CN107445900A - 一种具有手性碳的苯并咪唑配体、苯并咪唑金属配合物及其制备方法和应用 - Google Patents
一种具有手性碳的苯并咪唑配体、苯并咪唑金属配合物及其制备方法和应用 Download PDFInfo
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 title claims abstract description 31
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- C—CHEMISTRY; METALLURGY
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/06—Cobalt compounds
- C07F15/065—Cobalt compounds without a metal-carbon linkage
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- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
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Abstract
本发明涉及一种具有手性碳的苯并咪唑配体、苯并咪唑金属配合物及其制备方法和应用,所述苯并咪唑配体的结构式如式(Ⅰ)所示:式(Ⅰ);所述具有手性碳的苯并咪唑金属配合物的结构式如式(Ⅱ)或式(Ⅲ)所示:。本发明提供的具有手性碳的苯并咪唑配体上的两个N原子能够和金属离子有效配位生成具有生物活性的苯并咪唑金属配合物,该苯并咪唑金属配合物为双核锌配合物或双核钴配合物,结构稳定,具有良好的荧光性质和抗肿瘤活性,可应用于制备新型的抗食道癌肿瘤药物。本发明提供的具有手性碳的苯并咪唑配体的制备方法操作简单,成本低,制备得到的具有手性碳的苯并咪唑配体纯度高,产率高。
Description
技术领域
本发明属于抗肿瘤药物领域,具体涉及一种具有手性碳的苯并咪唑配体、苯并咪唑金属配合物及其制备方法和应用。
背景技术
食管癌(Esophageal cancer)是全球第八大常见的恶性肿瘤,每年约3.8%的新增癌症病例和5.4%的癌症死亡病例是由食管癌引起的。在我国,食管癌被称为第四大恶性肿瘤,每年因食管癌死亡的病例约占全部癌症死亡病例的8.8%。
当前,针对食管癌晚期的治疗,药物化疗仍然是最主要的方法和手段,以顺铂(cisplatin)为代表的铂类药物仍然是食管癌化疗的首选药物。但是顺铂在临床使用中也存在一些较大的问题,一方面其容易产生毒副作用,如神经毒性、肝毒性、肾毒性、耳毒性和骨髓毒性等,从而严重影响病人的治疗效果和生活质量;另一方面,顺铂水溶性较差,是非口服药物,长期使用容易诱发严重的抗药性,进一步限制了它们在临床上的广泛使用。
因此,研发新的非铂类抗肿瘤金属药物已成为当前食管癌化疗的迫切需要。
发明内容
本发明的目的在于克服现有技术铂类药物治疗食管癌毒副作用大和易诱发抗药性的缺陷,提供一种具有手性碳的苯并咪唑配体。本发明提供的具有手性碳的苯并咪唑配体上的两个N原子能够和金属离子有效配位生成具有生物活性的苯并咪唑金属配合物,该苯并咪唑金属配合物可用于制备抗食道癌药物,有效抑制食道癌细胞生长。
本发明的另一目的在于提供上述具有手性碳的苯并咪唑配体的制备方法。
本发明的另一目的在于提供上述具有手性碳的苯并咪唑配体在制备具有手性碳的苯并咪唑金属配合物中的应用。
本发明的另一目的在于提供一种具有手性碳的苯并咪唑金属配合物。
本发明的另一目的在于提供上述具有手性碳的苯并咪唑金属配合物的制备方法。
本发明的另一目的在于提供上述具有手性碳的苯并咪唑金属配合物在制备食管癌化疗药物中的应用。
为实现上述发明目的,本发明采用如下技术方案:
一种具有手性碳的苯并咪唑配体,所述苯并咪唑配体的结构式如式(Ⅰ)所示:
式(Ⅰ)。
本发明提供的具有手性碳的苯并咪唑配体为顺,顺,顺,顺-2,2',2'',2'''-环戊烷四苯并咪唑,其咪唑环的两个N原子能够和金属离子有效配位生成苯并咪唑金属配合物。
上述具有手性碳的苯并咪唑配体的制备方法,所述制备方法为:将顺,顺,顺,顺-1,2,3,4-环戊烷四羧酸和邻苯二胺混合均匀置于磷酸中,在180~185℃条件下搅拌反应6~6.5h,生成墨绿色的反应物,冷却至室温后加入蒸馏水,用碱液中和至弱碱性,得到棕黄色固体,洗涤、过滤,重结晶后,得到的浅黄色固体即所述具有手性碳的苯并咪唑配体。
上述制备方法操作简单,成本低,制备得到的具有手性碳的苯并咪唑配体纯度高,产率高。
优选地,所述顺,顺,顺,顺-1,2,3,4-环戊烷四羧酸和邻苯二胺按物质的量比为1:4.0~4.2。
优选地,所述碱液为氢氧化钠溶液、碳酸钠溶液,氢氧化钾溶液、碳酸钾溶液或氨水溶液。
上述具有手性碳的苯并咪唑配体在制备具有手性碳的苯并咪唑金属配合物中的应用也在本发明的保护范围内。
一种具有手性碳的苯并咪唑金属配合物,所述金属配合物的结构式如式(Ⅱ)或式(Ⅲ)所示:
式(Ⅱ) 式(Ⅲ)。
锌和钴都是人体内必不可少的微量金属元素,在体内广泛参与生命活动,基于锌和钴的苯并咪唑配合物具有良好的生物活性。本发明提供的具有手性碳的苯并咪唑金属配合物为双核锌配合物或双核钴配合物,结构稳定,具有良好的荧光性质和抗肿瘤活性,可应用于制备新型的抗食道癌肿瘤药物药物。
上述具有手性碳的苯并咪唑金属配合物的制备方法,所述制备方法为:将金属氯化物与苯并咪唑配体溶于易挥发溶剂中,混合均匀,待溶剂挥发后得到的块状单晶即所述具有手性碳的苯并咪唑金属配合物,所述金属氯化物为ZnCl2或CoCl2·6H2O。
本发明提供的制备方法可成功制备得到具有良好的荧光性质和抗肿瘤活性的具有手性碳的苯并咪唑金属配合物。
优选地,所述金属化合物与苯并咪唑配体按物质的量比为2.0~2.2:1。
优选地,所述易挥发有机溶剂为甲醇、乙醇或 N,N-二甲基甲酰胺中的一种。
上述具有手性碳的苯并咪唑金属配合物在制备食管癌化疗药物中的应用也在本发明的保护范围内。
与现有技术相比,本发明具有如下有益效果:
本发明提供的具有手性碳的苯并咪唑配体上的两个N原子能够和金属离子有效配位生成具有生物活性的苯并咪唑金属配合物,该苯并咪唑金属配合物为双核锌配合物或双核钴配合物,结构稳定,具有良好的荧光性质和抗肿瘤活性,可应用于制备新型的抗食道癌肿瘤药物。本发明提供的具有手性碳的苯并咪唑配体的制备方法操作简单,成本低,制备得到的具有手性碳的苯并咪唑配体纯度高,产率高。
附图说明
图1为本发明提供的苯并咪唑双核锌配合物的配位环境单晶结构;
图2为本发明提供的苯并咪唑双核钴配合物的配位环境单晶结构;
图3为本发明提供的苯并咪唑配体、苯并咪唑双核锌配合物和苯并咪唑双核钴配合物在DMF溶剂中的紫外光谱图;
图4为本发明提供的苯并咪唑配体、苯并咪唑双核锌配合物和苯并咪唑双核钴配合物在DMF溶剂中的荧光发射光谱图;
图5为本发明提供的苯并咪唑双核钴配合物的循环伏安测试图;
图6为本发明提供的苯并咪唑配体、苯并咪唑双核锌配合物、苯并咪唑双核钴配合物和顺铂对食道癌Eca109细胞生长抑制作用结果图。
具体实施方式
下面结合实施例对本发明做进一步的描述。这些实施例仅是对本发明的典型描述,但本发明不限于此。下述实施例中所用的试验方法如无特殊说明,均为常规方法;所使用的原料,试剂等,如无特殊说明,均为可从常规市场等商业途径得到的原料和试剂。
实施例1 具有手性碳的苯并咪唑配体
本实施例提供的具有手性碳的苯并咪唑配体(cttb)的反应式及合成步骤如下:
将顺,顺,顺,顺-1,2,3,4-环戊烷四羧酸(2.46 g, 0.01 mol)和邻苯二胺(4.32 g,0.04 mol)混合均匀置于85%磷酸中,在180~185℃条件下加热搅拌6~6.5小时,生成墨绿色的反应物,冷却至室温后加入蒸馏水稀释,用氨水中和得到棕黄色固体,经蒸馏水洗涤3次,过滤,乙醇重结晶后,得到浅黄色固体顺,顺,顺,顺-2,2',2'',2'''- 环戊烷四苯并咪唑,即配体(cttb)。产量:4.50 g,产率:74.12%。
元素分析C36H33N9O (cttb·DMF),理论计算值:C, 71.15%; H, 5.47%; N,20.74%. 实验值: C, 71.28%; H, 5.81%; N, 20.83%。红外光谱数据 (KBr, cm-1):3385w, 3173 w, 3061 w, 2917 w, 1629 m, 1530 m, 1444 s, 1274 w, 1024 w, 745 s.
1H NMR (400 MHz, DMSO-d 6, ppm) δ: 7.58-7.39 (m, 8H), 7.14-7.08 (m, 8H),4.93-4.78 (m, 1H), 4.66 (m, 2H), 4.40-4.31 (m, 2H), 4.13-4.06 (m, 1H), 2.87(DMF-CH3), 2.72 (DMF-CH3)。
实施例2 具有手性碳的苯并咪唑双核锌配合物[ Zn2(cttb)Cl4 ]
本实施例提供的具有手性碳的苯并咪唑双核锌配合物[ Zn2(cttb)Cl4 ]的反应式及合成步骤如下:
将ZnCl2 (0.272g, 0.002mol) 和实施例1制备得到的苯并咪唑配体(0.534g,0.001mol)在加热状态下溶解于20ml的DMF溶剂中,将混合物搅拌均匀,自然挥发7天得到浅黄色块状的配合物单晶,制得顺,顺,顺,顺-2,2',2'',2'''-环戊烷四苯并咪唑双核锌配合物Zn2(cttb)Cl4·DMF,即苯并咪唑双核锌配合物。产量0.64g,产率 72.72%。
元素分析C36H33Cl4Zn2N9O [Zn2(cttb)Cl4·DMF],理论计算值:C, 49.12%; H,3.78%; N, 14.32%. 实验值: C, 49.28%; H, 3.88%; N, 14.46%。红外光谱数据 (KBr,cm-1):3429 w, 3185 w, 3122 w, 2920 w, 1624 m, 1533 m, 1453 s, 1278 w, 1044 w,748 s。
在DMF中得到的单晶分子结构如图1所示。主要单晶数据:Mr = 880.25,晶系,Monoclinic,空间群,P21/n,a = 10.8490(13),b = 14.7440(17),c = 15.1099(18) Å,α =78.6234, β = 78.4587,γ = 88.739(2)°,V = 2321.2(5) Å3,Z = 2,D c = 1.259 g/cm3,λ= 0.71073 nm,μ(MoKα) = 1.299 mm-1,F (000) = 896,S = 1.096,Final R indices [I>2sigma(I)],R1 = 0.0511,wR2 = 0.1439。
实施例3 具有手性碳的苯并咪唑双核钴配合物[ Co2(cttb)Cl4 ]
本实施例提供的具有手性碳的苯并咪唑双核钴配合物([ Co2(cttb)Cl4 ])的反应式和合成步骤如下:
将CoCl2·6H2O (0.476g, 0.002mol) 和实施例1制备得到的苯并咪唑配体(0.534g,0.001mol)在加热下溶解于20ml的DMF溶剂中,将混合物搅拌均匀,自然挥发7天得到浅棕色块状的配合物单晶,制得顺,顺,顺,顺-2,2',2'',2'''-环戊烷四苯并咪唑双核钴配合物Co2(cttb)Cl4·2DMF·H2O,即苯并咪唑双核钴配合物。产量0.59g,产率 62.15%。
元素分析C39H42Cl4Co2N10O3 [Co2(cttb)Cl4·2DMF·H2O],理论计算值:C,48.87%;H,4.42%; N,14.61%;实验值:48.65%;H,4.61%;N,14.76%。红外光谱数据 (KBr,cm-1):3395w, 3190 w, 3116 w, 2933 w, 1621 m, 1531 m, 1451 s, 1275 w, 1042 w, 746 s。
在DMF中得到的单晶分子结构如图2所示。主要单晶数据:Mr = 883.37,晶系,Triclinic,空间群,P -1,a = 10.8639(5),b = 14.8690(5),c = 15.2812(6) Å,α =78.002(3),β = 78.919(4),γ = 88.106(3)°,V = 2369.44(16) Å3,Z = 2,D c = 1.238 g/cm3,λ = 0.71073 nm,μ(MoKα) = 0.963 mm-1,F (000) = 900,S = 1.083,Final Rindices [I>2sigma(I)],R1 = 0.0634, wR2 = 0.1904。
性能测试:
(1)紫外吸收、荧光发射光谱检测
将实施例1、2和3制备得到的苯并咪唑配体(cttb)、苯并咪唑双核锌配合物(Zn2(cttb)Cl4)、苯并咪唑双核钴配合物(Co2(cttb)Cl4)进行紫外吸收光谱检测和荧光发射光谱检测,在DMF溶剂中的紫外吸收检测结果如图3所示,荧光发射光谱检测结果如图4所示。
检测结果表明,苯并咪唑双核锌配合物和苯并咪唑双核钴配合物在260~300nm之间有较强的紫外吸收,吸收峰型与配体相似;两种双核配合物均具有荧光性质,在310nm的光激发下其最大发射波长在373nm处。
(2)循环伏安测试
将实施例3提供的苯并咪唑双核钴配合物(Co2(cttb)Cl4)进行循环伏安测试(CHI660B电化学工作站,三电极体系,玻碳电极为工作电极,Ag/AgCl电极为参比电极,铂丝电极为辅助电极,0.1mol·L-1 Bu4N·ClO4为支持电解质,扫描速率25~500mv/s),在DMF溶液中的循环伏安扫描结果如图5所示。
循环伏安测试表明,苯并咪唑双核钴配合物具有氧化还原活性,在扫描速度为100mv/s时,其阴极峰电势Epc为-0.744 V,阳极峰电势Epa为-0.569 V,峰电势差为0.175 V,峰电流比Ipa/ Ipc 为 0.122。
(3)体外抗肿瘤活性检测
在体外活性测试中采用食道癌Eca109细胞评价配合物的抗肿瘤活性,以本领域常规的顺铂作为阳性对照。采用常规MTT法进行细胞活力检测,观察样品对肿瘤细胞活力的影响以评价配合物抗肿瘤效果,具体步骤如下:
按预实验测定的细胞生长速率,接种一定数目的对数期细胞于96孔板,以控制在药物作用终止时对照组细胞OD值约1.0左右。细胞贴壁后,将药物稀释成一定的梯度浓度,每浓度设3复孔,分实验组、溶剂对照组及调零组加药,倒置显微镜下观察细胞生长情况并拍照记录。在72 h后,采用MTT法进行细胞活力检测,每孔加入20μl MTT溶液,继续培养4 h,小心吸除孔内液体,避免接触孔内结晶物,每孔加入100ml的DMSO,于恒速摇床上避光摇晃。待结晶物充分溶解后,在酶标仪上读取OD值(波长570 nm,参考波长630 nm),测得吸光度A值。生长抑制率的计算公式为:生长抑制率(%)=(1-OD实验组/ OD对照组)×100%。根据各浓度的抑制率可作图得到剂量反应曲线,作图软件为GraphPad Prism 5,从图中可估算得药物的半数抑制浓度IC50,采用Logit法精确计算药物的IC50。
苯并咪唑双核锌配合物、苯并咪唑双核钴配合物和顺铂对食道癌Eca109细胞生长抑制作用如图6所示。从图6可知,锌配合物和钴配合物的抗肿瘤活性明显高于顺铂,锌配合物对Eca109细胞半数抑制浓度IC50值为33.92µM,钴配合物的IC50值为37.28µM,低于顺铂的IC50(43.99µM),与自由配体的IC50 (34.54µM)相当,该锌配合物和钴配合物具有明显的抗肿瘤活性。
Claims (9)
1.一种具有手性碳的苯并咪唑配体,其特征在于,所述苯并咪唑配体的结构式如式(Ⅰ)所示:
式(Ⅰ)。
2.权利要求1所述具有手性碳的苯并咪唑配体的制备方法,其特征在于,所述制备方法为:将顺,顺,顺,顺-1,2,3,4-环戊烷四羧酸和邻苯二胺混合均匀置于磷酸中,在180~185℃条件下搅拌反应6~6.5h,生成墨绿色的反应物,冷却至室温后加入蒸馏水,用碱液中和至弱碱性,得到棕黄色固体,洗涤、过滤,重结晶后,得到的浅黄色固体即所述具有手性碳的苯并咪唑配体。
3.根据权利要求2所述具有手性碳的苯并咪唑配体的制备方法,其特征在于,所述顺,顺,顺,顺-1,2,3,4-环戊烷四羧酸和邻苯二胺的物质的量比为1:4.0~4.2。
4.根据权利要求2所述具有手性碳的苯并咪唑配体的制备方法,其特征在于,所述碱液为氢氧化钠溶液、碳酸钠溶液,氢氧化钾溶液、碳酸钾溶液或氨水溶液。
5.权利要求1所述具有手性碳的苯并咪唑配体在制备具有手性碳的苯并咪唑金属配合物中的应用。
6.一种具有手性碳的苯并咪唑金属配合物,其特征在于,所述金属配合物的结构式如式(Ⅱ)或式(Ⅲ)所示:
式(Ⅱ) 式(Ⅲ)。
7.权利要求6所述具有手性碳的苯并咪唑金属配合物的制备方法,其特征在于,所述制备方法为:将金属氯化物与权利要求1所述苯并咪唑配体溶于易挥发溶剂中,混合均匀,待溶剂挥发后得到的块状单晶即所述具有手性碳的苯并咪唑金属配合物;所述金属氯化物为ZnCl2或CoCl2·6H2O。
8.根据权利要求7所述具有手性碳的苯并咪唑金属配合物的制备方法,其特征在于,所述金属氯化物与苯并咪唑配体的物质的量比为2.0~2.2:1。
9.权利要求6所述具有手性碳的苯并咪唑金属配合物在制备食管癌化疗药物中的应用。
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