CN117883569A - 一种光动力铱配合物在制备预防或治疗癌症药物中的应用 - Google Patents
一种光动力铱配合物在制备预防或治疗癌症药物中的应用 Download PDFInfo
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Abstract
本发明提供了一种光动力铱配合物在制备预防或治疗癌症药物中的应用。本发明的光动力铱配合物合成原料易得、成本低、产品纯度大、产率高,制备得到的光动力铱配合物能够在自然状态下稳定存在,能够作为药物的有效成分,在一定强度的光照下抑制肿瘤细胞的活性,短期内能够抑制机体肿瘤细胞的增殖,从而达到预防和治疗癌症的效果,同时不影响机体各组织器官的正常生理活动,生理相容性好。
Description
技术领域
本发明涉及医药化工技术领域,特别涉及一种光动力铱配合物在制备预防或治疗癌症药物中的应用。
背景技术
光动力疗法(PDT)是用光敏药物和激光活化治疗过度增殖细胞相关的疾病例如癌症的一种新方法。光动力疗法的治疗原理是基于光敏剂在特定波长光的照射下,能够产生单态氧等活性物质,这些活性物质可以杀死肿瘤细胞或破坏异常增生的血管等组织。光敏剂对正常组织没有明显的毒性作用,因此光动力疗法被认为是一种局部选择性高、全身毒性低的治疗方法。由于传统的有机卟啉必须用相对较短波长的光激活,并且在缺氧环境中不起作用,而通过引入具有低3MMCT(金属-金属间电荷转移)激发态的混合金属复合物已经克服了这些限制。
然而,目前发现的可用于预防和治疗癌症的光动力配合物很少,并且存在对肿瘤细胞的治疗效果不理想,治疗周期长并且生物相容性不高的问题。因此,亟需一种相容性好、对肿瘤细胞杀伤力强且治疗周期短的光动力金属配合物。
发明内容
针对现有技术中的缺陷,本发明提出了一种光动力铱配合物在制备预防或治疗癌症药物中的应用;
所述铱配合物具有结构式(I):
其中,每个A1~A5独立地选自C,N;
R1选自氢,卤素,–CN,–OR’,–N(R’)2,–SR’,–P(R’)2,–C(O)R’,–C(O)OR’,–C(O)NR’,–SOR’,–SO2R’,–SO3R’,–P(O)(R’)2,–P(O)(OR’)R’,–P(O)(OR’)2,C1~C40烷基,C2~C40烯基,C2~C40炔基,C3~C20环烷基,C3~C20杂环烷基,C6~C20芳基,C6~C20杂芳基;上述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基任选被一个或多个取代基取代,所述取代基独立地选自:卤素,–CN,–OR’,–N(R’)2,C1~C20烷基,C2~C20烯基,C2~C20炔基,C3~C20环烷基,C3~C20杂环烷基,C6~C20芳基,C6~C20杂芳基;
环B和环C独立地选自苯基,萘基,蒽基,芴基,吡啶基,嘧啶基,哒嗪基,吡嗪基,喹啉基,异喹啉基,苯并嘧啶基,苯并哒嗪基,苯并吡嗪基,噻吩基,吡咯基,吡唑基,噻唑基,咪唑基,噁唑基,1,2,4-三氮唑,1,2,3-三氮唑,异噁唑基,异噻唑基,吲哚基,苯并咪唑基,苯并噻吩基,苯并噻唑基,所述环B和环C任选地被一个或多个取代基RC或RB取代,RC或RB独立地选自:–O(R”),S(R”),N(R”)2,SO(R”),SO2(R”),P(R”)2,PO(R”)2,PO(OR”)(R”),PO(OR”)2,Si(R”)3,C1~C40烷基,C2~C40烯基,C2~C40炔基,C1~C20卤代烷基、C1~C8烷氧基,C3~C8环烷基,C3~C8杂环烷基,C3~C8芳基,C3~C8杂芳基;其中,R”独立地选自氢,卤素,C1~C8烷基,C1~C8卤代烷基,C3~C8环烷基,C3~C8杂环基,C3~C8芳基,C3~C8杂芳基;
X为–O–;–C(O)O–;–S–;–S(O)2O–;–P(O)2O–;–BR”’–;–NR”’–;其中,R”’独立地选自氢,C1~C8烷基,C1~C8卤代烷基,C3~C8环烷基,C3~C8杂环基,C3~C8芳基,C3~C8杂芳基;
O为0;q和p独立地为0~10的整数;
R2选自Cl,Br,I,CN,OCN,SCN,和C1~C8烷基,C1~C8烷氧基,C1~C8酰氧基,C5~C36芳基,C5~C36杂环芳基,C2~C36炔基。
在一些实施例中,A1~A5为C;
在一些实施例中,R1为甲基、丁基;
在一些实施例中,R3为溴离子、氰离子;
在一些实施例中,式(I)光动力铱配合物式中的二齿配体
具体选自
中的任意一种。
在一些实施例中,所述光动力铱配合物为以下化合物中的任意一种:
本发明结构通式中所用连接金属铱和配体间的“虚线”是指配位共价键,其中包括但不限于单键、双键等。
本发明的光动力铱配合物的结构可以通过核磁共振法1H NMR测定得到,测定方法为本领域常规的方法。
在一些实施例中,所述癌症选自乳腺癌、胃癌、结肠癌、直肠癌、子宫内膜癌、头颈癌、肝细胞癌、肺癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌、肾细胞癌、血液系统恶性肿瘤、睾丸癌、中枢神经系统癌、口腔癌、鼻癌、宫颈癌、间皮瘤、肉瘤、甲状腺癌、硬纤维瘤中的任意一种或多种。
在一些实施例中,所述预防和治疗癌症的药物为一种药物组合物。
本发明还提供一种药物组合物,其有效成分为含有结构式(I)的光动力铱配合物。
在本发明中,提及的药物组合物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
在本发明中,提及的药物组合物可以制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式。上述各种剂型的药物均可以按照药学领域的常规方法制备。
本发明还提供一种细胞增殖抑制剂,所述细胞增殖剂含有所述铱配合物;所述细胞为癌细胞。
综上,与现有技术相比,本发明达到了以下技术效果:
1、本发明的光动力铱配合物和其合成方法,原料易得,成本低,产品纯度大,产率高,能够在自然状态下稳定存在。
2、本发明的光动力铱配合物具有良好的抗癌活性,能够在一定强度的光照下在肿瘤组织中激活,抑制肿瘤细胞的活性;添加含光动力铱配合物的药物能够在短期内抑制机体肿瘤细胞的增长,达到预防和治疗癌症的效果。
3、本发明的光动力铱配合物在杀死癌细胞过程中,不影响机体各组织器官的正常生理活动,生理相容性好。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,应当理解,以下附图仅示出了本发明的某些实施例,因此不应被看作是对范围的限定,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他相关的附图。
图1为本发明实施例3的光动力铱配合物Ir-C1的光物理测试图,包括吸收、激发和发射光谱;
图2为本发明实施例3的光动力铱配合物Ir-C4的光物理测试图,包括吸收、激发和发射光谱;
图3为本发明实施例4的细胞毒性测试结果;其中,(a)为ROS检测免疫荧光图,比例尺:500nm;(b)为不同铱配合物浓度下HCT 116癌细胞的细胞存活率;(c)为光照下Ir-C1和Ir-C4的IC50值;
图4为本发明实施例5的动物体内抗肿瘤实验流程图;
图5为本发明实施例5的Ir-C1对小鼠HCT 116肿瘤的有效治疗效果图;其中(a)为不同治疗条件下肿瘤大小对比图;(b)为(a)的重量统计结果;(c)为HCT116肿瘤细胞组织切片的H&E苏木精-伊红染色实验图;所有数据均以平均值表示±标准偏差(*P<0.05,**P<0.01,***P<0.001,由未配对的双侧t检验确定);比例尺:100μm;
图6为本发明实施例6的Ir-C1体内光动力治疗的毒性分析结果;不同组治疗后第16天小鼠的血液生化指标,包括肝功能测试:丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、碱性磷酸酶(ALP),肾功能指标:尿素(UREA)、肌酐(CREA)、(UA)尿酸和血常规指标:肌酸激酶(CK)、肌酸激酶同工酶(CK-MB);
图7为本发明实施例6的不同组治疗后第16天小鼠的心脏、肝脏、脾脏、肺和肾脏的H&E染色切片图像;所有数据均以平均值表示±标准偏差表示;n=3,比例尺为100μm。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案,下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分的实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都应当属于本发明保护的范围。
所有起始原料均为市售材料。合成和光物理所用试剂分别为分析纯和色谱纯试剂。所用仪器未注明生产厂商者,视为可以通过市售购买得到的常规产品。
本发明化合物的制备方法不做限制,典型但非限制地以下述配合物为示例,其合成路线及制备方法如下:
合成三齿配体前体:
(1)1,3-双咪唑-1-基苯(目标产物1)的制备:
100mL带有搅拌子的圆底烧瓶中分别加入1,3-二溴苯(2.36g,10mmol),咪唑(4.08g,60mmol),碘化亚铜(95mg,0.5mmol),碳酸钾(25.3g,0.183mol)和二甲亚砜(60mL)。此混合物在150℃下反应两天后,将反应冷却到60℃之后通过硅藻土过滤,并且用30mL乙酸乙酯洗涤提取有机产物三次。合并有机溶液并旋蒸去除乙酸乙酯,减压蒸馏除去二甲亚砜。有机产物用二氯甲烷溶解(200mL),30mL有机相用水洗涤三次。有机相用无水硫酸镁干燥、过滤、旋蒸,获得白色固体产物,为目标产物1,3-双咪唑-1-基苯(产量2.09g,产率99%)。1HNMR(400兆赫兹,氘代氯仿):δ=7.93(s,2H),7.63(t,J=8.0Hz,1H),7.45(s,2H),7.42(d,J=1.9Hz,1H),7.35(s,2H),7.27(s,2H)ppm。
(2)二碘1,1’-(1,3-苯基)双(3-丁基-1H-咪唑-3-鎓)盐(目标产物2)的制备:
往带有磁子的25mL希莱克管(Schlenk tube)中加入目标产物1(1.0g,4.63mmol),碘甲烷(6.57g,46.3mmol)和乙腈(15mL)。溶液在氮气氛围下加热到90℃并持续搅拌。过滤收集淡黄色沉淀并用大量乙腈洗涤得到目标产物2。产量1.56g,产率68%。1H NMR(400兆赫兹,氘代DMSO):δ=9.86(d,J=1.7Hz,2H),8.36(t,J=1.9Hz,2H),8.31–8.27(m,1H),8.09–7.89(m,5H),4.00ppm(s,6H)。
(3)二溴1,1’-(1,3-苯基)双(3-丁基-1H-咪唑-3-鎓)盐(目标产物3)的制备:
往带有磁子的25mL希莱克管中加入目标产物1(5.8g,27.6mmol),正溴丁烷(18.9g,138mmol)和乙腈(15mL)。溶液在氮气氛围下加热到90℃并持续搅拌。溶液在氮气氛围下加热到90℃并持续搅拌。12小时后将乙腈旋蒸去除,固体残留物溶解于50mL乙醇中,再浓缩至大约5mL体积,加入20mL乙醚。快速收集白色沉淀,得到目标产物3。产量10.7g,产率80%。
1H NMR(400兆赫兹,氘代DMSO):δ=10.04(s,2H),8.50-8.41(m,2H),8.38(t,J=2.2Hz,1H),8.16-8.07(m,2H),8.02-7.90(m,3H),4.29(t,J=7.2Hz,4H),1.89(p,J=7.4Hz,4H),1.34(h,J=7.4Hz,4H),0.93ppm(t,J=7.3Hz,6H)。
实施例1铱配合物Ir-C1的合成
其中,[Ir(cod)Cl]2为铱金属前体为双(1,5-环辛二烯)氯化铱(I)二聚体;NEt3为有机碱三乙胺;反应溶剂MeCN为乙腈;2-EtOEtOH为2-乙氧基乙醇;
在氮气保护下往带有磁子的25mL希莱克管中加入目标产物2(441mg,0.89mmol),铱金属前体([Ir(cod)Cl]2,300mg,0.45mmol),乙腈(15mL)和三乙胺(1mL),利用针头将氮气引入并为溶液除气5分钟,加热到90℃,4小时后停止反应。将有机溶剂低压去除后,在氮气保护下加入qupt(250mg,0.89mmol)和2-乙氧基乙醇(20mL)。将混合物加热到150℃并反应24小时,停止反应冷却至室温后过滤。减压除去溶剂,之后用5mL乙醇洗涤,得到红色粉末状的中间体1,中间体不需要进一步纯化。
随后将中间体1加入至带有磁子的两口瓶中,并加入氰化银(119mg,0.89mmol)以及10mL N,N–二甲基甲酰胺。反应液加热到100℃,2小时后停止反应。减压除去N,N–二甲基甲酰胺,得到红色发光固体。采用硅胶柱层析色谱分离,流动相采用二氯甲烷至二氯甲烷/乙酸乙酯(体积比为5:1),得到目标产物Ir-C1(121mg,0.16mmol),为红色粉末,产率18%。1H NMR(400兆赫兹,氘代氯仿):δ=10.69-10.54(m,1H),9.46(d,J=7.9Hz,1H),8.47(t,J=8.2Hz,2H),8.12(t,J=7.8Hz,1H),7.97(t,J=7.5Hz,2H),7.77(dt,J=18.9,6.8Hz,2H),7.46(d,J=1.7Hz,2H),7.38-7.31(m,1H),7.23(d,J=7.8Hz,2H),7.07(t,J=7.6Hz,1H),6.64(d,J=2.1Hz,2H),6.35(d,J=7.4Hz,1H),2.72(s,6H)ppm.13CNMR(126MHz,CDCl3):δ=144.28,144.19,140.24,133.47,133.16,133.11,131.62,131.47,130.98,130.48,130.03,129.91,129.63,129.07,127.69,126.23,122.95,122.70,121.07,115.46,115.27,108.21,35.63ppm.ESI-MS:[M+H]+:m/z:736.1802;calculated:736.1801。
实施例2铱配合物Ir-C4的合成
在氮气保护下往带有磁子的25mL希莱克管中加入目标产物3(726mg,1.5mmol),铱金属前体([Ir(cod)Cl]2,500mg,0.75mmol),乙腈(15mL)和三乙胺(1mL),利用针头将氮气引入并为溶液除气5分钟,加热到9090℃,4小时后停止反应。将有机溶剂低压去除后,在氮气保护下加入qupt(420mg,1.5mmol)和2-乙氧基乙醇(20mL)。将混合物加热到150℃并反应24小时。停止反应冷却至室温后过滤。减压除去溶剂,之后用乙醇(5mL)洗涤,得到红色粉末的中间体2。中间体不需要进一步纯化。
随后,将中间体2加入至带有磁子的两口瓶中,并加入氰化银(201mg,1.5mmol)以及N,N–二甲基甲酰胺(10mL)。反应液加热到100℃,2小时后停止反应。减压除去N,N–二甲基甲酰胺,得到红色发光固体。采用硅胶柱层析色谱分离,流动相采用二氯甲烷至二氯甲烷/乙酸乙酯(体积比为5:1)得到目标产物Ir-C4(201mg,1.5mmol),为红色粉末,产率32%。
1H NMR(400兆赫兹,氘代氯仿):δ=10.68(d,J=8.8Hz,1H),9.48(dd,J=7.9,1.7Hz,1H),8.58-8.42(m,2H),8.14(ddd,J=8.7,6.8,1.6Hz,1H),8.03-7.92(m,2H),7.86-7.70(m,2H),7.49(d,J=2.1Hz,2H),7.35(dd,J=8.5,7.1Hz,1H),7.27-7.18(m,2H),7.07(t,J=7.6Hz,1H),6.68(d,J=2.1Hz,2H),6.38(dd,J=7.3,1.0Hz,1H),2.97(ddd,J=13.2,10.8,5.6Hz,2H),2.83(ddd,J=13.2,10.7,5.6Hz,2H),1.19-1.03(m,2H),0.79-0.59(m,2H),0.29-0.05(m,10H)ppm.13C NMR(126MHz,CDCl3):δ=155.05,153.70,144.50,144.18,143.91,141.95,140.14,133.30,133.00,131.35,131.12,130.96,130.35,130.12,129.95,129.63,127.66,126.24,122.94,122.73,119.80,115.58,115.28,108.12,49.72,33.44,19.21,13.02ppm.ESI-MS:[M+H]+:m/z:820.2742;calculated:820.2740。
实施例3铱配合物Ir-C1和Ir-C4的光物理性能测试
溶液态光谱测定:将材料溶解于二氯甲烷溶液中(浓度均为2×10-5M),除去空气后测定。在电子振动吸收光谱中,小于320nm的紫外吸收峰归属于配体的π-π*跃迁。330nm~540nm的吸收带分别归属于单重态的金属到配体电荷转移(1MLCT)或单重态配体中心的电荷跃迁/配体配体电荷转移(1LC/1LLCT)。大于540nm的弱吸收带归因于三重态的金属到配体电荷转移(3MLCT)和三重态配体中心的电荷跃迁/配体配体电荷转移(3LC/3LLCT)。
配合物Ir-C1和Ir-C4的吸收和发射光谱数据见表1:
表1配合物Ir-C1和Ir-C4的吸收和发射光谱数据
配合物Ir-C1的吸收和发射光谱见图1,Ir-C4的吸收和发射光谱见图2。
结果显示,Ir-C1和Ir-C4的发射峰最高峰位于637nm和632nm,量子产率为0.52和1.00,色度CIE坐标(国际照明委员会坐标,Commission International de L‘E Clairagecooridinates),Ir-C1的CIE坐标(x,y)为(0.68,0.33),Ir-C4的CIE坐标为(0.67,0.33)。
实施例4铱配合物Ir-C1和Ir-C4的毒性测试
对Ir-C1和Ir-C4的进行细胞毒性测试以评估材料在细胞内产生活性氧(ROS,Reactive Oxygen Species)的能力及暗毒性、光毒性。
在光照或无光照条件下,测试Ir-C1和Ir-C4在细胞内产生ROS的情况。
使用ROS指示剂DCFH-DA(2',7'-二氯荧光素二乙酸酯,Sigma-Aldrich,D6883)作为氧化敏感荧光探针对ROS进行了表征。具体测试过程包括如下步骤:在黑暗的环境下,首先用浓度为10μM的DCFH-DA 100μL孵育HCT 116(人结肠癌细胞)细胞30分钟,再用PBS(磷酸盐缓冲液)洗涤3次,加入含10μM铱配合物的DMSO溶液100μL,孵育1h后,用白色LED光0.3W/cm2照射4min。同时,平行实验的另一组细胞避光进行,空白对照实验在相同实验环境下进行。通过CCK-8(Cell Counting Kit-8细胞计数试剂)试验分析铱配合物孵化24h后对HCT116的细胞毒性作用。
荧光及细胞存活率结果如图3所示,在无光照下,配合物Ir-C1和Ir-C4处理下的HCT 116细胞活性氧水平与对照组无差别。光照之后,Ir-C1和Ir-C4的ROS水平均提高,而无添加铱配合物的对比组ROS水平不变(图3a)。不同浓度的Ir-C1和Ir-C4细胞光毒性实验显示(图3b),避光条件下,添加Ir-C1和Ir-C4对细胞活性无明显影响,说明Ir-C1和Ir-C4具有低细胞毒性和良好的生物相容性。在光照下,当添加的配合物浓度达到0.1μM,细胞活性显著降低,显示了较好的细胞毒性。光照下Ir-C1和Ir-C4的IC50值分别为38nM和45nM(图3c)。
实施例5Ir-C1的动物体内抗肿瘤评估
由于Ir-C1在HCT 116癌细胞中表现出优异的光动力治疗效果,因此在小鼠体内参照图4的步骤进行抗肿瘤实验,进一步研究配合物Ir-C1的治疗效果。
在雌性BALB/C小鼠(6周,体重18g)的腋部皮下注射100μL HCT 116细胞(1*107cell/mL)PBS悬液。当小鼠肿瘤体积达到80mm3时,将荷瘤小鼠随机分为4组,每组3只。
组1注射PBS+1%DMSO(100μL,腋部皮下),正常饲养,不进行白光光照;组2注射PBS+1%DMSO(100μL,腋部皮下),每次每只光照20min,隔日重复操作(白光光照的电功率为0.5W);组3:Ir-C1,10mg/kg(100μL,腋部皮下),正常饲养,不进行白光光照;组4:Ir-C1,10mg/kg(100μL,腋部皮下),每次每只光照20min,隔日重复操作。记录治疗期间小鼠体重和肿瘤体积,14天后,处死小鼠,并收集小鼠肿瘤H&E染色。
结果如图5a、b所示,14天后,组1的平均肿瘤重量接近2.63g,组2、组3与组1相似,为2.32g和2.18g,而组4明显抑制肿瘤生长,平均肿瘤重量只有0.40g,肿瘤对比其他参比组小了5倍以上。图5c的H&E苏木精-伊红染色结果显示,组4的肿瘤组织中出现了严重的肿瘤细胞破坏并伴有明显的坏死,而对照组的肿瘤细胞活性不变,说明铱配合物Ir-C1具有优越的抗肿瘤作用。
实施例6Ir-C1的光动力治疗的毒性分析
实验动物处理与实施例5相同,后进行Ir-C1在小鼠体内光动力治疗的毒性分析。检测血液生化指标:(1)肝功能指标,包括丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)和碱性磷酸酶(ALP);(2)肾功能指标,包括尿素(UREA)、肌酐(CREA)和尿酸(uricacid);(3)血常规指标,包括肌酸激酶(CK)和肌酸激酶同工酶(CK-MB);
结果如图6所示,与组1、组2相比,组3和组4的所有参数均在正常参考范围内。
之后治疗14天后对所有组的主要器官(心脏,肝脏,脾脏,肺,肾)进行病理分析,由图7的H&E染色切片结果显示,Ir-C1的添加并没有出现明显的组织病理学损伤或组织炎症。这些结果表明,所制备的Ir-C1在体内显示低毒性并具备优异的生物相容性。
综上所述,本发明实施例中的铱配合物能够在光照条件下抑制肿瘤的生长,治疗周期短,并且在用药过程中生物相容性好、毒性低,能用于制备预防和治疗癌症的药物以及组合物。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种光动力铱配合物在制备用于预防和治疗癌症的药物中的应用;所述光动力铱配合物的结构如式(I)所示:
其中,每个A1~A5独立地选自C,N;
R1选自氢,卤素,–CN,–OR’,–N(R’)2,–SR’,–P(R’)2,–C(O)R’,–C(O)OR’,–C(O)NR’,–SOR’,–SO2R’,–SO3R’,–P(O)(R’)2,–P(O)(OR’)R’,–P(O)(OR’)2,C1~C40烷基,C2~C40烯基,C2~C40炔基,C3~C20环烷基,C3~C20杂环烷基,C6~C20芳基,C6~C20杂芳基;上述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基任选被一个或多个取代基取代,所述取代基独立地选自:卤素,–CN,–OR’,–N(R’)2,C1~C20烷基,C2~C20烯基,C2~C20炔基,C3~C20环烷基,C3~C20杂环烷基,C6~C20芳基,C6~C20杂芳基;
环B和环C独立地选自苯基,萘基,蒽基,芴基,吡啶基,嘧啶基,哒嗪基,吡嗪基,喹啉基,异喹啉基,苯并嘧啶基,苯并哒嗪基,苯并吡嗪基,噻吩基,吡咯基,吡唑基,噻唑基,咪唑基,噁唑基,1,2,4-三氮唑,1,2,3-三氮唑,异噁唑基,异噻唑基,吲哚基,苯并咪唑基,苯并噻吩基,苯并噻唑基,所述环B和环C任选地被一个或多个取代基RC或RB取代,RC或RB独立地选自:–O(R”),S(R”),N(R”)2,SO(R”),SO2(R”),P(R”)2,PO(R”)2,PO(OR”)(R”),PO(OR”)2,Si(R”)3,C1~C40烷基,C2~C40烯基,C2~C40炔基,C1~C20卤代烷基、C1~C8烷氧基,C3~C8环烷基,C3~C8杂环烷基,C3~C8芳基,C3~C8杂芳基;其中,R”独立地选自氢,卤素,C1~C8烷基,C1~C8卤代烷基,C3~C8环烷基,C3~C8杂环基,C3~C8芳基,C3~C8杂芳基;
X为–O–;–C(O)O–;–S–;–S(O)2O–;–P(O)2O–;–BR”’–;–NR”’–;其中,R”’独立地选自氢,C1~C8烷基,C1~C8卤代烷基,C3~C8环烷基,C3~C8杂环基,C3~C8芳基,C3~C8杂芳基;
O为0;q和p独立地为0~10的整数;
R2选自Cl,Br,I,CN,OCN,SCN,和C1~C8烷基,C1~C8烷氧基,C1~C8酰氧基,C5~C36芳基,C5~C36杂环芳基,C2~C36炔基。
2.根据权利要求1所述的应用,其特征在于,式(I)光动力铱配合物式中的二齿配体
选自
中的任意一种。
3.根据权利要求1~2任一项所述的应用,其特征在于,所述光动力铱配合物为以下化合物中的任意一种:
4.根据权利要求1~3任一项所述的应用,其特征在于,所述癌症选自乳腺癌、胃癌、结肠癌、直肠癌、子宫内膜癌、头颈癌、肝细胞癌、肺癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌、肾细胞癌、血液系统恶性肿瘤、睾丸癌、中枢神经系统癌、口腔癌、鼻癌、宫颈癌、间皮瘤、肉瘤、甲状腺癌、硬纤维瘤中的任意一种或多种。
5.根据权利要求1~3任一项所述的应用,其特征在于,所述预防和治疗癌症的药物为一种药物组合物。
6.一种药物组合物,其特征在于,其有效成分为含有权利要求1所述的光动力铱配合物。
7.一种细胞增殖抑制剂,其特征在于,所述细胞增殖剂含有权利要求1所述的光动力铱配合物。
8.根据权利要求7所述的细胞增殖抑制剂,其特征在于,所述细胞为癌细胞。
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