CN111875604A - 一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物及其制备方法和应用 - Google Patents
一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及生物医药技术领域,具体涉及一类线粒体靶向和光动力治疗的β‑咔啉鎓盐的荧光化合物及其制备方法和应用,具有通式Ⅰ所示结构:本发明基于β‑咔啉生物碱母环的吲哚并吡啶的三环平面骨架结构,利用其较强的供电子能力、较优的刚性及共轭体系,在β‑咔啉3位引入醛基,与甲基取代的喹啉鎓盐或萘啶鎓盐等亲脂性阳离子通过羟醛缩合反应,获得一类具有线粒体靶向和光动力治疗效应的β‑咔啉鎓盐荧光化合物。该化合物本身具有较低暗毒性、光动力治疗效果等,也适用于线粒体靶向的荧光探针,可以优先靶向进入肿瘤组织和细胞,从而进行的体内外肿瘤荧光诊断成像,并在特定波长光照射后产生单线态氧,从而有效杀伤肿瘤细胞,可用于肿瘤诊断治疗一体化。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物及其制备方法和应用。
背景技术
癌症的发生发展是一种多种信号通路和多种基因共同参与的复杂生物学过程,相比正常细胞,肿瘤细胞具有无限增殖、组织转移、能量代谢异常等特点。因此,提出了以线粒体为靶标的癌症治疗新策略。众所周知,线粒体是真核细胞物质和能量代谢的“动力工厂”,与肿瘤发生发展存在着莫大的联系,但线粒体在癌细胞中的作用机制目前并未被完全阐明。常见的肿瘤细胞线粒体的靶向基团是亲脂性阳离子,其原理在于肿瘤细胞相比正常细胞具有较高的线粒体膜电位。根据能斯特定律,每增加线粒体膜电位一个单位,则聚集在线粒体内膜中的亲脂性阳离子化合物浓度就会提高10倍,使得亲脂性阳离子更能靶向肿瘤细胞线粒体内膜。最典型的例子是具有线粒体靶向作用的罗丹明-123。但目前研究较多的是治疗过程中细胞整体环境的变化,缺乏基于线粒体靶向的肿瘤细胞诊断和治疗一体化策略。鉴于此,设计新型线粒体靶向的荧光化合物进行体内外肿瘤细胞和组织的荧光成像诊断和/或治疗具有重要意义。
光动力学疗法(PDT)作为一种新型肿瘤治疗方法,它基于光敏剂在肿瘤组织的特异性吸收和选择性滞留,通过特定波长的激发光照射光敏剂产生细胞毒性物质,从而有效杀伤肿瘤细胞并达到治疗目的。研究表明,光动力学疗法利用光敏剂的荧光特性,已经在癌症的诊断和治疗中发挥越来越重要的作用。鉴于此,利用线粒体靶向,将促进癌细胞对亲脂阳离子荧光探针的摄取和保留增加,同时进行光动力治疗,为开发新的、更具选择性的肿瘤诊断和/或治疗的分子探针提供理论依据。鉴于此,本发明开发设计了具有线粒体靶向、低暗毒性和光动力治疗的小分子荧光化合物,对癌症早期检测、诊断和/或治疗具有重大应用价值。
发明内容
针对以上问题,本发明提供了一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物及其制备方法和应用,具有靶向线粒体进行体内外荧光成像诊断、发挥光动力治疗效果的医药用途,特别是体内外肿瘤细胞和组织的荧光成像诊断和/或治疗。
为了实现上述目的,本发明采用的技术方案如下:
一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物,具有通式Ⅰ所示结构:
其中,R1代表H、C1-C6烷基、炔基取代的C1-C6烷基、卤代C1-C6烷基、或甲氧基取代的C1-C6烷基;R2代表H、C1-C6烷基、或者甲氧基取代的苯基;R3代表C1-C6烷基、炔基取代的C1-C6烷基、或者卤代C1-C6烷基;X代表CH、N、或者带C1-C6烷基取代的N正离子(卤负离子);Y-代表卤负离子、六氟磷酸根负离子、磺酸负离子、或者甲磺酸负离子;β-咔啉-3-乙烯基连接在AB环的2-7位。
优选的,所述R1代表H、CH3、CH2CH3;R2代表H、CH3、C(CH3)3、CH2CH(CH3)2;R3代表CH3、CH2CH3、炔丙基、炔丁基;X代表CH、N、或者带甲基或乙基取代的N正离子(卤负离子);Y-代表碘负离子、六氟磷酸根负离子、或者甲磺酸负离子;β-咔啉-3-乙烯基连接在AB环的2-7位。
优选的,所述β-咔啉鎓盐的荧光化合物的代号及其对应的结构如下:
表1通式Ⅰ部分化合物代号及其对应的结构
I1:(E)-4-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐;
I2:(E)-4-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-(丁-3-炔-1-基)喹啉-1-甲磺酸盐;
I3:(E)-4-(2-(9-(2-乙基)-1-甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐;
I4:(E)-4-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1,8-二甲基-1,8-萘啶-1,8-二碘盐;
I5:(E)-4-(2-(1-(1-(叔丁基)-9-甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐;
I6:(E)-4-(2-(1-(1-(异丁基)-9-甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐;
I7:(E)-5-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐;
I8:(E)-5-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-乙基喹啉-1-碘盐。
本发明的另一目的是提供一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物I的制备方法,将9-R1-1-R2-9H-吡啶并[3,4-b]吲哚-3-甲醛(1)与甲基取代的喹啉鎓盐或萘啶鎓
其中,所述R1代表H、CH3、CH2CH3;R2代表H、CH3、C(CH3)3、CH2CH(CH3)3;R3代表CH3、CH2CH3、炔丙基、炔丁基;X代表CH、N、或者带甲基或乙基取代的N正离子(卤负离子);Y-代表碘负离子、六氟磷酸根负离子、甲磺酸负离子;β-咔啉-3-乙烯基连接在AB环的2-7位。
优选的,所述制备方法具体为:
将9-R1-1-R2-9H-吡啶并[3,4-b]吲哚-3-甲醛(1)与4-或5-甲基的喹啉鎓盐或萘啶鎓盐(2)溶于无水乙醇中,滴加催化量哌啶或乙酸铵,回流反应8~12小时,通过重结晶或者色谱柱纯化得到β-咔啉鎓盐荧光化合物。
本发明的再一目的是提供一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物在制备靶向肿瘤细胞线粒体的荧光成像诊断中的应用,该β-咔啉鎓盐的荧光化合物具有靶向肿瘤细胞线粒体的荧光特性,可实现体内外的肿瘤组织或细胞的荧光成像。其中,肿瘤细胞为乳腺癌细胞、结肠癌细胞、肝癌细胞或胃癌细胞等。
本发明的又一目的是提供一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物在制备具有光动力肿瘤治疗的药物中的应用,可实现体内外的肿瘤组织或细胞的荧光成像和/或治疗。其中,β-咔啉鎓盐的荧光化合物经过激发光照射后产生单线态氧杀伤肿瘤细胞。
本发明有益效果:
1、本发明结合天然β-咔啉生物碱的吲哚并吡啶的三环平面骨架结构,利用其较强的供电子能力、较优的刚性及共轭体系,在3位通过羟醛缩合反应引入亲脂性阳离子(包括喹啉鎓盐或萘啶鎓盐),设计获得一类具有线粒体靶向和光动力治疗的β-咔啉鎓盐荧光化合物。
2、本发明的β-咔啉鎓盐的荧光化合物具有线粒体靶向的近红外荧光特性,可在体内或体外肿瘤细胞精准成像诊断;同时在特定波长光照射后有效产生单线态氧,有效杀伤肿瘤细胞,并且具有低暗毒性的优点,在肿瘤诊断和/或治疗方面的应用前景广阔。
3、本发明的β-咔啉鎓盐的荧光化合物可以从激发的单重态光敏剂弛缓到基态产生荧光,也可以通过系间窜越跃至激发三重态,将能量直接转移到氧气并转换成高活性的单线态氧从而产生细胞毒性并杀伤肿瘤细胞,具有较好的线粒体靶向性、近红外特性、低暗毒性的特点,在肿瘤诊断或治疗方面应用广阔。
附图说明
图1为本发明荧光化合物部分化合物在1%DMSO的水溶液的紫外吸收光谱图(横坐标为波长,纵坐标为吸光度值);
图2为本发明荧光化合物部分化合物在1%DMSO的水溶液的荧光发射光谱图(横坐标为波长,纵坐标为荧光强度);
图3为本发明荧光化合物部分化合物单线态氧捕获剂DPBF的紫外吸光谱(横坐标为波长,纵坐标为吸光度值);
图4为本发明部分化合物在1~25μM下和1μMMitoTrackerred同时共染Hela细胞线粒体定位验证共聚焦荧光成像图;
图5为本发明部分化合物在1~25μM下和1μMMitoTrackerred同时共染HT29细胞线粒体定位验证共聚焦荧光成像图。
具体实施方式
为了进一步阐明本发明,下面给出一系列实施例,这些实施例完全是例证性的,它们仅用来对本发明具体描述,不应当理解为对本发明的限制。
实施例1:(E)-4-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐(I1)的制备;
将1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛(2.24g,10mmol)和1,4-二甲基喹啉-1-碘盐(2.85g,10mmol)加入单口瓶中,加入5ml无水乙醇,随后加入1滴哌啶,回流过夜,TLC监测反应至完全,反应液降温抽滤,再次重结晶纯化得到红色固体(I1)4.2g,产率为85.7%。(I1)谱图数据为:ESI-MS(m/z):492[M+H]+;1HNMR(d6-DMSO,400MHz):δ9.29(d,J=6.5Hz,1H,Ar-H),8.86(d,J=8.5Hz,1H,Ar-H),8.59(s,1H,Ar-H),8.56–8.37(m,3H,Ar-H,CH),8.34–8.20(m,3H,Ar-H,CH),8.12–8.04(m,1H,Ar-H),7.77(d,J=8.4Hz,1H,Ar-H),7.72–7.63(m,1H,Ar-H),7.38–7.34(m,1H,Ar-H),4.50(s,3H,CH3),4.20(s,3H,CH3),3.15(s,3H,CH3)。
实施例2:(E)-4-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-(丁-3-炔-1-基)喹啉-1-甲磺酸盐(I2)的制备;
参照实施例1中(I1)的合成方法,由4-甲基-1-(丁-3-炔-1-基)喹啉-1-甲磺酸盐代替方法中的1,4-二甲基喹啉-1-碘盐,最后得到红棕色固体(I2)3.9g,产率为79.6%。(I2)谱图数据为:ESI-MS(m/z):498[M+H]+;1HNMR(d6-DMSO,400MHz):δ9.31(d,J=6.6Hz,1H,Ar-H),8.89(d,J=8.6Hz,1H,Ar-H),8.58(s,1H,Ar-H),8.58–8.41(m,3H,Ar-H,CH),8.37–8.25(m,3H,Ar-H,CH),8.15–8.07(m,1H,Ar-H),7.80(d,J=8.4Hz,1H,Ar-H),7.71–7.64(m,1H,Ar-H),7.42–7.34(m,1H,Ar-H),4.69–4.61(m,2H,CH2),4.26(s,3H,CH3),3.17(s,3H,CH3),2.14(s,1H,CH),2.10–2.04(m,2H,CH2)。
实施例3:(E)-4-(2-(9-(2-乙基)-1-甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐(I3)的制备;
参照实施例1中(I1)的合成方法,由9-乙基-1-甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛代替方法中的1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛,最后得到红色固体(I3)4.7g,产率为80.5%。(I3)谱图数据为:ESI-MS(m/z):506[M+H]+;1HNMR(d6-DMSO,400MHz):δ9.28(s,1H,Ar-H),8.85(d,J=8.4Hz,1H,Ar-H),8.57(s,1H,Ar-H),8.54–8.39(m,3H,Ar-H,CH),8.33–8.23(m,3H,Ar-H,CH),8.13–8.05(m,1H,Ar-H),7.73(d,J=8.4Hz,1H,Ar-H),7.70–7.62(m,1H,Ar-H),7.32–7.29(m,1H,Ar-H),4.53(s,3H,CH3),4.25–4.17(m,2H,CH2),3.16(s,3H,CH3),2.72–2.59(m,3H,CH3)。
实施例4:(E)-4-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1,8-二甲基-1,8-萘啶-1,8-二碘盐(I4)的制备;
参照实施例1中(I1)的合成方法,由1,4,8-三甲基-1,8-萘啶-1,8-二碘盐代替方法中的1,4-二甲基喹啉-1-碘盐,最后得到深红色固体(I4)5.3g,产率为84.2%。(I4)谱图数据为:ESI-MS(m/z):635[M+H]+;1HNMR(d6-DMSO,400MHz):δ9.36(d,J=8.5Hz,2H,Ar-H),8.79(s,1H,Ar-H),8.66–8.57(m,3H,Ar-H,CH),8.39–8.23(m,3H,Ar-H,CH),8.16–8.09(m,1H,Ar-H),7.74–7.68(m,1H,Ar-H),7.39–7.34(m,1H,Ar-H),4.59(s,6H,CH3),4.24(s,3H,CH3),3.17(s,3H,CH3)。
实施例5:(E)-4-(2-(1-(1-(叔丁基)-9-甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐(I5)的制备;
参照实施例1中(I1)的合成方法,由1-叔丁基-9-甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛代替方法中的1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛,由1,4-二甲基喹啉-1-碘盐代替方法中的1,4-二甲基喹啉-1-碘盐,最后得到红色固体(I5)4.3g,产率为80.6%。(I5)谱图数据为:ESI-MS(m/z):534[M+H]+;1HNMR(d6-DMSO,400MHz):δ9.32(d,J=6.8Hz,1H,Ar-H),8.87(d,J=8.6Hz,1H,Ar-H),8.59(s,1H,Ar-H),8.52–8.38(m,3H,Ar-H,CH),8.36–8.22(m,3H,Ar-H,CH),8.14–8.06(m,1H,Ar-H),7.79(d,J=8.4Hz,1H,Ar-H),7.74–7.65(m,1H,Ar-H),7.39–7.34(m,1H,Ar-H),4.51(s,3H,CH3),4.22(s,3H,CH3),2.71(s,9H,CH3)。
实施例6:(E)-4-(2-(1-(1-(异丁基)-9-甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐(I6)的制备;
参照实施例1中(I1)的合成方法,由1-异丁基-9-甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛代替方法中的1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛,由1,4-二甲基喹啉-1-碘盐代替方法中的1,4-二甲基喹啉-1-碘盐,最后得到红色固体(I6)4.1g,产率为76.1%。(I6)谱图数据为:ESI-MS(m/z):534[M+H]+;1HNMR(d6-DMSO,400MHz):δ9.26(d,J=6.8Hz,1H,Ar-H),8.85(d,J=8.6Hz,1H,Ar-H),8.56(s,1H,Ar-H),8.50–8.39(m,3H,Ar-H,CH),8.34–8.22(m,3H,Ar-H,CH),8.15–8.09(m,1H,Ar-H),7.76(d,J=8.4Hz,1H,Ar-H),7.71–7.68(m,1H,Ar-H),7.35–7.30(m,1H,Ar-H),4.49(s,3H,CH3),4.20(s,3H,CH3),2.75–2.69(m,2H,CH2),2.45–2.39(m,1H,CH),2.05–1.89(m,6H,CH3)。
实施例7:(E)-5-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐(I7)的制备;
参照实施例1中(I1)的合成方法,由1,5-二甲基喹啉-1-碘盐代替方法中的1,4-二甲基喹啉-1-碘盐,最后得到深红色固体(I7)2.1g,产率为42.8%。(I7)谱图数据为:ESI-MS(m/z):492[M+H]+;1HNMR(d6-DMSO,400MHz):δ9.12(s,1H,Ar-H),8.88(d,J=8.8Hz,1H,Ar-H),8.48(d,J=9.4Hz,1H,Ar-H),8.31(s,1H,Ar-H),8.08(d,J=8.4Hz,2H,Ar-H),7.87–7.79(m,5H,Ar-H,CH),7.64(d,J=7.3Hz,2H,Ar-H),4.38(s,3H,CH3),2.99(s,3H,CH3),2.75(s,3H,CH3)。
实施例8:(E)-5-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-乙基喹啉-1-碘盐(I8)的制备;
参照实施例1中(I1)的合成方法,由5-甲基-1-乙基喹啉-1-碘盐代替方法中的1,4-二甲基喹啉-1-碘盐,最后得到黑色固体(I8)2.3g,产率为44.6%。(I8)谱图数据为:ESI-MS(m/z):506[M+H]+;1HNMR(d6-DMSO,400MHz):δ9.16(d,J=6.4Hz,1H,Ar-H),8.65–8.49(m,2H,Ar-H),8.30(s,1H,Ar-H),8.01–7.92(m,2H,Ar-H,CH),7.86–7.75(m,3H,Ar-H,CH),7.61–7.55(m,2H,Ar-H),7.42–7.35(m,2H,Ar-H),4.78–4.73(m,2H,CH2),3.01–2.94(m,3H,CH3),2.90(s,3H,CH3),2.79(s,3H,CH3)。
实施例9:本发明荧光化合物的紫外吸收光谱测试
以荧光化合物I1、I3、I5、I7作为代表化合物,参照图1,将本发明荧光化合物溶于含1%DMSO的水溶液中,配制成1-25μM的检测液。采用紫外-可见分光光度计测试其紫外吸收光谱数据,结果显示本发明荧光化合物紫外最大吸收波长在420-470nm范围内。其中化合物I1紫外最大吸收波长在455nm左右,其峰值随化合物I1的浓度增加而增加(图1a);化合物I3紫外最大吸收波长在465nm左右,其峰值随化合物I3的浓度增加而增加(图1b);化合物I5紫外最大吸收波长在470nm左右,其峰值随化合物I5的浓度增加而增加(图1c);化合物I7紫外最大吸收波长在435nm左右,其峰值随化合物I7的浓度增加而增加(图1d)。
实施例10:本发明荧光化合物的荧光光谱测试
以荧光化合物I1、I3、I5、I7作为代表化合物,参照图2,将本发明荧光化合物溶于含1%DMSO的水溶液中,配制成1-25μM的检测液。采用荧光光谱仪测试其荧光发射光谱数据,结果显示本发明荧光化合物最大发射波长在510-660nm范围内。其中化合物I1在650nm左右的荧光峰值随化合物I1的浓度增加而增加(图2a);其中化合物I3在655nm左右的荧光峰值随化合物I3的浓度增加而增加(图2b);其中化合物I5在620nm左右的荧光峰值随化合物I5的浓度增加而增加(图2c);其中化合物I7在520nm左右的荧光峰值随化合物I7的浓度增加而增加(图2d)。
实施例11:本发明荧光化合物的单线态氧产生试验
以荧光化合物I1、I3、I7作为代表化合物,参照图3,采用紫外光谱法检测本发明化合物产生单线态氧的能力。以1,3-二苯基苯并呋喃(DPBF)作为单线态氧的捕获剂,具体的方法是将本发明化合物和捕获剂DPBF的溶液混合,然后再用激光照射一定时间。由于捕获剂本身在415nm处具有特征吸收,DPBF与单线态氧的反应极易进行。在光敏剂经光照射后,产生单线态氧可以与捕获剂DPBF发生化学反应,生成无色的产物,捕获剂DPBF在415nm处的紫外吸收强度降低。本发明化合物在500~650nm激光(15mW/cm2)照射0、1、3、5分钟后,检测DPBF在415nm处的吸光度值的变化。其中化合物I1在415nm左右的吸光值随激光照射增加而降低(图3a);其中化合物I3在415nm左右的吸光值随激光照射时间增加而降低(图3b);其中化合物I7在415nm左右的吸光值随激光照射时间增加而降低(图3c)。该实验证明了本发明化合物在激光照射后能有效产生单线态氧,可以用于光动力治疗。
实施例12:本发明荧光化合物的细胞毒性试验
以荧光化合物I1~I8作为代表化合物,采用四甲基氮唑蓝比色法(MTT)体外毒性试验评价了本发明化合物对人结肠癌细胞HT29细胞株的光暗毒性。暗毒性实验首先取一瓶处于指数生长期状态良好的HT29细胞,加入0.25%胰蛋白酶消化,使贴壁细胞脱落,制成每毫升含2×104~4×104个细胞的悬液。取细胞悬液接种于96孔板上,每孔180μL,置恒温CO2培养箱中培养24小时。换液,避光下加入受试化合物(化合物用DMSO溶解后用PBS稀释,受试化合物浓度为12.5μM),每孔20μL,继续避光培养48小时后。将MTT加入96孔板中,每孔20μL,培养箱中反应4小时。吸去上清液,每孔加入150μLDMSO,平板摇床上振摇5分钟。用酶联免疫检测仪在波长为570nm处测定每孔的吸收度,计算细胞存活率。
光毒性实验方法与暗毒性实验方法基本相同,不同之处是当加入药物培育48小时之后,采用光照条件,500~650nm激光(15mW/cm2)照射10分钟后,更换新鲜的完全培养液,于培养箱中继续培养12小时,然后每孔加入20μLMTT溶液,培养4小时后,同样计算细胞存活率。
实验结果发现本发明化合物对肿瘤细胞的暗毒性较小,激光照射后,细胞存活率显著降低,说明本发明化合物的光动力治疗效果显著(表2)。
表2本发明部分化合物对人癌细胞的存活率%(12.5μM)
ND:未测试。
实施例13:采用共聚焦显微镜进行线粒体定位实验
以荧光化合物I1、I3、I4、I5、I7作为代表化合物,参照图4-5,采用共聚焦显微镜进行线粒体定位实验,HT29或Hela细胞由DMEM培养液在激光共聚焦皿中培养12~24h,加入1~25μM的受试化合物,将其放置置于37℃、含5%CO2的细胞培养箱中孵育半小时。接着用pH=7.4的磷酸盐缓冲溶液洗涤3次后,再加入1μM的线粒体染色剂MitoTrackerred溶液并继续孵育半小时后用pH=7.4的磷酸盐缓冲溶液洗涤3次,将孵育好的细胞置于共聚焦显微镜的载物台上进行共聚焦荧光成像,设置MitoTrackerred:λex=488nm,λem=500-550nm;设置受试化合物激发波长:I1~I6为λex=488nm,λem=630-660nm;I7、I8为λex=405nm,λem=525-550nm。
结果表明本发明所述化合物的荧光图像重叠良好,重叠系数在0.78~0.83,表明β-咔啉鎓盐类荧光化合物均能够靶向肿瘤细胞中线粒体,且靶向效果显著,为医学诊断提供了一种可行的手段,应用前景广阔。
以上对本发明的实施例进行了详细说明,但所述内容仅为本发明的较佳实施例,不能被认为用于限定本发明的实施范围。凡依本发明申请范围所作的均等变化与改进等,均应仍归属于本发明的专利涵盖范围之内。
Claims (10)
2.根据权利要求1所述的一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物,其特征在于:所述R1代表H、CH3、CH2CH3;R2代表H、CH3、C(CH3)3、CH2CH(CH3)2;R3代表CH3、CH2CH3、炔丙基、炔丁基;X代表CH、N、或者带甲基或乙基取代的N正离子(卤负离子);Y-代表碘负离子、六氟磷酸根负离子、或者甲磺酸负离子;β-咔啉-3-乙烯基连接在AB环的2-7位。
3.根据权利要求2所述的一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物,其特征在于:所述β-咔啉鎓盐的荧光化合物的代号及其对应的结构如下:
I1:(E)-4-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐;
I2:(E)-4-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-(丁-3-炔-1-基)喹啉-1-甲磺酸盐;
I3:(E)-4-(2-(9-(2-乙基)-1-甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐;
I4:(E)-4-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1,8-二甲基-1,8-萘啶-1,8-二碘盐;
I5:(E)-4-(2-(1-(1-(叔丁基)-9-甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐;
I6:(E)-4-(2-(1-(1-(异丁基)-9-甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐;
I7:(E)-5-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-甲基喹啉-1-碘盐;
I8:(E)-5-(2-(1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1-乙基喹啉-1-碘盐。
5.根据权利要求4所述的一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物I的制备方法,其特征在于:所述R1代表H、CH3、CH2CH3;R2代表H、CH3、C(CH3)3、CH2CH(CH3)3;R3代表CH3、CH2CH3、炔丙基、炔丁基;X代表CH、N、或者带甲基或乙基取代的N正离子(卤负离子);Y-代表碘负离子、六氟磷酸根负离子、甲磺酸负离子;β-咔啉-3-乙烯基连接在AB环的2-7位。
6.根据权利要求4所述的一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物I的制备方法,其特征在于:所述制备方法具体为:
将9-R1-1-R2-9H-吡啶并[3,4-b]吲哚-3-甲醛(1)与4-或5-甲基的喹啉鎓盐或萘啶鎓盐(2)溶于无水乙醇中,滴加催化量哌啶或乙酸铵,回流反应8~12小时,通过重结晶或者色谱柱纯化得到β-咔啉鎓盐荧光化合物。
7.根据权利要求1-4任一项所述的一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物在制备靶向肿瘤细胞线粒体的荧光成像诊断中的应用。
8.根据权利要求7所述的一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物在制备靶向肿瘤细胞线粒体的荧光成像诊断中的应用,其特征在于:所述肿瘤细胞为乳腺癌细胞、结肠癌细胞、肝癌细胞或胃癌细胞。
9.根据权利要求1-4任一项所述的一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物在制备具有光动力肿瘤治疗的药物中的应用。
10.根据权利要求9所述的一类线粒体靶向和光动力治疗的β-咔啉鎓盐的荧光化合物在制备具有光动力肿瘤治疗的药物中的应用,其特征在于,所述β-咔啉鎓盐的荧光化合物经过激发光照射后产生单线态氧杀伤肿瘤细胞。
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