示，未处理的对照细胞快速迁移，而用混价Cu(I/II)配合物处理的细胞迁移明显降低，这表明混价Cu(I/II)配合物抑制了A549细胞的迁移能力，即具有抗转移能力。
实施例2制备的混价铜配合物蛋白组学研究：
蛋白质组学分析是一种高分辨率且通量高的过程，可提供蛋白质水平上涉及疾病或生物学过程的高级信息，并且该知识可用于揭示治疗剂的潜在抗癌机制。经过质量验证后，对5471种蛋白质进行了定量。其中，根据标准：P <0.05，比率≥1.2（上调）或比率≤0.883（下调），观察到与对照组相比，混价铜配合物处理组差异积累的1001种蛋白质。在这些差异蛋白中598种上调，403中蛋白下调。为了确定这些差异表达蛋白的特征和功能，对它们进行了基于细胞成分，生物学过程和分子功能的Gene Ontology（GO）分类分析。差异表达的蛋白质的GO分析结果如图4所示。以GO条目中> 40％的基因百分比为限。细胞成分（cellular component）分析表明，大多数差异蛋白属于protein-containing complex（含蛋白质的复合物），membrane（膜），organelle part（细胞器部分），organelle（细胞器）和cell part（细胞部分）。生物学过程（biological process）分析表明，大多数差异蛋白属于biological regulation（生物调节），developmental process（发育过程），metabolicprocess（代谢过程），response to stimulus（对刺激的反应），cellular process（细胞过程），localization（定位）和cellular component organization or biogenesis（细胞成分的组织或生物发生）。分子功能（molecular function）的GO分类分析表明，大多数差异蛋白属于binding（结合）和catalytic activity（催化活性）。
为了确定差异表达的蛋白质是否在某些功能类型中显着富集，我们进一步使用GO分类对差异表达的蛋白质进行了富集分析。图5中显示了10个最丰富的GO项。其中细胞成分GO富集分析条目主要与mitochondrial matrix，mitochondrial respiratory chaincomplex I和catalytic step 2 spliceosome有关。分子功能的GO富集分析条目主要与pre-mRNA binding，NADH dehydrogenase (ubiquinone) activity和2 iron, 2 sulfurcluster binding相关。生物过程的GO富集分析条目主要与ubiquinone biosyntheticprocess，mitochondrial electron transport, NADH to ubiquinone和mitochondrialrespiratory chain complex I assembly等有关。
Kyoto Encyclopedia of Genes and Genomes（KEGG）途径分析能够更系统和全面地了解细胞的生物学过程。因此，我们研究了显着富集的KEGG途径，以确定受Cu(I/II)配合物处理显着影响的信号转导和代谢途径。如图6所示，10个最重要的作用通路是：Valine,leucine and isoleucine degradation，Microbial metabolism in diverseenvironments，Citrate cycle (TCA cycle)，Oxidative phosphorylation，Carbonmetabolism，Parkinson disease，Non-alcoholic fatty liver disease (NAFLD)，Spliceosome，Huntington disease和Thermogenesis。以上10个作用通路表明，混价铜配合物可以通过能量代谢途径，如Citrate cycle，Oxidative phosphorylation和Thermogenesis，作用于癌细胞。
Claims (6)
1.一种N-杂环硫代氨基脲混价铜配合物，其特征在于，所述混价铜配合物的化学式为[CuII 2(L)2(Cl)2CuI(Cl)]，其中L为(1Z, 2E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼硫代亚氨基；
该混价铜配合物的结构式如下：
。
2.如权利要求1所述的N-杂环硫代氨基脲混价铜配合物的制备方法，其特征在于：将CuCl2·2H2O加入到含有(E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼碳硫酰胺的甲醇溶液中，55-65℃回流1-2小时；然后，常温静置、析晶，收集晶体，即得到所述的混价铜配合物。
3.如权利要求2所述的N-杂环硫代氨基脲混价铜配合物的制备方法，其特征在于：所述CuCl2·2H2O与(E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼碳硫酰胺的摩尔比为3:2；
所述(E)-N-甲基-2-(苯基(吡啶-2-基)亚甲基)肼碳硫酰胺与甲醇溶液的配比为1mmol:10 mmol。
4.如权利要求1所述的N-杂环硫代氨基脲混价铜配合物的应用，其特征在于：所述混价铜配合物在制备抗癌药物中的应用。
5.如权利要求1所述的N-杂环硫代氨基脲混价铜配合物的应用，其特征在于：所述混价铜配合物在制备抗癌细胞转移药物中的应用。
6.如权利要求1所述的N-杂环硫代氨基脲混价铜配合物的应用，其特征在于：所述混价铜配合物在制备抑制癌细胞能量代谢药物中的应用。
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