CN114835706B - 一种n^n配体及其应用 - Google Patents
一种n^n配体及其应用 Download PDFInfo
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- CN114835706B CN114835706B CN202210508970.7A CN202210508970A CN114835706B CN 114835706 B CN114835706 B CN 114835706B CN 202210508970 A CN202210508970 A CN 202210508970A CN 114835706 B CN114835706 B CN 114835706B
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- 239000003446 ligand Substances 0.000 title claims abstract description 29
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- 238000002156 mixing Methods 0.000 claims description 11
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- 150000001875 compounds Chemical class 0.000 claims description 9
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- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 7
- 239000012298 atmosphere Substances 0.000 claims description 7
- 201000010881 cervical cancer Diseases 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 4
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- FXNSVEQMUYPYJS-UHFFFAOYSA-N 4-(2-aminoethyl)benzenesulfonamide Chemical compound NCCC1=CC=C(S(N)(=O)=O)C=C1 FXNSVEQMUYPYJS-UHFFFAOYSA-N 0.000 claims description 3
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- 239000007795 chemical reaction product Substances 0.000 claims description 3
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 3
- 150000003057 platinum Chemical class 0.000 claims description 3
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/6456—Spatial resolved fluorescence measurements; Imaging
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Abstract
本发明公开了一种结构式如式Ⅰ所示的N^N配体:式Ⅰ;并进一步合成了含有N^N配体的磷光环金属铂配合物;所述磷光环金属铂配合物具有较强近红外荧光发射能力,能够用于作为细胞诊疗成像试剂,本发明配合物在体外显示出对碳酸酐酶的高亲和力和有效抑制作用,且对不同的肿瘤细胞具有不同的抑制作用,在癌症治疗领域具有应用前景,本发明化合物制备简单,适于工业化生产和市场推广应用。
Description
技术领域
本发明涉及一种N^N配体,以及磷光环金属铂配合物属及其应用,属于生物医学检测和成像领域。
背景技术
顺铂虽然在治疗癌症方面取得了很大的成功,但也极易引起耐药性等副作用。与顺铂及其衍生物不同,非经典结构铂(Ⅱ)配合物具有多种化学结构修饰的可能性,是一种很有前途的抗癌药物,可作为顺铂的替代品。通过合理的设计和策略,开发具有非经典结构的新型多靶点抗癌药物是可以实现的。除单一DNA损伤外,靶向和干扰癌细胞线粒体的代谢或功能也被报道为克服单一耐药、提高治疗效果和杀伤癌细胞选择性的有效策略。与顺铂(5%)较差的细胞核摄取相比,结构设计的非经典结构铂(Ⅱ)配合物往往表现出特定的细胞器选择性和增强的细胞摄取,也具有多重诊疗作用。由于优异的光稳定性、高的量子产率、大的Stokes位移和长寿命发光,环金属化铂(Ⅱ)配合物被认为是生物成像和生物传感的理想候选材料。这些特性促使我们致力于环金属化铂配合物基治疗平台的构建。
碳酸酐酶(CAIX)是一种跨膜蛋白,仅在多种发育和侵袭性肿瘤(如结肠、宫颈、食道、肺、骨和乳腺)等非正常组织中过表达,其转录受缺氧诱导因子(HIF-1a)调控。CAIX的主要功能是通过催化CO2水合生成质子和碳酸氢盐来调节胞外和胞内的pH平衡。根据以往的报道,肿瘤代谢可以通过破坏pH调节蛋白和生物能代谢途径来调节癌细胞的缺氧和酸性微环境来重塑。因此,抑制CAIX可以成为肿瘤治疗的潜在靶点,增强对多种实体瘤的有效选择性杀伤,提高光动力疗法(PDT)在缺氧条件下的治疗效率。
综上,碳酸酐酶抑制剂与环金属铂配合物构建的新型诊疗试剂可能具有较大的探索与研究价值。
发明内容
本发明提供了一种结构式如式Ⅰ所示的N^N配体:
式Ⅰ。
上述N^N配体的制备方法如下:
(1)将1,10-菲罗啉-5-氨基加入到氯仿中,室温条件下搅拌并使其充分溶解;
(2)在步骤(1)溶液中加入对甲苯磺酰胺,搅拌,当溶液颜色由淡黄色变为橙黄色后,加入戊二酸酐,然后在惰性气氛、60-80℃下回流反应48-72h,制得化合物;
(3)在溶剂存在条件下,将步骤(2)化合物与1-羟基苯并三唑、水溶性碳二亚胺、N,N-二异丙基乙胺、4-(2-氨乙基)苯磺酰胺混合,在惰性气氛、70-80℃下回流反应18h,反应产物除去溶剂后,使用氧化铝色谱法进行纯化,制的N^N配体。
本发明另一目的是提供结构式如式Ⅱ所示的磷光环金属铂配合物:
式Ⅱ,其中/>选自/>;/>为。
上述磷光环金属铂配合物的制备方法如下:
(1)在溶剂存在条件下,将四氯铂酸钾与芳香环类化合物混合,在惰性气氛、80-90℃下回流反应48h,析出沉淀,沉淀洗涤干燥得到铂桥联前体;
所述四氯铂酸钾与芳香环类化合物的摩尔比为1:1-3,溶剂为乙二醇乙醚和水的混合溶剂(体积比为2:1);芳香环类化合物选自;
(2)在惰性气氛、溶剂存在条件下,将步骤(1)铂桥联前体与银盐混合,反应20-24h脱氯,过滤,滤液为中间产物;
所述铂桥联前体与银盐的摩尔比为1:2-3;银盐为AgCF3SO3 ;溶剂为乙腈、二氯甲烷、甲醇、丙酮中的一种;
(3)在惰性气氛下,将步骤(2)中间产物与N^N配体混合,60-80℃下回流反应20-24h,过滤洗涤,制得磷光环金属铂配合物;铂桥联前体: N^N配体化合物的摩尔比为1:2-4;
所述N^N配体化合物为。
本发明另一目的是将上述磷光环金属铂配合物应用在制备碳酸酐酶抑制剂中,在细胞毒性测试中,具有苯磺酰胺的配合物对不同的肿瘤细胞具有不同的抑制作用,其中 1b配合物对碳酸酐酶过表达的MDA-MB-231细胞的细胞毒性是顺铂的15.24倍,并且与不含有苯磺酰胺的2b配合物相比,1b配合物的毒性是其3.8倍,说明了具有苯磺酰胺的1b对MDA-MB-231细胞具有特异性;本发明磷光环金属铂配合物具有较强近红外荧光发射能力,可以利用其本身的荧光进行成像;
本发明化合物制备工艺简单,适用于工业化生产和市场推广应用。
附图说明
图1是实施例1的核磁共振氢谱(1H-NMR,d6-DMSO)图;
图2是实施例2的核磁共振氢谱(1H-NMR,d6-DMSO)图;
图3是实施例6的核磁共振氢谱(1H-NMR,d6-DMSO)图;
图4是实施例1的高分辨质谱图;
图5是实施例2的高分辨质谱图;
图6是实施例3的高分辨质谱图;
图7是实施例4的高分辨质谱图;
图8是实施例5的高分辨质谱图;
图9是实施例6的高分辨质谱图;
图10是实施例7的高分辨质谱图;
图11是实施例3、4、5、6、7的配合物在PBS溶剂下的紫外吸收图;
图12是实施例3、4、5、6、7的配合物在CH3CN溶剂下的紫外吸收图;
图13是实施例3、4、5、6、7的配合物在CH2Cl2溶剂下的紫外吸收图;
图14是实施例3、4、5在PBS溶剂下的荧光光谱图;
图15是实施例3、4、5在CH3CN溶剂下的荧光光谱图;
图16是实施例3、4、5在CH2Cl2溶剂下的荧光光谱图;
图17是配合物1b、1c的分子对接图;
图18是配合物1b、1c在对改变细胞环境的pH值的研究图;
图19是配合物1a、1b、1c、2b、2c的油水分布示意图;
图20是配合物1b在肿瘤细胞中的摄取结果图;
图21是配合物1b在肿瘤细胞中的摄取与定位结果;
图22是配合物1b、2b对MDA-MB-231细胞的诱导细胞凋亡的流式结果分析图。
具体实施方式
下面通过实施例对本发明作进一步详细说明,但本发明保护范围不局限于所述内容,实施例中制备的化合物用核磁共振氢谱、质谱确定化合物的结构;实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用材料或设备未注明生产厂商者,均为可以通过购买获得的常规产品,使用的方法如无特殊说明均为常规方法;
实施例1:配体L1的合成(C17H15N3O3)
称取1,10-菲罗啉-5-氨基(390 mg, 2 mmol),加入60 mL CH3Cl,室温条件下搅拌使其充分溶解后,加入对甲苯磺酰胺(PTSA,76 mg, 0.4 mmol),在室温条件下搅拌3 min,当溶液从淡黄色变为橙黄色后,再加入戊二酸酐(1.37 g, 12 mmol)后,在氩气保护下,置于60℃油浴锅回流反应72h,反应液中有白色粘性固体析出,反应结束后,冷却至室温,过滤,获得滤渣,滤渣用CH3Cl和超纯水交替洗涤3次后,通过布氏漏斗过滤,得到的固体烘干,得白色固体产物,产率:70.1%;配体L1核磁共振氢谱图见图1,高分辨质谱图见图4;ESI-MS(CH3OH): m/z 310.12, [M+H]+;1H NMR (600 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.18(s, 1H), 9.22 – 9.09 (m, 1H), 9.08 – 8.99 (m, 1H), 8.64 (d, J = 8.0 Hz, 1H),8.48 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 7.85 (dd, J = 8.3, 4.2 Hz, 1H), 7.77(dd, J = 8.0, 4.3 Hz, 1H), 2.60 (t, J = 7.1 Hz, 2H), 2.37 (t, J = 7.2 Hz,2H), 1.92 (p, J = 6.9 Hz, 2H).
实施例2:N^N配体L2的合成(C25H25N5O4S)
将实施例1制得的L1配体(222.56 mg, 0.72mmol)、1-羟基苯并三唑 (199.97 mg,1.48 mmol)、水溶性碳二亚胺 (279.882 mg, 1.46 mmol) 和 N,N-二异丙基乙胺 (250 μL, 1.52 mmol) 加入到含有4-(2-氨乙基)苯磺酰胺(276.08 mg,1.38 mmol)的二甲基甲酰胺(10mL)溶液中;将溶液在氩气气氛下、70℃回流反应18h;反应产物在50℃真空下除去溶剂,使用氧化铝柱色谱法进行纯化,使用洗脱剂(二氯甲烷 :甲醇=1:1)洗脱,收集洗脱液,50 ℃真空浓缩干燥,得到白色固体,产率:60.41%;N^N配体L2核磁共振氢谱图见图2,高分辨质谱图见图5;ESI-MS (CH3OH): m/z 492.1693, [M+H]+;1H NMR (600 MHz, DMSO-d 6) δ9.10 (dd, J = 4.1, 1.2 Hz, 1H), 9.01 (dd, J = 4.2, 1.5 Hz, 1H), 8.73 (dd, J =8.4, 1.3 Hz, 1H), 8.47 (dd, J = 8.1, 1.4 Hz, 1H), 8.19 (s, 1H), 8.15 (t, J =5.4 Hz, 1H), 7.84 (dd, J = 8.4, 4.3 Hz, 1H), 7.77 (dd, J = 8.1, 4.3 Hz, 1H),7.69 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 3.34 – 3.26 (m, 4H), 2.77(t, J = 7.2 Hz, 3H), 2.53 (t, J = 7.5 Hz, 2H), 2.19 (t, J = 7.4 Hz, 2H), 1.89(p, J = 7.4 Hz, 2H).
实施例3:配合物1a的合成(C37H33F5N6O7PtS2)
1、按摩尔比1:2的比例,将四氯铂酸钾与2-(2,4-二氟苯基)吡啶混合,并溶解在乙二醇乙醚和超纯水的混合溶剂(体积比2:1)中,在氮气气氛、80℃下回流搅拌配位反应,反应时间为48h,反应结束后,将反应液浓缩至2mL后,加入20mL的超纯水,在2-4℃冰水浴中处理2h后,过滤,所得固体用乙醚洗3次,再用超纯水洗3次,烘干,得黄绿色铂桥联前体,产率为93%;
2、在50mL圆底烧瓶中加入铂桥联前体(60 mg,0.071mmol),再加入AgCF3SO3(36.70mg,0.142mmol),15mL的乙腈,在氮气气氛、常温下反应24h,过滤,除去AgCl沉淀;
3、滤液真空浓缩并干燥后,加入实施例2的N^N配体L2(140.35 mg,0.296mmol),并溶解在二氯甲烷和甲醇的混合溶剂(体积比2:1)中,在氮气气氛、60℃下冷凝回流反应24h,反应结束后,过滤,取滤渣,用乙醚、二氯甲烷、甲醇、乙腈分别洗3次后,烘干,得红色固体配合物1a,产率: 65.93%,高分辨质谱图见图6;ESI-MS (CH3OH): m/z 876.1720, [M−CF3SO3]+.1H NMR (600 MHz, DMSO-d6) δ 10.27 – 10.16 (m, 1H), 9.22 – 8.94 (m, 2H), 8.71(d, J = 8.4 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.23– 8.10 (m, 1H), 8.05 – 8.01 (m, 1H), 7.97 (dd, J = 14.3, 8.6 Hz, 1H), 7.94 –7.90 (m, 1H), 7.88 – 7.80 (m, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.68 – 7.55 (m,1H), 7.42 – 7.39 (m, 1H), 7.33 (s, 1H), 7.22 (dd, J = 17.7, 6.2 Hz, 1H), 3.32(d, J = 6.2 Hz, 2H), 2.80 (t, J = 6.6 Hz, 2H), 2.20 (t, J = 6.9 Hz, 2H), 1.94– 1.87 (m, 2H), 1.23 (s, 2H).
配合物1a不同溶剂下的紫外吸收和荧光发射
将合成的配合物1a称取1mg,加入二甲基亚砜配制成20mmol/L的母液,分别取3μL母液加入3个5mL的离心管中,加入27µL的二甲基亚砜,再分别用CH3CN、CH2Cl2、PBS缓冲液(pH7.0 - 7.4)配制成20μmol/L的溶液,通过紫外分光光度计检测获得紫外吸收光谱图,结果如图11、12、13所示,结果显示配合物1a,分别在PBS、CH2Cl2、CH3CN中500-550nm的强吸收峰属于MLCT峰,在200-300 nm的强吸收峰属于LLCT峰。
再分别取3μL母液加入3个5mL的离心管中,加入27µL的二甲基亚砜,分别CH3CN、CH2Cl2、PBS配制成20µmol/L的溶液,然后在410nm激发光下,通过荧光分光光度计测得荧光光谱图(最大发射为645nm),结果如图14-16所示,从图中可以看出配合物1a的光学性质,在CH2Cl2中的发射强度到达最大值,荧光最强。
实施例4:配合物1b的合成(C37H33F3N6O7PtS2)
1、按摩尔比1:2的比例,将四氯铂酸钾与2-苯基吡啶混合,并溶解在乙二醇乙醚和超纯水的混合溶剂(体积比2:1)中,在氮气气氛、80℃下回流搅拌配位反应,反应时间为48h,反应结束后,将反应液浓缩至2mL后,加入20mL的超纯水,在2-4℃冰水浴中处理2h后,过滤,所得固体用乙醚洗3次,再用超纯水洗3次,烘干,得黄绿色铂桥联前体,产率为95%;
2、在50mL圆底烧瓶中加入铂桥联前体(60mg,0.074mmol),再加入AgCF3SO3(37.79mg,0.148mmol),15mL乙腈,在氮气气氛、常温下反应24 h,过滤,除去AgCl沉淀;
3、将滤液真空浓缩干燥后,加入实施例2的N^N配体L2(153.49mg,0.296mmol),并溶解在二氯甲烷和甲醇的混合溶剂(体积比2:1)中,在氮气气氛、65℃下冷凝回流反应22h,反应结束后,过滤,取滤渣,用乙醚、二氯甲烷、甲醇、乙腈分别洗3次后,烘干,得红色固体配合物1a,产率: 65.93%,高分辨质谱图见图7;ESI-MS (CH3OH): m/z 840.1906, [M−CF3SO3]+. 1H NMR 1H NMR (600 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.69 (d, J = 5.4 Hz,1H), 9.07 (d, J = 56.6 Hz, 2H), 8.75 (d, J = 7.9 Hz, 1H), 8.64 (d, J = 6.9Hz, 1H), 8.48 (d, J = 7.0 Hz, 1H), 8.39 (d, J = 7.5 Hz, 1H), 8.23 – 8.19 (m,1H), 8.05 – 8.02 (m, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.90 (dd, J = 7.9, 5.5Hz, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.80 – 7.73 (m, 5H), 7.55 (t, J = 7.7 Hz,1H), 7.43 (dd, J = 19.7, 7.6 Hz, 2H), 7.33 (s, 1H), 2.81 (t, J = 6.9 Hz, 2H),2.54 (t, J = 8.3 Hz, 2H), 2.20 (t, J = 6.8 Hz, 2H), 2.00 (ddt, J = 19.0,12.5, 6.0 Hz, 2H), 1.94 – 1.87 (m, 2H).
配合物1b在不同溶剂下的紫外吸收和荧光发射
将合成的配合物1a称取1 mg,加入二甲基亚砜配制成20mmol/L的母液,分别取3μL母液加入3个5mL的离心管中,加入27µL的二甲基亚砜,再分别用CH3CN、CH2Cl2、PBS缓冲液(pH7.0 - 7.4)配制成20µmol/L的溶液,通过紫外分光光度计检测获得紫外吸收光谱图,结果如图11、12、13所示,结果显示配合物1b,分别在PBS、CH2Cl2、CH3CN中500-550 nm的强吸收峰属于MLCT峰,在200-300 nm的强吸收峰属于LLCT峰。
再分别取3μL母液加入3个5mL的离心管中,加入27µL的二甲基亚砜,分别CH3CN、CH2Cl2、PBS配制成20µmol/L的溶液,然后在410nm激发光下,通过荧光分光光度计测得荧光光谱图(最大发射为645nm),结果如图14-16所示,从图中可以看出配合物1b的光学性质,在CH2Cl2中的发射强度到达最大值,荧光最强。
实施例5:配合物1c的合成(C39H33F3N6O7PtS2)
1、按摩尔比1:2的比例,将四氯铂酸钾与苯并喹啉混合,并溶解在乙二醇乙醚和超纯水的混合溶剂(体积比2:1)中,在氮气气氛、80℃下回流搅拌配位反应,反应时间为48h,反应结束后,将反应液浓缩至2mL后,加入20mL的超纯水,在2-4℃冰水浴中处理2 h后,过滤,所得固体用乙醚洗3遍,再用超纯水洗3遍,烘干,得黄绿色铂桥联前体,计算产率为95%;
2、在50mL圆底烧瓶中加入铂桥联前体(60mg,0.074mmol),再加入AgCF3SO3(37.79mg,0.148mmol),15mL乙腈,在氮气气氛、常温下反应24h,过滤,除去AgCl沉淀;
3、将滤液真空浓缩干燥后,加入实施例2的N^N配体L2(144.68 mg,0.296 mmol),并溶解在二氯甲烷和甲醇的混合溶剂(体积比2:1)中,在氮气气氛、70℃下冷凝回流反应24h,反应结束后,过滤,取滤渣,分别用乙醚、二氯甲烷、甲醇、乙腈分别洗3次后,烘干,得红色固体配合物1a,产率: 66.71%,高分辨质谱图见图8;ESI-MS (CH3OH): m/z 864.1917, [M−CF3SO3]+;1H NMR (600 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.12 (s, 1H), 9.01 (d, J =19.2 Hz, 1H), 8.78 – 8.74 (m, 1H), 8.60 (t, J = 8.3 Hz, 1H), 8.33 – 8.28 (m,1H), 8.18 – 8.13 (m, 1H), 8.05 – 7.93 (m, 4H), 7.88 (s, 1H), 7.75 (d, J = 7.9Hz, 3H), 7.65 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 6.9 Hz, 2H), 7.33 (s, 2H),7.23 (d, J = 6.8 Hz, 1H), 7.21 – 7.17 (m, 1H), 7.14 (dd, J = 5.7, 3.2 Hz,1H), 2.83 – 2.79 (m, 2H), 2.58 – 2.53 (m, 2H), 2.20 (t, J = 6.9 Hz, 2H), 2.03– 1.94 (m, 2H), 1.93 – 1.89 (m, 2H).
配合物1c在不同溶剂下的紫外吸收和荧光发射
将合成的配合物1c称取1 mg,加入二甲基亚砜分别配制成20 mmol/L的母液,分别取3 μL母液加入3个5 mL的离心管中,加入27 µL的二甲基亚砜,再分别用CH3CN、CH2Cl2、PBS缓冲液(pH7.0 - 7.4)配制成20 µmol/L的溶液,通过紫外分光光度计检测获得紫外吸收光谱图,结果如图11、12、13所示,结果显示配合物1c,分别在PBS、CH2Cl2、CH3CN中500-550 nm的强吸收峰属于MLCT峰,在200-300 nm的强吸收峰属于LLCT峰。
再分别取3 μL母液加入3个5 mL的离心管中,加入27 µL的二甲基亚砜,分别CH3CN、CH2Cl2、PBS配制成20 µmol/L的溶液,然后在410 nm激发光下,通过荧光分光光度计测得荧光光谱图(最大发射为655 nm),结果如图14-16所示,从图中可以看出配合物1c的光学性质,在CH2Cl2中的发射强度到达最大值,荧光最强。
实施例6:配合物2b的合成(C29H23F3N4O6PtS)
1、按摩尔比1:2的比例,将四氯铂酸钾与2-苯基吡啶混合,并溶解在乙二醇乙醚和超纯水的混合溶剂(体积比2:1)中,在氮气气氛、80℃下回流搅拌配位反应,反应时间为48h,反应结束后,将反应液浓缩至2mL后,加入20mL的超纯水,在2-4℃冰水浴中处理2 h后,过滤,将所得固体用乙醚洗3次,再用超纯水洗3次,烘干,得黄绿色的铂桥联前体,计算产率为93%;
2、在50mL圆底烧瓶中加入铂桥联前体(60 mg,0.069mmol),再加入AgCF3SO3(35.52mg,0.138 mmol),15mL乙腈,在氮气气氛、常温反应24 h,过滤,除去AgCl沉淀;
3、将滤液真空浓缩干燥后,加入配体L1(96.6 mg,0.296 mmol),并溶解在二甲基甲酰胺溶液(体积15mL)中,在氮气气氛、80 ℃下冷凝回流反应24 h,反应结束后,过滤,取滤渣,分别用乙醚、二氯甲烷、甲醇、乙腈分别洗3次后,烘干,得红色固体配合物2b,产率:66.71%,高分辨质谱图见图9;化学式:C29H23F3N4O6PtS;ESI-MS (CH3OH): m/z 864.1917,[M−CF3SO3]+;1H NMR (600 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.68 (d, J = 76.5 Hz,1H), 9.43 (d, J = 56.9 Hz, 1H), 9.14 (s, 1H), 9.05 (s, 1H), 8.98 (d, J = 24.2Hz, 1H), 8.83 – 8.77 (m, 1H), 8.68 – 8.64 (m, 1H), 8.35 (s, 1H), 8.15 (d, J =10.1 Hz, 1H), 7.97 (d, J = 19.6 Hz, 2H), 7.92 – 7.87 (m, 1H), 7.67 (s, 1H),7.45 (s, 1H), 7.27 – 7.13 (m, 1H), 2.62 (s, 2H), 2.42 – 2.37 (m, 2H), 2.03 –1.94 (m, 2H).
配合物2b在不同溶剂下的紫外吸收。
将合成的配合物2b称取1mg,加入二甲基亚砜分别配制成20mmol/L的母液,分别取3 μL母液加入3个5mL的离心管中,加入27µL的二甲基亚砜,再分别用CH3CN、CH2Cl2、PBS缓冲液(pH7.0 - 7.4)配制成20µmol/L的溶液,通过紫外分光光度计检测获得紫外吸收光谱图,结果如图11、12、13所示,结果显示配合物2b,分别在PBS、CH2Cl2、CH3CN中500-550nm的强吸收峰属于MLCT峰,在200-300nm的强吸收峰属于LLCT峰。
实施例7:配合物2c的合成(C31H23F3N4O6PtS)
1、按摩尔比1:2的比例,将四氯铂酸钾与苯并喹啉混合,并溶解在乙二醇乙醚和超纯水的混合溶剂(体积比2:1)中,在氮气气氛、80℃下回流搅拌配位反应,反应时间为48h,反应结束后,将反应液浓缩至2mL后,加入20mL的乙醚,在2-4℃冰水浴中处理2h后,过滤,将所得固体用乙醚洗3次,再用超纯水洗3次,烘干,得黄绿色的铂桥联前体,产率为93%;
2、在50mL圆底烧瓶中加入铂桥联前体(60mg,0.050mmol),再加入AgCF3SO3(25.65mg,0.100mmol),15mL乙腈,在氮气气氛、常温反应24 h,过滤,除去AgCl沉淀;
3、将滤液真空浓缩干燥后,加入配体L1(90.91mg,0.296mmol),并溶解在二甲基甲酰胺溶液(体积15mL)中,在氮气气氛、80℃下冷凝回流反应24h,反应结束后,过滤,取滤渣,分别用乙醚、二氯甲烷、甲醇、乙腈分别洗3次后,烘干,得红色固体配合物2c,产率:54.6%,高分辨质谱图见图10。ESI-MS (CH3OH): m/z 864.1917, [M−CF3SO3]+;1H NMR (600 MHz,DMSO-d 6) δ 10.23 (s, 1H), 9.88 – 9.36 (m, 1H), 9.13 (s, 1H), 9.06 – 9.01 (m,1H), 8.73 (dd, J = 24.0, 7.8 Hz, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.50 – 8.35(m, 1H), 8.27 (s, 1H), 7.97 – 7.87 (m, 2H), 7.86 – 7.80 (m, 2H), 7.78 (d, J =7.6 Hz, 1H), 7.74 – 7.57 (m, 2H), 7.54 (t, J = 7.4 Hz, 1H), 2.61 (d, J = 6.3Hz, 2H), 2.38 (dd, J = 11.5, 4.2 Hz, 2H), 2.03 – 1.96 (m, 2H).
配合物2c在不同溶剂下的紫外吸收
将合成的配合物2c称取1 mg,加入二甲基亚砜分别配制成20 mmol/L的母液,分别取3μL母液加入3个5mL的离心管中,加入27µL的二甲基亚砜,再分别用CH3CN、CH2Cl2、PBS缓冲液(pH7.0 - 7.4)配制成20µmol/L的溶液,通过紫外分光光度计检测获得紫外吸收光谱图,结果如图11、12、13所示,结果显示配合物1c,分别在PBS、CH2Cl2、CH3CN中500-550nm的强吸收峰属于MLCT峰,在200-300nm的强吸收峰属于LLCT峰。
实施例8:配合物荧光量子产率的检测
荧光量子产率可用于表征物质荧光发光能力的大小,依据下列公式进行计算:
YU:待测物质的量子产率;YS:参比物质的量子产率;FU:待测物质的积分荧光强度;FS:参比物质的积分荧光强度;AU:待测物质的紫外吸光度;AS:参比物质的紫外吸光度。
选用[Ru(bpy)3](PF6)2为参比物质,称取1 mg,加入相应体积的二甲基亚砜配制成20mmol/L,取3µL加入到5个5mL的离心管里,加入27µL的二甲基亚砜,再分别加入CH3CN、PBS缓冲液、CH2Cl2配制成20µmol/L的溶液,通过紫外分光光度计,测定配置溶液的紫外吸收值,最终使得每一种溶剂下在在最大吸收波长处的吸光度为0.05。当溶液吸光度为0.05时,用最大吸收波长激发测定其荧光,并计算荧光积分强度。
分别称取1a、1b、1c、2b、2c配合物0.5mg加入二甲基亚砜中配制成20mmol/L,取3µL到5mL的离心管里,每管加入27μL的二甲基亚砜,再分别加入CH3CN、CH2Cl2、PBS缓冲液配制成20µmol/L的初始浓度溶液备用,利用备用液调节样品浓度使得配合物在每一种溶剂条件下最大吸收波长处的紫外的吸光度接近于0.05。当溶液吸光度接近0.05时,用最大吸收波长激发测定其荧光光谱,计算相应的荧光光谱积分大小。用上述计算公式计算出每一种配合物的荧光量子产率,数据如下表所示;结果显示配合物2b、2c在二氯甲烷溶液中荧光量子产率较低,说明可能是因为配合物2b、2c配体中含有羧酸吸电子基诱导荧光强度降低和发射磷光峰位置的蓝移。
表1. 本发明制备得到的环金属铂配合物的荧光量子产率
。
实施例9:磷光环金属铂配合物的抗肿瘤活性测定
利用实施例2、3、4、5、6、7制备得到的N^N配体、环金属铂配合物为实验组,以顺铂作为对照组,测定其对HeLa(人宫颈癌细胞株)、A549(人非小细胞肺癌细胞)、MDA-MB-231(人三阴性乳腺癌细胞)、HLF(人肺成纤维细胞)、LO2(人正常肝细胞)的细胞毒性,具体测定方法如下:
采用四唑盐(MTT)比色法测定,将受试肿瘤细胞分别用胰酶消化成单细胞悬液,采用血球计数板进行计数,调整细胞浓度为5×104/mL,接种于96孔板,每孔160μL,培养24h后,再加入不同浓度的药物,置于在5% CO2、37℃的培养箱中孵育48h,于孵育结束前4h加入MTT 20μL/孔;4h后弃上清液,加入DMSO 150μL/孔,振动5min后用酶标仪测定OD值,波长设置为492nm;计算受试肿瘤细胞的存活率,同时作图并求出IC50值,评价配合物的抗肿瘤活性;结果见表2,实验结果显示具有苯磺酰胺结构1a、1b、1c配合物相比于2b、2c具有更好的抗肿瘤活性,其中配合物1b对MDA-MB-231细胞(CAIX过表达株)的抗肿瘤活性(IC50=3.37 μM)最好,其细胞毒性是顺铂的4.05倍,因此具有苯磺酰胺结构的配合物对MDA-MB-231细胞系具有较为明显的抑制作用;
表2本发明制备得到的环金属铂配合物的细胞毒性
。
实施例10:配合物1b、配合物1c的分子对接
对接采用的分子来自于PDB数据库CAIX 与乙酰唑胺的共晶结构(PDB:3AIA)。蛋白的预先处理,除去多余的水分子,并用薛定谔软件进行优化。对接采用的软件为AutoDockVina。计算得到的结果用pymol进行绘画。
分子对接可以用来评估配合物和碳酸酐酶(CAIX)的结合能力的强弱。我们选择了CAIX与临床使用的磺胺抑制剂乙酰唑胺的复合物的晶体结构(PBD: 3IAI)作为受体分子,进一步研究了配合物1b、1c和碳酸酐酶蛋白的结合情况,AAZ(乙酰唑胺)为对照组,从图17中看出,1b和1c只有苯磺酰胺部分可以进入到口袋中,由于苯磺酰胺的部分和环金属铂(Ⅱ)之间是由较长的碳链间接的,因此环金属铂(Ⅱ)没有进入到蛋白口袋中;
配合物1b的苯环酰胺中的N原子与碳酸酐酶蛋白中的Zn2+进行配位,并且苯环酰胺中的两个氧原子与HIS 94和THR 199有氢键作用,配合物中的酰胺键的氧原子与GLN 67有氢键作用。配合物1c的苯环酰胺中的N原子与蛋白中的Zn2+进行配位,并且和THR 200有氢键作用,苯环酰胺中其中一个氧原子与HIS 94有氢键作用。综上所述,配合物1b和1c的结合方式和AAZ的相似。我们进一步对配合物的结合能进行了计算,结果发现配合物1c(-8.100kcal/mol) < AAZ (-7.850 kcal/mol) < 配合物1b (-7.575 kcal/mol),因此所制备的配合物的结合能力与对照组AAZ相比排序是1b > AAZ > 1c,可能是因为配合物1c中苯并喹啉的部分暴露在口袋外面的部分较多,并且苯磺酰胺部分与活性中心的配位较差,因此结合能相对低一些。
实施例11:配合物1b、1c、2b、2c的CAIX体外抑制活性
首先把蛋白配置成1.1ng/L的碳酸酐酶蛋白工作液,检测剂4-硝基邻苯二甲酸配置成浓度为1mM的母液;具体操作如下:
1、在96孔板中加入碳酸酐酶蛋白工作液(36μL/孔),再分别加入不同浓度铂(Ⅱ)配合物(1b-1c)和乙酰唑胺(AAZ)(4μL/孔),其中乙酰唑胺(AAZ)为阳性对照组,空白组加PBS缓冲溶液;
2、然后将其置于摇床上,摇15min后再加入4-硝基邻苯二甲酸(40μL/孔),放入恒温培养箱中培养4-5h后,采用酶标仪读取405nm处的吸收值,并通过以下公式计算出抑制率;
;
结果见表3,从表中可以看出配合物1b的抑制效率比配合物2b明显好,配合物1c的抑制效率比配合物2c明显好,说明含有L2配体的配合物比含有L1配体的配合物在体外对碳酸酐酶的抑制效率明显;
表3不同化合物对 CAIX 的体外抑制活性
。
实施例12:配合物1b、1c对细胞环境的pH值的影响
选用MDA-MB-231细胞检测细胞体外环境pH的变化,将生长状态良好的MDA-MB-231细胞用胰酶消化下来,接种于6孔板中,用含有5% CO2的培养箱37℃培养。当接种的细胞培养至细胞密度70%时,用pH计检测培养液pH值;然后加入配合物1a、1b、1c和顺铂,(设置2个浓度分别为20μmol/L和10μmol/L),继续培养24h,培养结束后,用pH计测量培养液pH值,计算两次差值,并进行分析;结果见图18,结果显示,与空白组(不添加配合物)比较,用配合物和顺铂孵育24h后肿瘤细胞的体外环境的pH值下降幅度较低,这意味着所制备的具有苯磺酰胺结构的铂类药物进入到细胞后对细胞内的碳酸酐酶有显著的抑制效果,从而降低了肿瘤细胞体外的酸化程度。
实施例13:配合物1a、1b、1c、2b、2c的脂水分布系数
配合物1a、1b、1c、2b、2c的脂水分配系(log Pow)是采用了经典的正辛醇/水摇瓶法测定。首先,将正辛醇和水的混合溶液进行预处理(置于摇床上震荡24 h),静置1 h待溶液分层,用注射器取等体积正辛醇和水溶液放入离心管中,再将铂(Ⅱ)配合物加入离心管中直到溶液过饱和。有固体析出后停止添加,并将离心管放置摇床上震荡48h。震荡结束后静置1h,待溶液分层后分别用注射器取各相溶液,通过紫外分光光度计检测正辛醇/水相的吸收值,通过一下公式进行计算;
结果见图19,结果显示配合物2b的亲水性强于配合物1b,配合物2c的亲水性也强于配合物1c,说明是因为配合物2b、2c中羧酸基团的存在,可能诱导配合物2b、2c亲水性增强。而配合物1c的脂溶性强于配合物1b,配合物2c的脂溶性也强于2b,说明是因为增加了辅助配体分子结构中苯环共轭数量,导致配合物1c、2c的脂溶性增强。
实施例14:配合物1b在肿瘤细胞中的摄取情况
将生长状态良好的HeLa (人宫颈癌细胞株)和MDA-MB-231(人乳腺癌细胞系)用胰酶消化下来,接种于共聚焦培养皿中,用含有5% CO2的培养箱37℃培养;当HeLa细胞的密度培养至70%时,加入配合物1b,最终药物孵育细胞的浓度为10μmol/L,分别培养2 h、6 h和24h,用PBS 洗涤两次,立刻用激光共聚焦显微镜观察;配合物1b的最大激发为:516nm,收集波长范围是645 ± 20 nm。结果见图20,配合物1b在24h时可以进入细胞内。
实施例15:配合物1b在肿瘤细胞中的摄取与定位情况
通过激光共聚焦显微镜拍摄配合物1b在肿瘤细胞中的摄取与定位情况,具体实验方法和结果如下:
将生长状态良好的HeLa (人宫颈癌细胞株)和MDA-MB-231(人乳腺癌细胞系)用胰酶消化下来,接种于共聚焦培养皿中,用含有5% CO2的培养箱37℃培养;当细胞的密度培养至70%时,加入配合物1b,最终药物孵育细胞的浓度为10μmol/L,继续培养24h,加入相应浓度的亚细胞器荧光(溶酶体深红色荧光染料(Ex=596nm,Em=619±20nm),线粒体深红色荧光染料(Ex=644nm,Em=665±20nm),内质网蓝色染料(Ex=374nm,Em=430±20nm),细胞核仁红色染料Styo59(Ex=622nm,Em=645±20nm)染料进行染色,孵育10-15min后去除培养基,用PBS 洗涤两次,立刻用激光共聚焦显微镜观察。
结果见图21,配合物1b在Hela细胞中与核仁染料Syto59有高度的定位效果;在MDA-MB-231细胞中与溶酶体的定位系数较高,和线粒体染料完全没有定位效果。由此可以证明配合物1b可以很好的被细胞摄取并进入到细胞核中。
实施例16:配合物1b、配合物2b抗肿瘤作用研究
通过流式细胞仪测定配合物1b、2b诱导MDA-MB-231细胞凋亡能力,具体实验方法和结果如下:
取生长状态良好的MDA-MB-231细胞用胰酶消化下来,用DMEM培养基稀释成单细胞悬液,接种于Corning六孔板中,每个孔200μL,于37 ℃下培养24h后,分别加入浓度为5μmol/L、10μmol/L和20μmol/L的配合物1b以及浓度为5μmol/L、10μmol/L和20μmol/L的配合物2b进行细胞凋亡刺激,孵育24h后,用胰酶消化并收集细胞,加入195µL Annexin V-FITC结合液轻轻重悬细胞,然后加入5µL Annexin V-FITC和10µL碘化丙啶(PI)染色液,轻轻混匀;于室温下避光孵育10~20min,随后置于冰浴中,并用铝箔进行避光;之后用流式细胞仪进行检测。
配合物1b、2b对MDA-MB-231细胞的诱导细胞凋亡能力的影响结果如图22所示,用1b处理的MDA-MB-231细胞主要是在早期凋亡阶段,并且表现出浓度依赖性,用1b处理48h后,早期凋亡和晚期凋亡的细胞总数的百分比从4.36%(5μM)增加到了97.1%(10μM)又增加到了98.2%(20μM),用2b处理48h后,早期凋亡和晚期凋亡的细胞总数的百分比从7.78%(5μM)增加到了9.78%(10μM)又增加到了14.56%(20μM),说明了碳酸酐酶靶向的配合物1b具有更好的细胞毒性和选择性。
Claims (6)
1.结构式如式Ⅰ所示的N^N配体:
式Ⅰ
2.权利要求1所述的N^N配体的制备方法,其特征在于,步骤如下:
(1)将1,10-菲罗啉-5-氨基加入到氯仿中,室温条件下搅拌并使其充分溶解;
(2)在步骤(1)溶液中加入对甲苯磺酰胺,搅拌,溶液颜色由淡黄色变为橙黄色后,加入戊二酸酐,然后在惰性气氛、60-80℃下回流反应48-72h,制得化合物
(3)在溶剂存在条件下,将步骤(2)化合物与1-羟基苯并三唑、水溶性碳二亚胺、N,N-二异丙基乙胺、4-(2-氨乙基)苯磺酰胺混合,在惰性气氛、70-80℃下回流18h,反应产物真空干燥除去溶剂后,使用氧化铝色谱法进行纯化,制得N^N配体。
3.结构式如式Ⅱ所示的磷光环金属铂配合物:
式Ⅱ其中/>选自/>为
4.权利要求3所述的磷光环金属铂配合物在制备碳酸酐酶抑制剂中的应用。
5.权利要求3所述的磷光环金属铂配合物在制备细胞诊疗成像试剂中的应用。
6.权利要求3所述的磷光环金属铂配合物在制备抗肿瘤药物中的应用;
当磷光环金属铂配合物结构式如下时,所述肿瘤选自人宫颈癌、人非小细胞肺癌、人三阴性乳腺癌:
当磷光环金属铂配合物结构式如下时,所述肿瘤选自人宫颈癌、人非小细胞肺癌、人三阴性乳腺癌:
当磷光环金属铂配合物结构式如下时,所述肿瘤选自人宫颈癌、人非小细胞肺癌:
当磷光环金属铂配合物结构式如下时,所述肿瘤选自人宫颈癌、人非小细胞肺癌、人三阴性乳腺癌:
当磷光环金属铂配合物结构式如下时,所述肿瘤选自人宫颈癌:
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