CN106008609B - 一种环金属铂配合物及其制备方法 - Google Patents
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Abstract
本发明公开了一种环金属铂配合物及其制备方法，其中环金属铂配合物的结构式为：
Description
一、技术领域
本文涉及一种环金属铂配合物及其制备方法，是一种对癌细胞杀伤性强、对健康细胞毒性小、能与蛋白质结合导致荧光增强的抗癌药物。
二、背景技术
癌症是当今人类世界所面临最主要的社会问题之一，它的产生是由很多社会或自然问题引起，比如：人口老龄化，吸烟、空气污染、水污染等。如何有效的预防和治疗癌症已经成为科学研究的当务之急。现阶段临床治疗癌症的方式主要有：手术治疗、放射治疗以及化学治疗三种方式。但是，手术治疗创伤大、风险高及产生并发症等缺陷；放射治疗在杀死癌细胞的同时也会损伤健康细胞，且癌症往往会在8-10个月内复发；化学疗法是目前临床上最常用的治疗方式，很多研究已经制备出各种安全有效的独自或联合作用抗癌药物。
通常来说，化学疗法所使用的药物主要来源是：天然产物的提取和人工合成。紫杉醇、喜树碱等天然提取物是临床上常用的抗癌药物。然而，对于天然提取抗癌药物有几个问题仍需解决：i)高昂的价格、ii)复杂的提取过程、iii)副作用及抗药性、iv)抗癌作用机理不明确。而人工合成抗癌药物的可设计性体现出明显优势。在人工合成药物中，顺铂及其类似物在临床上最有效也是应用最广泛的抗癌药物。但其作用机理尚不明确。文献报道，Pt类抗癌药物产生作用主要是通过同DNA/RNA结合或者使溶酶体自溶从而导致细胞死亡。在治疗过程中对健康细胞产生很大的伤害，而且经长时间使用会使癌细胞产生耐药性。因此，设计合成高效、低毒的新型化学药物对于攻克癌症具有重要意义。
申请人对本申请的主题进行了如下的文献检索：
1、scholar.glgoo.org网检索结果：(2016/4/28)
2、中国知网检索结果：
检索方式一：
篇名-蛋白质诱导荧光增强抗癌药物：无相关文献。
篇名-两种蛋白质诱导荧光增强抗癌药物-环金属铂配合物及其制备方法：无相关文献。
检索方式二：
全文-蛋白质诱导荧光增强抗癌药物：无相关文献。
全文-两种蛋白质诱导荧光增强抗癌药物-环金属铂配合物及其制备方法：无相关文献。
三、发明内容
本发明旨在提供一种环金属铂配合物及其制备方法。本发明以廉价易得的苯甲醛、苯乙酮等为原料，简单高效的合成了有机配体，与氯亚铂酸钾反应，得到目标产物—环金属铂配合物。性质研究表明，本发明环金属铂配合物能够对蛋白质产生荧光增强响应，可应用于活体细胞显影成像。细胞毒性实验表明本发明环金属铂配合物对癌细胞—小鼠乳腺癌细胞(4T1)具有较强的杀伤性，对健康细胞—小鼠胚胎成纤维细胞(3T3)毒性很小。因此，本发明环金属铂配合物在抗癌药物研究领域具有广阔的应用前景。
本发明环金属铂配合物的结构式为：
本发明环金属铂配合物的制备方法，包括如下步骤：
1、在500mL的圆底烧瓶中加入2.12g(20mmol)苯甲醛、6.05g(50mmol)苯乙酮及250mL乙醇，室温搅拌5分钟后加入溶于少量水的5.60g(100mmol)氢氧化钾，常温反应12小时，随后加入150mL 35wt％的氨水，升温至60℃反应4小时；反应结束后冷却至室温，减压抽滤，所得固体用乙醇重结晶，得到中间体1，为白色粉末状固体3.68g。
2、在250mL的圆底烧瓶中加入0.40g(1.3mmol)2，4，6-三苯基吡啶、0.42g(1.0mmol)氯亚铂酸钾及50mL乙酸，130℃下反应3天，反应结束后冷却至室温，抽滤，乙腈重结晶得目标产物Z1，为黄绿色固体；向所得目标产物Z1中加入6mL DMSO，180℃下反应至固体全部溶解，冷却至室温，倒入大量蒸馏水，抽滤得黄色固体，柱层析分离(中性氧化铝装柱，二氯甲烷做洗脱剂)得目标产物Z2，为黄色粉末状固体。
本发明反应过程如下：
与已有技术相比，本发明的有益效果体现在：
1、本发明环金属铂配合物具有对癌细胞杀伤性强、对健康细胞毒性低的特点，可以开发为新一类抗癌药物；
2、本发明环金属铂配合物与蛋白质结合产生荧光增强效应，且光稳定性好，可以应用于生物显影；
3、本发明环金属铂配合物能够对健康细胞的细胞质染色，对癌细胞的细胞核染色，便于进行药物跟踪，进一步进行药物抗癌机理研究。
4、本发明环金属铂配合物含有重金属铂原子，能够运用透射电镜(TEM)分析该化合物在细胞内的分布，探索其作用机理。
5、本发明原料易得、合成路线简短，合成条件温和，产率较高，易于商品化。
四、附图说明
图1是两种目标产物环金属铂配合物的晶体结构图(Z1左，Z2右；氢原子被删掉)，CCDC号Z1:1018678；Z2:1018679，表明两种环金属铂配合物是尚未见报道的新化合物。
图2是牛血清蛋白同两种环金属铂配合物(Z1左，Z2右)结合的荧光光谱，由图可知：随铂配合物浓度增加，牛血清蛋白的荧光淬灭，铂配合物荧光增强，表明环金属铂配合物与蛋白质结合产生荧光增强效应。
图3是环金属铂配合物及顺铂对小鼠乳腺癌细胞(4T1)和小鼠胚胎成纤维细胞(3T3)的毒性测试。分别用不同浓度Z1，Z2和顺铂的PBS溶液培养两种细胞24小时。通过酶标仪测试了不同浓度下的两种环金属铂配合物和顺铂对细胞的毒性大小，结果表明，两种环金属铂配合物对癌细胞的杀伤作用比顺铂更好，而对健康细胞的毒性远低于顺铂，说明两种环金属铂配合物可以作为抗癌药物应用于生物体。
图4是环金属铂配合物对健康细胞(小鼠胚胎成纤维细胞：3T3)和癌细胞(人类肝癌细胞：HepG2)的生物显影图。用含有10μM环金属铂配合物的培养基培养细胞30分钟，用PBS缓冲溶液洗涤3次。通过共聚焦显微成像，得到双光子荧光图、明场图、叠加图。从图中看出，环金属配合物在健康细胞与癌细胞中具有不同的分布：在健康细胞中铂配合物主要分布在细胞质中，而在癌细胞中主要分布在细胞核上，说明该类配合物抗癌机理是破坏细胞核。
图5是环金属铂配合物对健康细胞(3T3)和癌细胞(HepG2)的透射电镜图。由图可见：两种铂配合物分布在健康细胞的细胞质中，而在癌细胞的细胞核上，进一步证明两种铂配合物可以进入癌细胞的细胞核。
五、具体实施方式
1、在500mL的圆底烧瓶中加入2.12g(20mmol)苯甲醛、6.05g(50mmol)苯乙酮及250mL乙醇，室温搅拌5分钟后加入溶于少量水的5.60g(100mmol)氢氧化钾，常温反应12小时，随后加入150mL 35wt％的氨水，升温至60℃反应4小时；反应结束后冷却至室温，减压抽滤，所得固体用乙醇重结晶，得到中间体1，为白色粉末状固体3.68g。收率：60％。1H NMR(400MHz,DMSO)δ8.35(d,J＝7.7Hz,4H),8.21(s,2H),8.06(d,J＝7.6Hz,2H),7.72–7.45(m,9H).
2、在250mL的圆底烧瓶中加入0.40g(1.3mmol)2，4，6-三苯基吡啶、0.42g(1.0mmol)氯亚铂酸钾及50mL乙酸，130℃下反应3天，反应结束后冷却至室温，抽滤，乙腈重结晶得目标产物Z1，为黄绿色固体；向所得目标产物Z1中加入6mL DMSO，180℃下反应至固体全部溶解，冷却至室温，倒入大量蒸馏水，抽滤得黄色固体，柱层析分离(中性氧化铝装柱，二氯甲烷做洗脱剂)得目标产物Z2，为黄色粉末状固体。
Z1：M/z＝577，1H NMR(400MHz,DMSO)δ8.06(d,J＝8.3Hz,2H),7.83(dd,J＝19.3,6.7Hz,4H),7.73(d,J＝7.7Hz,1H),7.63(s,1H),7.46–7.23(m,6H),7.06(t,J＝7.3Hz,1H),6.95(dd,J＝18.6,11.6Hz,1H),2.39(s,3H).
Z2：M/z＝578。1H NMR(400MHz,CDCl3)δ7.84(dd,J＝7.5,1.0Hz,2H),7.74–7.69(m,2H),7.60–7.47(m,7H),7.31(td,J＝7.4,1.3Hz,2H),7.15(td,J＝7.5,1.3Hz,2H),3.80–3.60(m,6H).13C NMR(400MHz,CDCl3)29(CH3),118.0(CH),127.0(C),127.4(CH),127.6(CH),129.0(CH),129.3(CH),138.0(C),140.0(C)152.0(C),158(CH).
表1是两种环金属铂配合物和顺铂对癌细胞的IC50。从表中可以直观的看出两种环金属铂配合物和顺铂对小鼠乳腺癌细胞(4T1)的IC50值分别是3.26、2.56和12.27μM，表明两种环金属铂配合物具有比顺铂更好的抗癌效果。
表1
Claims (2)
1.一种环金属铂配合物，其特征在于其结构式为：
2.一种权利要求1所述的环金属铂配合物的制备方法，其特征在于包括如下步骤：
(1)在500mL的圆底烧瓶中加入20mmol苯甲醛、50mmol苯乙酮及溶剂乙醇，室温搅拌5分钟后加入溶于水的100mmol氢氧化钾，常温反应12小时，随后加入150mL氨水，升温至60℃反应4小时；反应结束后冷却至室温，减压抽滤，所得固体用乙醇重结晶，得到中间体1，为白色粉末状固体；
所述中间体1的结构式为：
(2)在250mL的圆底烧瓶中加入1.3mmol 2，4，6-三苯基吡啶、1.0mmol氯亚铂酸钾及50mL乙酸，130℃下反应3天，反应结束后冷却至室温，抽滤，乙腈重结晶得目标产物Z1，为黄绿色固体；向所得目标产物Z1中加入6mL DMSO，180℃下反应至固体全部溶解，冷却至室温，倒入大量蒸馏水，抽滤得黄色固体，柱层析分离得目标产物Z2，为黄色粉末状固体；柱层析分离的洗脱液为二氯甲烷。
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