CN113461740B - 一种铱配合物及其制备方法和应用 - Google Patents
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Abstract
本发明涉及医药技术领域，特别涉及一种铱配合物及其制备方法和应用，该配合物应用于抗非黑色素瘤皮肤癌的光动力治疗具有较强的疗效，在光照条件下可以破坏NAD+/NADH氧化还原平衡引起细胞死亡，对人非黑色素瘤鳞状皮肤癌细胞株具有很强的生长抑制能力(IC50＝0.0003μM/0.3nM)。对于研究高效低毒的金属配合物光敏剂有重要的意义，以期为临床开发新型的金属抗非黑色素瘤皮肤癌药物奠定理论和实验基础。
Description
技术领域
本发明涉及医药技术领域，特别涉及一种铱配合物及其制备方法和应用。
背景技术
癌症已经成为威胁人类健康的重大疾病，据统计，癌症是全球第二大死因。根据统计，2020年全球新增癌症病例达到1930万，将近1000万人死于癌症，其中非黑色素瘤皮肤癌新增病例占6.2％，位居不同癌症新增病例数第四。由于皮肤癌所发生的皮肤层次和病理类型不同，目前临床上治疗皮肤癌主要是以局部外用药、激光和手术等多种治疗手段联合治疗。
光动力治疗被认为是临床具有良好靶向性的新型肿瘤治疗方法，其作用基础是利用光激发聚集在肿瘤内部的光敏剂，产生活性氧有效杀伤病变组织，同时可减少对病灶周边正常组织的杀伤，以此来获取最佳的治疗效果。目前临床上用于治疗皮肤癌较为成熟的治疗方法是利用5-氨基酮戊酸(5-ALA)进行光动力治疗，具有组织选择性好、操作简便的优点，但是临床数据显示，5-ALA在治疗皮肤癌上的临床疗效稳定性差，不同个体患者的临床疗效差异较大，研究开发新的高效低毒的光敏剂成为研究热点。
与有机化合物相比,金属配合物分子结构具有更好的可塑性，可以通过在配体上修饰引入其它分子活性基团改善其光物理和化学性质，并且金属配合物相对比较稳定，容易在体内环境产生药效，用于肿瘤光动力治疗具有极大的临床应用前景。
发明内容
针对现有技术中的上述不足，本发明提供一种铱配合物。
本发明的另一个目的在于提供上述铱配合物的制备方法。
本发明的另一个目的在于提供上述铱配合物的应用。
本发明的目的通过以下技术方案予以实现：
一种铱配合物，其机构如式(I)：
简记为Ir。
所述铱配合物的制备方法，包括以下步骤：
S1.将2,2':6',2"-三联吡啶和三氯化铱在乙二醇中反应制得铱前体；
S2.再将步骤S1得到的铱前体和2,4,6-三苯基吡啶在乙二醇中反应，反应完毕后加入六氟磷酸盐溶液，即得。
优选地，所述步骤S2中，反应温度为160～200℃，反应时间为22～26h。
优选地，所述步骤S2中，反应温度为180℃，反应时间为24h。
所述铱配合物在抗癌药物上的应用。
所述铱配合物在抗非黑色素瘤鳞状皮肤癌癌细胞的药物上的应用。
与现有技术相比，本发明具有以下技术效果：
本发明公开了一种新型的铱金属配合物及其制备方法，该配合物应用于抗非黑色素瘤皮肤癌(A431细胞)的光动力治疗具有较强的疗效，在光照条件下可以破坏NAD+/NADH氧化还原平衡引起细胞死亡，对人非黑色素瘤鳞状皮肤癌细胞株具有很强的生长抑制能力(IC50＝0.0003μM/0.3nM)。对于研究高效低毒的金属配合物光敏剂有重要的意义，以期为临床开发新型的金属抗非黑色素瘤皮肤癌药物奠定理论和实验基础。
附图说明
图1本发明实施例的铱配合物分子结构；
图2本发明实施例的铱配合物的氢谱核磁共振图谱；
图3本发明实施的铱配合物的紫外吸收和荧光发射光谱；
图4本发明实施例铱配合物对NADH的光催化氧化能力；
图5本发明实施例铱配合物对A431肿瘤细胞的暗毒性和光毒性。
具体实施方式
下面对本发明的具体实施方式作进一步说明。在此需要说明的是，对于这些实施方式的说明用于帮助理解本发明，但并不构成对本发明的限定。此外，下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
下述实验例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
实施例1
一种铱配合物其结构式如图1所示。具体如下：
160℃下，2,2':6',2"-三联吡啶(233.3mg,1mmol)和三氯化铱(328.4mg,1.1mmol)在乙二醇(8mL)中反应，搅拌反应15分钟后将反应液抽滤后得到目标铱前体，为红色固体，产率30.2％。将获得的铱前体和2,4,6-三苯基吡啶在乙二醇(10mL)中于180℃下反应，24小时后冷却至室温，加入六氟磷酸盐溶液。搅拌1小时，得到目标铱配合物(Ir)，将得到的铱配合物粗品经中性氧化铝柱色谱(溶剂：甲醇/二氯甲烷＝1/99)纯化，得到铱配合物，为红色固体，产率为36.4％。通过质谱如图2，和核磁表征，1H NMR(400MHz,DMSO-d6)δ9.07(d,J＝8.2Hz,2H),8.85(d,J＝7.5Hz,2H),8.56(s,2H),8.49(t,J＝8.2Hz,1H),8.30(d,J＝7.3Hz,2H),8.19(d,J＝7.7Hz,2H),8.06(t,J＝7.9Hz,2H),7.83(d,J＝5.9Hz,2H),7.74–7.67(m,2H),7.61(t,J＝7.3Hz,1H),7.38(t,J＝6.7Hz,2H),6.95(t,J＝7.5Hz,2H),6.71(t,J＝7.8Hz,2H),6.08(d,J＝8.4Hz,2H).ESI-MS:[M-PF6 -]+(m/z)：Calc.,731.1783；Found,731.1764。
上述方法获得的铱配合物进一步进行以下实验。
实施例2铱配合物的紫外吸收和荧光发射性质
将含铱配合物(10μM)的不同溶剂溶液的石英比色皿分别放在紫外分光光度计或荧光分光光度计中检测溶液的吸光度和在激发光为465nm的荧光发射强度，结果如图3所示，可见铱配合物的荧光发射强度与溶剂的极性相关。
实施例3铱配合物光催化氧化NADH的能力
将含铱配合物(5μM)和NADH(A339nm＝1)的PBS溶液置于石英比色皿中，放在465nm光源下辐射5min(光剂量为11.7J/cm2)，检测溶液光照前后的吸光度。结果如图4所示，铱配合物在465nm光辐射下，能将还原型辅酶Ⅰ(NADH)氧化成其氧化态(NAD+)，铱配合物对NADH有光催化氧化能力。
实施例4铱配合物对不同肿瘤细胞的暗毒性和光毒性
利用MTT比色法来分析铱配合物对不同肿瘤细胞的抗增殖效应。MTT，中文名叫噻唑蓝，是一种四唑盐，在活细胞中，线粒体内的琥珀酸脱氢酶可将MTT还原，生成一种蓝紫色产物-甲臜(可溶于DMSO)，且该产物在595nm处有吸收峰，故可用A595nm来分析细胞增殖情况。
MTT实验步骤如下：
①先复苏1管A431肿瘤细胞，用新鲜培养液(DMEM培养基+10％胎牛血清+1％盘尼西林和链霉素)培养，传代2次后使用。
②待细胞到达对数生长期时，以10000个/孔的细胞密度接种至2块96孔板中(每孔用100μL培养液培养细胞，一板为光照组，另一板为黑暗组)，送入恒温箱(310K,5％CO2)中培养。
③待其贴壁后，吸出原有培养基，每孔分别加入100μL不同浓度的铱配合物(Ir)和5-氨基酮戊酸(5-ALA)的新鲜培养液，轻轻晃匀，在恒温箱中避光孵育。
④孵育8h后，将光照组的细胞培养板置于525nm波长蓝光灯下光照10min(光剂量为29.56J/cm2)，黑暗对照组的细胞一直置于温箱中避光培养，光照结束后，放回培养箱继续避光孵育。
⑤孵育40h后，在每孔中加入10μL MTT(5mg/mL)，于37℃温箱中继续孵育4h后，吸去上清液，每孔加200μL二甲基亚砜(DMSO)，用酶标仪检测A595nm，计算细胞增殖抑制率，求出IC50值(抑制率等于50％的时候的药物浓度)。
如图5所示，MTT法检测不同浓度的铱配合物和5-ALA在黑暗与光照处理条件下对不同肿瘤细胞的杀伤作用效果不同。实验中的化合物在无光照情况下，对人鳞状皮肤癌细胞株A431没有毒性，但是在光照条件下铱配合物对A431肿瘤细胞株具有很强的生长抑制能力(IC50＝0.0003μM/0.3nM)，而对照的化合物如5-ALA(IC50＝135.58μM)在相同实验条件下对肿瘤细胞的生长抑制能力远远不如本发明的铱配合物，证明本专利的铱配合物具有开发成为高效低毒的光敏剂的巨大潜力。
以上所述仅为本发明专利的较佳实施例而已，并不用以限制本发明专利，凡在本发明专利的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明专利的保护范围之内。
Claims (5)
1.一种铱配合物，其特征在于，其结构式如式(I)：
2.权利要求1所述铱配合物的制备方法，其特征在于，包括以下步骤：
S1.将2,2':6',2"-三联吡啶和三氯化铱在乙二醇中反应制得铱前体；
S2.再将步骤S1得到的铱前体和2,4,6-三苯基吡啶在乙二醇中反应，反应完毕后加入六氟磷酸盐溶液，即得；
所述铱前体的结构式为：
3.根据权利要求2所述铱配合物的制备方法，其特征在于，所述步骤S2中，反应温度为160～200℃，反应时间为22～26h。
4.根据权利要求3所述铱配合物的制备方法，其特征在于，所述步骤S2中，反应时间为24h；反应温度为180℃。
5.权利要求1所述铱配合物在制备抗非黑色素瘤鳞状皮肤癌的药物中的应用。
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