CN112794862A - 长碳链苯基二羧酸基双核铜配合物的合成及抗肿瘤应用 - Google Patents
长碳链苯基二羧酸基双核铜配合物的合成及抗肿瘤应用 Download PDFInfo
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Abstract
本发明涉及配位化学技术领域,具体公开了一系列长碳链苯基二羧酸基抗肿瘤活性双金属核心配合物的制备及其抗肿瘤应用,式中,M为过渡金属二价铜离子,L1为3‑苯基戊二酸酸根,L2为螯合型、多环吡啶类配体2,2'‑联吡啶或邻菲罗啉。本发明以3‑苯基戊二酸、2,2'‑联吡啶、邻菲罗啉三个配体,按照一定比例协同为双中心金属离子配位。本发明制备的配合物具有良好的抗肿瘤活性,甚至超过顺铂。
Description
技术领域
本发明涉及配位化学技术领域,具体涉及一系列长碳链苯基二羧酸基抗肿瘤活性双金属核心配合物的制备及其抗肿瘤应用。
背景技术
自1965年Rosenberg等偶然发现顺铂具有抗动物肿瘤作用并呈现广谱的抗癌生物活性,无机金属配合物的抗癌活性研究及新抗癌活性金属配合物的设计,就吸引了众多科研人员的目光。至今已有数千个新的铂配合物被合成出来,并进行了抗肿瘤活性筛选。超过28种铂类金属配合物进行了临床试验。目前,已在国内外上市的铂类抗肿瘤药物有奥沙利铂、奈达铂、顺铂、卡铂、米铂、依铂和乐铂等。虽然应用广泛,药物种类繁多,但铂系药物仍在临床表现出较严重的毒副性和耐药性。故此,非铂类金属配合物化疗药物的研发备受关注。
金属配合物广泛用于癌症化学疗法和抗癌剂。复杂广泛的配置构型(平面型,四面体型和八面体型等),金属离子和配体本身的固有特性提供了丰富的潜在生物学靶点。一些金属离子在复合物中具有分子内相互作用,或者可以与有机配体相互作用,这可以被利用来获得更好的活性。此外,与复杂的有机合成相比,金属配合物的制备具有反应速度快,一步合成和高重复性的优点。芳香基脂肪链含氧型多羧基配体,有着显著的柔性结构与广泛多样的配位模式,而且常被配位化学合成者所选用。该类配体的柔性脂肪链及多羧基氧型结构为配合物分子的构筑提供出近乎无限的可能性,而芳香基团则对配合物分子晶体内超分子π作用网络提供了作用力基础。在合成具有生物活性金属配合物的过程中,使用芳香基脂肪链多羧酸配体,但随着其脂肪链长度的不断增加,配合物分子的脂溶性也随之增加,并较明显的提高配合物与靶细胞的结合活性,继而表达出更高生物活性。但使用含长脂肪链结构配体的同时,也会伴随着过多自由旋转的碳链原子较大的热震动,而带来合成配合物单晶与其晶体结构解析的不便利性。
发明内容
针对现有技术中存在的不足,本发明目的之一是提供一类新的具有药用价值的金属配合物。
本发明的金属配合物,通式是[Cu2(L1)2(L2)2]。
式中,铜离子为正二价,L1为3-苯基戊二酸酸根(-C11H10O4);式中L2为螯合型、多环吡啶类配体2,2′-联吡啶或邻菲罗啉。
本发明筛选的金属配合物分别是:
①3-苯基戊二酸阴离子·2,2′-联吡啶合铜(II)
[Cu2(3-phenylglutaric acid)2(2,2′-bipyridine2)2]
其结构式如下:
②3-苯基戊二酸阴离子·邻菲罗啉·羟基合铜(II)
[Cu2(3-phenylglutaric acid)2(2,2′-bipyridine2)2(hydroxyl)2]
其结构式:
本发明上述两金属配合物的合成路线表示如下:
所述两金属配合物均为深蓝色块状晶体,均为三斜晶系,空间群均为P-1。
所述3-苯基戊二酸阴离子·2,2'-联吡啶合铜(II)的晶胞参数为 α/°=1108.135(5),β/°=105.520(5),γ/°=97.642(5),所述配合物中Cu与L1的羧基上O配位、与L2吡啶环上的N配位。
所述3-苯基戊二酸阴离子·邻菲罗啉·羟基合铜(II)的晶胞参数为 α/°=115.384(13),β/°=99.523(10),γ/°=101.637(12),所述配合物中Cu与L1的羧基上O配位、与L2吡啶环上的N配位。
具体操作如下:
将4-6mmol/L 3-苯基戊二酸乙醇溶液与4-6mmol/L氯化铜水溶液混合,然后用0.1-1.0mol/L(优选为0.5mol/L)的KOH溶液调节反应体系pH值在3-10,然后在搅拌条件下反应4-6小时,再加入4-6mmol/L多环吡啶类配体2,2'-联吡啶或邻菲罗啉的乙醇溶液,而后再持续搅拌反应2-4小时,停止反应并过滤反应液,将过滤所得清液静置,析出深蓝色晶体,用40-60v/v%乙醇(优选为50v/v%乙醇)洗涤,干燥。
上述反应体系中,3-苯基戊二酸、二价铜离子以及多环吡啶类配体的摩尔比之比控制在1:1:1。
本发明目的之二是提供上述金属配合物在制备具有抗癌活性药物中的用途。
与现有技术相比,本发明具有如下优点和有益效果:
本发明选用3-苯基戊二酸做为芳香基长脂肪链多羧酸配体,为避免在合成中出现多羧酸桥联配位而产生配位聚合物,从而带来的目标化合物溶解性的降低,继而影响后续配合物生物活性的表达。本发明使用多环含氮螯合杂环物质,及时对合成中的长脂肪链多羧酸配合物在分子层面进行封端、切割操作。产出溶解性适中的非聚合型双金属核单分子配合物。同时,吡啶基团具有的刚性平面也具有辅助配合物多表达生物活性的潜力。铜是人体内不可替代的微量元素,在机体中对蛋白质、酶的平衡起着重要的调节作用。恶性营养不良综合征(Kwashiorkor)、脊髓病、白癜风等疾病主要与铜缺乏有关。铜是组成酶活性的重要部分。如果缺少铜,体内重要的酶活性急剧下降,严重时候会致骨骼生成障碍,造成骨质疏松后容易骨折。使用铜制备的铜金属抗癌药物相比现行的铂类金属抗癌药物的优势是:在一定量范围内人体对铜承受能力较大,相对减轻了金属药物对人体的副作用。
附图说明
图1为本发明实施例1合成的3-苯基戊二酸阴离子·2,2'-联吡啶合铜(II)的晶体结构。
图2为本发明实施例1合成的3-苯基戊二酸阴离子·邻菲罗啉·羟基合铜(II)的晶体结构。
具体实施方式
下面申请人将结合附图和实施例对本发明技术方案做进一步的详细阐述。
实施例1:
以2,2'-联吡啶或邻菲罗啉作为第二配体,以氯化铜作为中心离子起始金属盐,分别合成配合物1和配合物2
配置5mmol/L的第一配体3-苯基戊二酸乙醇溶液,取10ml向10mL、5mmol/L的氯化铜溶液中滴加、进行反应,滴加完成后,快速用0.5mol/L的KOH溶液调节pH值稳定在3-10均可(本实施例中,合成配合物1时本步骤测得pH=3.3,合成配合物2时本步骤测得pH=9.5),此时溶液中出现蓝色沉淀,继续搅拌反应5小时后,再加入5mmol/L的第二配体乙醇溶液10mL,而后再继续搅拌反应3小时后停止反应,过滤;将所得清液静置三到四周的时间(本实施例为25天),析出深蓝色铜(II)配合物粒状晶体。
分离出晶体,用无水乙醇和水体积比1:1的混合溶液洗涤,干燥,整个反应过程,3-苯基戊二酸、铜离子以及第二配体三者的摩尔比为1:1:1。可分别得到配合物1(当第二配体为2,2'-联吡啶时)和配合物2(当第二配体为邻菲罗啉时),配合物1和配合物2的晶体结构分别见图1和图2。
本发明所得配合物组成和结构明确,经红外光谱、元素分析测手段得到确证。
其中配合物1红外光谱为:IRν(cm-1),1587(νCOO),1425(νCOO),1210(νC-N),1161(νC=C),1584(νC=C);配合物2红外光谱为:IRν(cm-1),1598(νCOO),1412(νCOO),1213(νC-N),1169(νC=C),1157(νC=C),3414(νO-H)。元素分析:配合物1按理论结构式C42H36Cu2N4O8,计算值:C,59.22;H,4.26;N,6.58%,实测值:C,59.64;H,4.57;N,6.62%。配合物2按理论结构式C46H38Cu2N4O10,计算值:C,59.16;H,4.10;N,5.99%,实测值:C,59.55;H,4.24;N,6.08%。
配合物1和配合物2的晶体学数据测试方法:
(1)单晶结构解析
本发明所得配合物粒状晶体,确证为目标产物,并用X射线单晶衍射技术测定了两个配合物的晶体结构。
选取配合物粒状单晶,使用Rigaku gemini E单晶衍射仪,以经过石墨单色器的MoKa为靶源测试,在1.750°<θ<25.421°范围内收集衍射数据。结构解析采用了直接法。氢原子采用理论加氢法获得,其他非氢原子采用最小二乘法和各向异性修正。两个配合物晶体学数据详见下表。
表1配合物1、2晶体学数据
表2配合物1晶体键长
表3配合物1晶体键角
表4配合物2晶体键长
表5配合物2晶体键角
实施例2:
验证配合物1和配合物2是否具有明显抑癌作用
采用MTT比色法测试配合物对癌细胞株体外毒活性测试。
测试细胞全购自中国科学院典型培养物保藏委员会细胞库。待测细胞均培养于含体积分数为10%胎牛血清的RPMI 1640培养液中,置于37℃、体积分数为5%CO2的培养箱中传代培养。实验时分别消化收集处于对数生长期的各种细胞,调整细胞数为3×104个/ml,以每孔100μl接种于96孔培养板中,置CO2培养箱中培养24h后,将受试物储备液逐级稀释不同浓度梯次,每孔加入150μl溶液,最高浓度组溶剂终浓度不高于千分之一(溶剂为DMSO,下同),每个浓度下设置三个复孔。顺铂组各孔分别加入5个不同浓度的受试物,其终浓度分别为0.5、1、2、4、8μg/ml,每个浓度3个复孔;溶媒对照组加入150μl含千分之一DMSO的RPIM1640完全培养液,共设置6个复孔。培养72h后,弃去旧液,每孔用200μl生理盐水清洗后弃去,MTT储备液用RPIM1640完全培养液10倍稀释后,各孔加入终浓度为0.5mg/ml的MTT100μl,继续培养3h。3h后弃去旧液,每孔加入150μl溶剂,培养板振荡器震荡3min。于酶标仪492nm、630nm处测定每孔的吸光度值(A值)。各组A值取均值后,计算抑制百分数,计算公式如下:
细胞抑制率=[1-(A492sample-A630sample)/(A492Control-A630Control)]×100%
同时,采用IBMSPSS Statistics22软件对IC50值进行计算。下表汇总了配合物1、2的HEL(人红白细胞白血病细胞)、HepG2(人肝癌细胞)、SKOV-3(人卵巢癌细胞)三种人肿瘤细胞系的IC50值。对照组为顺铂。
表2配合物1、2、顺铂对肿瘤细胞株72h的体外毒活性
***:IC50值超过检测限,对肿瘤细胞的毒性相对很小。
毒性测试看出,配合物1有较强的细胞毒活性,与顺铂细胞毒活性较接近;而配合物2,表现出高细胞毒性,对HEL(人红白细胞白血病细胞)、HepG2(人肝癌细胞)、SKOV-3(人卵巢癌细胞)均比实际临床药物顺铂要强。
在本实施例中,申请人观察到,配合物1和配合物2在二甲基亚砜中均易溶,在水中部分溶解。
Claims (9)
2.一种权利要求1所述的金属配合物的制备方法,操作如下:
将4-6mmol/L 3-苯基戊二酸乙醇溶液与4-6mmol/L氯化铜水溶液混合,然后用KOH溶液调节反应体系pH值在3-10,然后在搅拌条件下反应4-6小时,再加入4-6mmol/L多环吡啶类配体2,2'-联吡啶或邻菲罗啉的乙醇溶液,而后再持续搅拌反应2-4小时,停止反应并过滤反应液,将过滤所得清液静置,析出深蓝色晶体,用40-60v/v%乙醇洗涤,干燥后得到产物。
3.根据权利要求2所述的制备方法,其特征在于:3-苯基戊二酸、二价铜离子以及多环吡啶类配体的摩尔比之比控制在1:1:1。
4.根据权利要求1所述的金属配合物,其特征在于:所述两金属配合物均为深蓝色块状晶体,均为三斜晶系,空间群均为P-1。
7.权利要求1、4、5或6所述的金属配合物在制备具有抗癌活性药物中的用途。
8.根据权利要求7所述的用途,其特征在于:所述癌为白血病、肝癌或者卵巢癌。
9.根据权利要求7所述的用途,其特征在于:所述癌由人红白细胞白血病细胞、人肝癌细胞或者人卵巢癌细胞引起。
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