CN113024450B - 一种二硫代甲酯钴(iii)配合物及其制备方法和应用 - Google Patents
一种二硫代甲酯钴(iii)配合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种二硫代甲酯钴(III)配合物及其制备方法和应用,钴(III)配合物化学式为[CoIII(L)2]·NO3,其中HL为(Z)‑2‑(苯基(吡啶‑2‑基)亚甲基)肼碳二硫代甲基酯。本发明钴(III)配合物制备简单,配合物在450‑650 nm的可见光谱区域中有明显的荧光,不仅可以用于体外细胞成像,还可以用于体内成像。配合物具有微摩尔级的抗癌活性,明显优于顺铂的抗癌活性。进一步的蛋白组学研究揭示,配合物执行其抗癌能力很可能是通过抑制肿瘤细胞的能量代谢。本发明的配合物不仅可以用于成像,还可以用于癌症的治疗,具有很好的应用价值。
Description
技术领域
本发明涉及钴配合物,具体是一种二硫代甲酯钴Co (III)配合物及其制备方法和应用。
背景技术
几十年来,过渡金属配合物由于其广泛的配位几何形状、配位金属离子的数量和类型、可变的氧化还原态以及配位配体的选择而成为药物化学中的关注焦点。钴是在所有动物中发现的必需微量元素,并被用作维生素B12的辅助因子。因此,它可以调节DNA的合成并维持神经系统和大脑的正常功能。也有证据表明维生素B12对于脂肪酸和氨基酸代谢以及正确的红细胞形成是必需的。钴的配位化学主要由Co(II)和Co(III)衍生物决定。具有低自旋d6电子构型的钴(III)配合物可以还原为d7钴(II)配合物,因此有助于配体的离去。因此,Co(III)/Co(II)通常用于设计和开发氧化还原活化的金属前药。最近,许多钴(III)配合物已发现在医学中的潜在应用。例如,双乙酰丙酮乙二亚胺(Doxovir)的钴(III)配合物作为一种有效的杀菌剂最近完成了II期临床试验。
另一方面,二硫代氨基甲酸酯席夫碱配体,其一般结构类似于三齿杂环硫代半碳胺和配体,最近因其抗增殖,抗阿米巴和抗菌活性而受到广泛关注。而且,这些配体同时具有软硫和硬氮供体原子,它们可以与各种金属离子配位形成具有有趣的理化性质和增强的生物学特性的金属配合物。 因此,在药用无机化学领域,具有二硫代氨基甲酸酯席夫碱配体的Co配合物作为抗癌剂显示出广阔的前景。
金属基配合物的细胞成像可提供有关其潜在生物学应用的有用信息。就癌症治疗而言,化合物成像不仅能提供有关确切肿瘤位置的信息,大小,形状及其与周围组织的关系,还可以实时监控治疗剂以及它们在肿瘤中的释放或激活,从而更好地制定治疗计划并预测治疗反应。本申请公开了一种二硫代甲酯Co(III)配合物不仅在体外和体内均具有良好的抗癌能力,还可以用于活细胞或体外以外的生物成像。
发明内容
本发明提供一种可以与钴离子螯合的(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯的配体,利用该配体,合成了一种二硫代甲酯钴(III)配合物。
实现本发明目的的技术方案如下:
一种二硫代甲酯钴(III)配合物,它的化学式为[CoIII(L)2]·NO3,其中HL为(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯;Co(II)金属与配体配位,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,由于空气氧化,Co(II)在溶液中迅速氧化为Co(III)配合物。
该二硫代甲酯钴(III)配合物的结构式如下:
X射线单晶衍射显示,二硫代甲酯钴(III)配合物属于三斜晶系,空间群P-1;晶胞参数为:a (Å) 9.6521(3), b (Å) 10.1324(3), c (Å) 16.8711(6), α (o) 80.874(6),β(o) 80.754(6), γ (o) 88.934(6);该配合物中的中心金属+3价钴离子与两个HL的硫醇式模式形成六配位结构。
上述式所示钴(III)配合物的制备方法如下:
将Co(NO3)2·6H2O加入到含有(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯的甲醇溶液中,在室温搅拌10 min;然后,室温静置、析晶,收集晶体,即得到所述的二硫代甲酯钴(III)配合物;
所述Co(NO3)2·6H2O与(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯的摩尔比为1:2;
所述(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯与甲醇溶液的配比为1mmol:10 mL。
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,提供所述的二硫代甲酯钴(III)配合物在癌细胞成像中的应用,研究表明上述配合物可富集于胰腺癌细胞(BxPC-3)的线粒体中。
本发明的另一目的在于,提供所述的二硫代甲酯钴(III)配合物在体内成像的应用。
本发明的另一目的在于,提供所述的二硫代甲酯钴(III)配合物在制备抗癌(如胰腺细胞癌)药物方面的应用。
本发明的优点:
(1)通过简单的实验步骤和实验条件,高效合成(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯配体及其钴(III)配合物。
(2)本发明所述钴(III)配合物可同时用于体外和体内成像。
(3)本发明所述钴(III)配合物可以有效杀死癌细胞,并在体内表现出好的抗癌能力。
附图说明
图1为本发明二硫代甲酯钴(III)配合物的晶体结构示意图。为了简洁,溶剂水分子被删除。
图2为用本发明的二硫代甲酯钴(III)配合物与线粒体染料MitoTracker DeepRed FM共孵育的人胰腺细胞癌细胞的共定位图像。
图3为本发明二硫代甲酯钴(III)配合物注射到裸鼠体内的活体成像图。
图4 为不同剂量的二硫代甲酯钴(III)配合物对人胰腺细胞癌(CFPAC-1)裸鼠移植瘤生长体积的变化作用。
图5 为不同剂量的二硫代甲酯钴(III)配合物对人胰腺细胞癌(CFPAC-1)异种移植的体重影响。
图6 为GO功能分类的差异累积蛋白。
图7 为GO富集分析差异表达的蛋白。
图8 为基于KEGG数据库的差异表达蛋白的通路分析。
具体实施方式
下面结合具体实施例进一步详细说明本发明技术方案。
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,肼碳二硫代甲酯和Co(NO3)2·6H2O购自Sigma-Aldrich。其余所有试剂和溶剂均从商业来源获得,并且无需进一步纯化即可使用。
(1)(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯配体(HL)的合成与表征:
通过在MeOH中回流苯基(吡啶-2-基)甲酮(0.92 g,5 mmol)和肼碳二硫代甲酯(0.61 g,5 mmol)1小时,得到含配体(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯的黄色溶液。 在4°C下缓慢蒸发溶剂,可生成HL的黄产物,产量1.19 g(82%)。计算值C14H13N3S2 (287.40): C, 58.51; H, 4.56; N, 14.62。实测值: C, 58.22; H, 4.71; N,14.32。m/z: 286.06 [M – H]+。
(2)二硫代甲酯Co(III)配合物的合成和结构表征:
将5 mmol 的Co(NO3)2·6H2O加入到含有10 mmol 的HL配体的甲醇(100 mL)溶液中,在室温搅拌10 min。然后将混合溶液放置在室温环境,通过缓慢蒸发滤液溶剂而获得褐色的块状二硫代甲酯Co(III)配合物,产率: 63%。计算值C28H30CoN7O6S4 (747.26): C,45.00; H, 3.97; N, 13.12。实测值: C, 45.67; H, 3.56; N, 13.58。
单晶结构表征:室温环境下,在具有λ = 0.71073 Å的 Mo-Kα源的Bruker SMARTApex II CCD衍射仪上收集二硫代甲酯Co(III)配合物的数据。配合物的结构由直接方法求解,并使用SHELXTL 5.1软件包进行结构优化。所有非氢原子进行各项异性热振动参数精修。选择的二硫代甲酯Co(III)配合物[CoIII(L)2]·NO3·3H2O晶体参数和键合参数列于表1和表2中。
表1. 二硫代甲酯Co(III)配合物的晶体数据;
表2. 二硫代氨基甲酸混价铜配合物的键长(Å)和键角(º);
X射线单晶衍射显示,二硫代甲酯钴(III)配合物属于三斜晶系,空间群P-1。如图1所示,该配合物中的中心金属+3价钴离子与两个HL的硫醇式模式形成六配位结构。
(3)二硫代甲酯钴(III)配合物体外抗胰腺癌活性研究:
人胰腺癌细胞(CFPAC-1,BxPc-3和AsPC-1)和人正常胚肺成纤维细胞(WI-38),用含10%的胎牛血清以及1%链霉素/青霉素的完全培养液置于含5%CO和37℃培养箱中培养。表3中可见,Co(III)配合物的IC50值显著低于HL配体的IC50值,表明HL配体的抗癌活性明显受到钴金属配位的影响。此外,Co(III)配合物显示出比顺铂更好的体外抗胰腺癌活性,对于CFPAC-1,BxPc-3和AsPC-1细胞,Co(III)配合物的IC50值分别比顺铂低8.2-,4.1- 和3.9-倍。
表3. 二硫代甲酯钴(III)配合物抑制人胰腺癌细胞系生长的IC50值(48 h, μM);
(4)二硫代甲酯钴(III)配合物细胞成像研究:
金属基复合物的细胞成像可提供有关其潜在生物学应用的有用信息。 几种具有固有荧光的金属络合物,例如Ir(III),Re(I)和Zn(II)络合物可促进活细胞中的细胞成像。如图2所示,共聚焦荧光显微镜能够观察到二硫代甲酯钴(III)配合物在人胰腺癌BxPc-3细胞中的成像能力。使用MitoTracker Deep Red FM进行的共定位研究表明,绿色和红色信号大量合并形成黄色,从而证实了二硫代甲酯钴(III)配合物主要在线粒体区域的积累。靶向线粒体具有显着的优势。因为,线粒体作为真核细胞的动力源,线粒体功能障碍可以阻止癌细胞的快速生长,甚至导致其死亡。而且线粒体中的抗癌药可以避免核切除修复机制,从而可以恢复DNA药物成瘾者。此外,与正常细胞相比,位于肿瘤细胞中的线粒体更容易发生线粒体功能障碍。
(5)二硫代甲酯钴(III)配合物体内成像研究:
小动物活体成像技术是采用高灵敏度制冷CCD 配合特制的成像暗箱和图像处理软件,使其可以直接监控活体生物体内药物的分布情况。取BALB/c裸鼠,腹腔注射Co(III)配合物,剂量为4 mg/kg,分别于药物注射0, 30, 60, 120 min后,在相同曝光强度及曝光时间下,获得荧光显像。用455–495 nm激发和535 nm发射光成像。 立即二硫代甲酯钴(III)配合物注射后,体内无荧光信号。 如图3所示,在30分钟后,观察到强烈的体内荧光,揭示了二硫代甲酯钴(III)配合物在生物成像中的潜在作用,该作用不仅限于体外或活细胞。2小时后,尽管体内荧光减弱,但仍然很明显,表明二硫代甲酯钴(III)配合物的半衰期较长,用于体内成像具有潜力。
(6)二硫代甲酯钴(III)配合物体内的抗胰腺癌作用:
首先建立人胰腺细胞癌CFPAC-1异种移植瘤模型。操作如下:取对数生长期的CFPAC-1细胞,在无菌条件下,接种于30只裸小鼠右侧腋下皮下,细胞接种量为5×106个/只。用游标卡尺测量移植瘤直径,待肿瘤生长至100 mm3左右时挑选生长状态良好且肿瘤大小均一性好的荷瘤裸鼠30只,随机分成3组,每组10只,即对照组、二硫代甲酯钴(III)配合物高剂量组(4 mg/kg)和二硫代甲酯钴(III)配合物低剂量组(2 mg/kg)。如图4所示,在给药第15天后,相对于对照组, 2 mg/kg和4 mg/kg的剂量组的肿瘤体积减小(P<0.05);而2mg/kg和4 mg/kg的剂量组老鼠的体重与对照组老鼠的体重无明显差异(图5)。这些结果表明,二硫代甲酯钴(III)配合物对人胰腺癌CFPAC-1肿瘤的治疗具有作用。
(7)二硫代甲酯钴(III)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,可以提供蛋白质水平上涉及疾病或生物学过程的高级信息,并且该知识对于揭示治疗剂的潜在抗癌机制非常有用。因此,为了获得二硫代甲酯钴(III)配合物的作用机理,进行了基于串联质量标签(TMT)的蛋白质组学分析。
为了获取差异表达蛋白的生物学作用,我们对二硫代甲酯钴(III)配合物进行了GO分析,GO分析是一种采用Gene Ontology分类系统来解释基因集合的技术,该技术依据基因的功能特性,将基因分配到一系列预先定义好的类别中。GO分析提供了一个功能注释以及分类基因数据集通用的描述框架。包括三个方面:细胞组分,分子功能和生物过程。如图6所示,根据GO条目中> 40%的基因百分比,细胞成分分析表明,大多数差异蛋白属于cellpart,organelle part,organelle,membrane和protein-containing complex。对于分子功能,主要差异蛋白属于binding和catalytic activity。生物过程中主要的差异蛋白为response to stimulus,biological regulation,cellular process,metabolic process和cellular component organization or biogenesis。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7中显示10个最丰富的GO项。进一步地,研究了显着富集的KEGG途径,可以确定受二硫代甲酯钴(III)配合物处理显著影响的信号转导和代谢途径。如图8所示,10个最重要的作用通路是:Microbial metabolism in diverse environments(不同环境下的微生物代谢),Metabolic pathways(代谢途径),Carbon metabolism(碳代谢),Biosynthesis ofsecondary metabolites(次生代谢产物的生物合成),Citrate cycle(TCA循环),Valine,leucine and isoleucine degradation(缬氨酸、亮氨酸和异亮氨酸降解),Proteasome(蛋白酶体),Thermogenesis(产热作用),Oxidative phosphorylation(氧化磷酸化)和Epstein-Barr virus infection(EB病毒感染)。从以上10个作用通路,我们可以发现,二硫代甲酯钴(III)配合物主要通过能量代谢途径作用癌细胞。
Claims (4)
1.一种二硫代甲酯钴(III)配合物的用途,其特征在于:所述二硫代甲酯钴(III)配合物在制备癌细胞成像荧光探针中的应用;
所述二硫代甲酯钴(III)配合物的化学式为[CoIII(L)2]·NO3,其中HL为(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯; Co(II)金属与配体配位,HL上的氢会脱去,配体变成阴离子,所以化学式中用L表示;
该配合物的结构式如下:
X射线单晶衍射显示,二硫代甲酯钴(III)配合物属于三斜晶系,空间群P-1;晶胞参数为:a (Å) 9.6521(3), b (Å) 10.1324(3), c (Å) 16.8711(6), α (o) 80.874(6), β(o)80.754(6), γ (o) 88.934(6);该配合物中的中心金属+3价钴离子与两个HL的硫醇式模式形成六配位结构。
2.根据权利要求1所述的二硫代甲酯钴(III)配合物的用途,其特征在于:所述二硫代甲酯钴(III)配合物作为非治疗目的细胞成像剂的应用。
3.一种二硫代甲酯钴(III)配合物的用途,其特征在于:所述二硫代甲酯钴(III)配合物在制备治疗胰腺癌药物中的应用;
所述二硫代甲酯钴(III)配合物与权利要求1所述的配合物相同。
4.根据权利要求1-3任一项所述的二硫代甲酯钴(III)配合物的用途,其特征在于:
所述的二硫代甲酯钴(III)配合物的制备方法是,将Co(NO3)2·6H2O加入到含有(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯的甲醇溶液中,在室温搅拌10 min;然后,室温静置、析晶,收集晶体,即得到所述的二硫代甲酯钴(III)配合物;
所述Co(NO3)2·6H2O与(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯的摩尔比为1:2;
所述(Z)-2-(苯基(吡啶-2-基)亚甲基)肼碳二硫代甲基酯与甲醇溶液的配比为1mmol:10 mL。
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