CN114773329B - 吩噁嗪酮吡啶鎓盐类化合物及其制备方法和应用 - Google Patents
吩噁嗪酮吡啶鎓盐类化合物及其制备方法和应用 Download PDFInfo
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- phenoxazinone
- pyridinium salt
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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吩噁嗪酮吡啶鎓盐类荧光化合物及其制备方法和应用。具有通式Ⅰ所示结构。本发明提供的一类吩噁嗪酮吡啶鎓盐类化合物吸收和发射光谱都处于近红外“光疗窗口”区(650‑900nm)，适用于荧光成像、肿瘤治疗等，吩噁嗪酮吡啶鎓盐类化合物具有线粒体靶向能力，低的暗毒性，在红光LED灯照射下能够产生超氧阴离子，具有较强的杀死肿瘤细胞作用，在线粒体荧光成像和光动力治疗中具有良好的应用前景。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及一类吩噁嗪酮吡啶鎓盐类化合物及其制备方法和应用，该吩噁嗪酮吡啶鎓盐类化合物具有线粒体靶向能力和Ⅰ型光动力治疗作用。
背景技术
光动力治疗是一种有效，微创和局部靶向的临床癌症治疗技术，它依靠光敏剂在适当波长的光照射下，通过两种不同的机制(Ⅰ型和Ⅱ型)产生活性氧，包括单线态氧、超氧自由基、羟基自由基等。在Ⅱ型中PDT中，通过能量转移的机制将3O2转化为1O2，这一过程高度依赖氧气浓度。然而，肿瘤部位的侵袭式快速增殖一般会造成肿瘤微环境乏氧，这将极大地降低光动力治疗的效率。而Ⅰ型光动力过程中光敏剂与相邻的各种底物分子之间通过电子转移或基于夺氢的光反应产生更多的细胞毒性活性氧(超氧阴离子、羟基自由基或H2O2等)，可以减轻缺氧限制，在有效消融肿瘤方面具有广阔前景。目前，光动力治疗已在临床试验中用于治疗肺、乳腺、前列腺、头颈、肝、肠、脑、食管和皮肤等肿瘤。
具有相对较高反应活性的活性氧本身寿命极短和对光的依赖性使其在受辐射限制的一定范围内扩散产生效应，这种特性一方面使PDT成为一种具有高度空间选择性和耐药性极低的有前途的治疗方法，另一方面有必要对ROS的空间位置和选择性产生加以控制来进一步实现更加高效的光动力治疗。线粒体是细胞内的重要亚细胞器，在细胞能量供应、信号传递、细胞分化、细胞死亡以及维持对细胞周期和细胞生长的控制方面起着重要的作用，线粒体对大量的活性氧(如单线态氧、自由基)非常敏感，一些靶向线粒体的光敏剂被证实显著提高了光动力治疗作用。另一方面，光敏剂的吸收波长在“光疗窗口”(650-900nm)中的红色或近红外(NIR)光区可以深入组织并减少对组织的光损伤。因此，合理地设计具有肿瘤细胞线粒体靶向能力的光疗窗口中光响应荧光光敏剂，可以通过I型途径，提供更有效的成像引导光动力治疗具有重要意义。
发明内容
本发明提供了一类靶向线粒体且可以高效产生超氧阴离子的吩噁嗪酮吡啶鎓盐类红光激活的荧光化合物，其结构通式如下所示：
通式(I)所示吩噁嗪酮吡啶鎓盐类化合物,
其中，R为C4-C8的烷基，苄基；X为Br，Cl，I。
优选的，所述R为正丁基，正戊基，正己基，正庚基，正辛基，苄基；X为Br，Cl，I。
优选地，上述的吩噁嗪酮吡啶鎓盐类化合物中，结构式如下：
上述的吩噁嗪酮吡啶鎓盐类化合物的制备方法，包含如下步骤：
1)将2-氨基-7-(二乙氨基)-3H-吩噁嗪-3-酮溶于氢溴酸中，用亚硝酸钠发生重氮化反应，然后与溴化亚铜进行Sandmeyer反应得2-溴-7-(二乙氨基)-3H-吩噁嗪-3-酮；
2)将2-溴-7-(二乙氨基)-3H-吩噁嗪-3-酮、4-乙烯基吡啶、三苯基膦、三乙胺和有机溶剂混合，进行Heck反应得化合物(E)-7-(二乙氨基)-2-(2-(吡啶-4-基)乙烯基)-3H-吩噁嗪-3-酮；
3)(E)-7-(二乙氨基)-2-(2-(吡啶-4-基)乙烯基)-3H-吩噁嗪-3-酮、卤代烷烃或卤化苄和有机溶剂反应得具有通式Ⅰ结构的吩噁嗪酮吡啶鎓盐类化合物；
反应式如下：
其中：R为C4-C8的烷基，苄基，X为氯、溴或碘。
上述的吩噁嗪酮吡啶鎓盐类化合物制备方法中，所述步骤1中，2-氨基-7-(二乙氨基)-3H-吩噁嗪-3-酮，亚硝酸钠，溴化亚铜的摩尔比为1：1：2；所述步骤2中，2-溴-7-(二乙氨基)-3H-吩噁嗪-3-酮，4-乙烯基吡啶，醋酸钯，三苯基膦和三乙胺的摩尔比为1：1.1～3：0.08～0.3：0.2～0.6：1～2；步骤3中，化合物(E)-7-(二乙氨基)-2-(2-(吡啶-4-基)乙烯基)-3H-吩噁嗪-3-酮和卤代烷试剂的摩尔比为1：3～15。
上述的吩噁嗪酮吡啶鎓盐类化合物制备方法中，所述步骤2)中，所述有机溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、二氧六环中的一种或多种；步骤3)中，所述有机溶剂为乙腈、甲醇、乙醇或甲苯中的一种或多种。
上述的吩噁嗪酮吡啶鎓盐类化合物在制备靶向肿瘤细胞线粒体的荧光成像剂中的应用。
上述的吩噁嗪酮吡啶鎓盐类化合物在制备光动力治疗光敏剂中的应用。
上述的吩噁嗪酮吡啶鎓盐类化合物在制备具有光动力肿瘤治疗作用药物中的应用。
进一步地，所述吩噁嗪酮吡啶鎓盐类荧光光敏剂经过激光或红光LED照射后可以产生超氧阴离子杀死肿瘤细胞。
进一步地，所述肿瘤为乳腺癌、肝癌、肺癌、前列腺癌、头颈癌，结肠癌、食管癌或黑色素瘤。
本发明中，不同化合物代号及其代表的化合物名称如下：
PVPC-6:(E)-4-(2-(7-(二乙基氨基)-3-氧代-3H-吩噁嗪-2-基)乙烯基)-1-己基吡啶碘化物；
PVPC-4:(E)-4-(2-(7-(二乙基氨基)-3-氧代-3H-吩噁嗪-2-基)乙烯基)-1-丁基吡啶溴化物；
PVPC-8:(E)-4-(2-(7-(二乙基氨基)-3-氧代-3H-吩噁嗪-2-基)乙烯基)-1-辛基吡啶碘化物；
PVPB:(E)-4-(2-(7-(二乙氨基)-3-氧代-3H-吩噁嗪-2-基)乙烯基)-1-苄基吡啶氯化物。
有益效果：
本发明提供的一类吩噁嗪酮吡啶鎓盐类化合物吸收和发射光谱都处于近红外“光疗窗口”区(650-900nm)，适用于荧光成像、肿瘤治疗等，吩噁嗪酮吡啶鎓盐类化合物具有线粒体靶向能力，低的暗毒性，在红光LED灯照射下能够产生超氧阴离子，具有较强的杀死肿瘤细胞作用，在线粒体荧光成像和光动力治疗中具有良好的应用前景；本发明公开的制备工艺简单，反应条件温和。
附图说明
图1-1为PVPC-4的质谱图、图1-2为PVPC-6的质谱图、图1-3为PVPC-8的质谱图、图1-4为PVPB的质谱图；
图2为实施例1中化合物PVPC-6的EPR图谱；
图3为实施例中化合物PVPC-4、PVPC-6、PVPC-8、PVPB的线粒体共定位。
图4为实施例中化合物PVPC-4、PVPC-6、PVPC-8、PVPB的MCF-7细胞的光毒性和暗毒性。
具体实施方式
下面结合附图和具体实施方式来对本申请作进一步的说明，以便本领域的技术人员更了解本申请，但这些实施例仅用于说明本发明而不用于限制本发明的范围，即所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。
因此，以下对提供的本发明一部分实施例的详细描述并非旨在限制要求保护的本发明范围，而是仅仅是本发明的选定实施例。基于本发明的实施例，本领域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，都属于本发明保护的范围。
实施例1：(E)-4-(2-(7-(二乙基氨基)-3-氧代-3H-吩噁嗪-2-基)乙烯基)-1-己基吡啶碘化物(PVPC-6)的制备：
将2-氨基-7-(二乙氨基)-3H-吩噁嗪-3-酮(283mg，1mmol)加入7mL 40％的HBr溶液中，降温至0℃，将NaNO2(69mg，1mmol)溶于3mL水中，缓慢滴加至上述反应液中，加毕0-5℃继续反应30min。将CuBr(287mg，2mmol)溶于5mL HBr溶液中。缓慢加入上述反应液中，加毕，室温反应3小时。NaOH稀溶液调pH至7-8，二氯甲烷萃取，有机层浓缩，剩余物硅胶柱色谱纯化(洗脱剂：二氯甲烷/甲醇＝80/1)，得2-溴-7-(二乙氨基)-3H-吩噁嗪-3-酮267mg，收率77.3％。1H NMR(400MHz,CDCl3):δ＝7.86(s,1H),7.57(d,J＝8Hz,1H),6.75(dd,J＝8Hz,1H),6.47(d,J＝4Hz,1H),6.43(s,1H),3.54-3.48(q,J＝8Hz,4H),1.31-1.27(t,J＝8Hz,6H).13C NMR(100MHz,CDCl3):δ＝178.0,152.3,150.0,147.1,139.4,135.4,132.3,129.4,127.0,111.4,104.9,96.0,45.5,12.6.TOF-MS calcd for[C16H15BrN2O2],346.0317,348.0296；found:347.0334[M+H]+,349.0316[M+2+H]+。
将2-溴-7-(二乙氨基)-3H-吩噁嗪-3-酮(208mg，0.6mmol)，4-乙烯基吡啶(94μL，0.9mmol)，三苯基磷(62mg，0.24mmol)，醋酸钯(28mg，0.12mmol)和15mL DMF加入100mL圆底烧瓶中，然后加入三乙胺100μL,然后氮气保护下于120℃反应8h，反应毕减压浓缩蒸出溶剂，剩余物硅胶柱色谱纯化(洗脱剂：二氯甲烷/甲醇＝30/1)。得148mg目标化合物(E)-7-(二乙氨基)-2-(2-(吡啶-4-基)乙烯基)-3H-吩噁嗪-3-酮，收率为66.5％。1H NMR(400MHz,CDCl3):δ＝8.58(d,J＝4.8Hz,2H),7.56-7.62(m,3H),7.39-7.43(m,3H),6.73(dd,J＝8.8,3.2Hz,1H),6.48(d,J＝2.8Hz,1H),6.34(s,1H),3.50(q,J＝7.2Hz,4H),1.29(t,J＝7.6Hz,6H)。13C NMR:(100MHz,CDCl3):δ＝184.1,151.9,150.4,150.2,147.0,144.6,140.7,136.4,132.0,130.3,129.6,127.3,127.2,121.2,110.9,106.0,96.2,45.4,12.7。TOF-MS calcdfor[C23H21N3O2],371.1634；found:372.1705[M+H]+。
将化合物(E)-7-(二乙氨基)-2-(2-(吡啶-4-基)乙烯基)-3H-吩噁嗪-3-酮(37mg，0.1mmol)溶于10mL乙腈中，加入1-碘代正己烷(215mg，1mmol)，回流反应24h，停止反应，减压浓缩，剩余物过碱性氧化铝柱子(洗脱剂：二氯甲烷/甲醇＝20/1)得PVPC-6产物11mg，收率19.8％.1H NMR(400MHz,CDCl3):δ＝9.15(d,J＝6.4Hz,2H),8.08(d,J＝6.4Hz,2H),7.79-7.80(d,2H),7.71(s,1H),7.56(d,J＝9.2Hz,1H),6.77(dd,J＝9.2,3.6Hz,1H),6.45(d,J＝3.6Hz,1H),6.28(s,1H),4.82(t,J＝7.6Hz,2H),3.53(q,J＝7.2Hz,4H),2.03(m,2H),1.25-1.42(m,12H),0.87(t,J＝6.8Hz,3H)。13C NMR(100MHz,CDCl3):δ＝183.4,153.8,152.8,150.5,147.4,144.2,139.2,136.8,134.3,133.7,132.9,128.4,126.3,124.5,111.8,106.2,96.1,61.2,45.7,31.7,31.2,25.8,22.4,14.0,12.8。TOF-MS[M-I]+:calcd for[C29H34N3O2 +],456.2646；found:456.2658。
实施例2：(E)-4-(2-(7-(二乙基氨基)-3-氧代-3H-吩噁嗪-2-基)乙烯基)-1-丁基吡啶溴化物(PVPC-4)的制备：
参照实施例1中(PVPC-6)的合成方法，将1-碘代正己烷替换为1-溴代丁烷，最后得到化
合物PVPC-4，表征数据如下：
1H NMR(400MHz,CDCl3):δ＝9.13(d,J＝6.4Hz,2H)，8.08(d,J＝6.4Hz,2H)，7.79(s，2H)，7.70(s，1H)，7.55(d，J＝9.2Hz,1H)，6.77(d，J＝9.2Hz,1H)，6.45(s，1H)，6.25(s,1H),4.81(t,J＝7.2Hz,2H),3.53(q,J＝7.2Hz,4H),2.03(m,2H),1.46(m,2H),1.30(t,J＝7.2Hz,6H),0.99(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3):δ＝183.3,153.8,152.9,150.5,147.4,144.1,139.0,136.8,134.4,133.6,132.9,128.5,126.2,124.5,111.9,106.2,96.1,60.9,45.7,33.6,19.4,13.6,12.8。
TOF-MS[M-Br]+:calcd for[C27H30N3O2 +],428.2333；found:428.2333。
实施例3：(E)-4-(2-(7-(二乙基氨基)-3-氧代-3H-吩噁嗪-2-基)乙烯基)-1-辛基吡啶碘化物(PVPC-8)的制备:
参照实施例1中(PVPC-6)的合成方法，将1-碘代正己烷替换为1-碘代正辛烷，最后得到化合物PVPC-8，表征数据如下：
1H NMR(400MHz,CDCl3):δ＝9.13(d,J＝6.6Hz,2H),8.08(d,J＝6.6Hz,2H),7.80(s，2H),7.71(s,1H),7.56(d,J＝9.2Hz,1H),6.77(d,J＝9.4Hz,1H),6.45(s,1H,),6.28(s,1H),4.80(t,J＝7.5Hz,2H),3.53(q,J＝7.2Hz,4H),2.03(m,2H),1.24-1.41(m,16H),0.86(t,J＝6.8Hz,3H)。
13C NMR(100MHz,CDCl3):δ＝183.4,153.8,152.8,150.5,147.4,144.1,139.1,136.8,134.4,133.7,132.9,128.4,126.2,124.5,111.8,106.2,96.1,61.2,45.7,31.7,31.7,29.0,26.1,22.6,14.1,12.8。
TOF-MS[M-I]+:calcd for[C31H38N3O2 +],484.2959；found:484.2958。
实施例4：(E)-4-(2-(7-(二乙氨基)-3-氧代-3H-吩噁嗪-2-基)乙烯基)-1-苄基吡啶氯化物(PVPB)的制备：
参照实施例1中(PVPC-6)的合成方法，将1-碘代正己烷替换为氯化苄，最后得到化合物PVPB，表征数据如下：
TOF-MS[M-Cl]+:calcd for[C30H28N3O2 +],462.2176；found:462.2191。
实施例5：吩噁嗪酮吡啶鎓盐类光敏剂的吸收光谱和发射光谱测试：
将化合物PVPC-4、PVPC-6、PVPC-8、PVPB分别配制成5×10-6mol/L的待测水溶液，移取2mL该待测溶液于比色皿中，进行吸收和发射光谱测试，化合物最大吸收波长和最大发射波长如表1。测试数据表明:本发明的吩噁嗪酮吡啶鎓盐类光敏剂的吸收和发射光谱都处于“光疗窗口”区，说明其适用于荧光成像、肿瘤治疗等。
表1各实施例中吩噁嗪酮吡啶鎓盐类光敏剂的光谱数据
实施例6：通过电子顺磁共振(EPR)分析检测PVPC-6在光照下超氧阴离子的生成
以实施例1中的化合物为例，使用5,5-二甲基-1-吡咯啉N-氧化物(DMPO)作为自旋捕集剂，使用Bruker A300 EPR Spectroscopy进行EPR测定。将PVPC-6以2×10-3M的稀释度溶解在100μL DMSO中，然后将5μL DMPO添加到PVPC-6溶液中，红色LED灯，50mW/cm2照射0或2分钟。以DMPO光照作为对照，最后，在室温下记录EPR信号，结果如附图2所示，纯DMPO溶液用红色LED灯照射或DMPO+PVPC-6不光照都没有EPR信号，而当DMPO+PVPC-6在红色LED灯下照射2分钟观察到顺磁性加合物的特征EPR信号，证明红光LED照射使PVPC-6产生超氧阴离子。该实验证明了本发明的吩噁嗪酮吡啶鎓盐类化合物能够产生超氧阴离子具有Ⅰ型光动力性质，可以用于肿瘤细胞和组织的光动力治疗。
实施例7：实施例中化合物的肿瘤线粒体定位
接种于共聚焦玻底皿中长势良好的MCF-7细胞与分别用实施例中的光敏剂PVPC-4、PVPC-6、PVPC-8、PVPB(400μM，200nM)染色1h，然后DPBS洗涤3次，加入商业线粒体染料MitoTracker Green(200μM，100nM)孵育20min，DPBS洗涤三次激光共聚焦成像(绿色通道：488nm激发，520±20nm收集；红色通道：633nm激发，640-690nm收集)来观察光敏剂红色荧光信号与MitoTracker Green的荧光信号的重叠情况，结果显示PVPC-4、PVPC-6、PVPC-8、PVPB在体外培养条件下可被肿瘤细胞高效摄取，显示强的红色荧光信号，与来自于线粒体的绿色荧光信号能够很好的重合，光敏剂PVPC-4、PVPC-6、PVPC-8、PVPB与Mito Tracker Green的共定位系数都大于0.8，结果见附图3和表2。所得结果表明本发明的吩噁嗪酮吡啶鎓盐类化合物能够靶向肿瘤细胞线粒体，且靶向效果显著，为线粒体荧光标记示踪和医学诊断提供了一种可行的方法。
表2光敏剂与Mito Tracker Green的共定位系数表
| 序号 | 光敏剂 | 商业线粒体染料 | 共定位系数(Pr) |
| 实施例1 | PVPC-6 | Mito Tracker Green | 0.89 |
| 实施例2 | PVPC-4 | Mito Tracker Green | 0.83 |
| 实施例3 | PVPC-8 | Mito Tracker Green | 0.82 |
| 实施例4 | PVPB | Mito Tracker Green | 0.83 |
实施例8：实施例中化合物对肿瘤细胞暗毒性和光毒性试验
将MCF-7细胞以每孔1×105数量接种于96孔板中孵育过夜。去除培养基后，向孔中加入100μL不同浓度(0-5μM)的PVPC-4、PVPC-6、PVPC-8、PVPB的PBS溶液，细胞继续在37℃孵育1h，然后将细胞在红色LED灯(50mW/cm2)下照射0分钟或10分钟，然后换成DMEM培养基，37℃孵育24小时，每孔加入CCK-8(10μL，5mg/mL)并在CO2培养箱中再培养2小时。然后在酶标仪上测量450nm处的吸光度。他们的CCK-8检测结果分别如附图4和表3所示。结果表明，这一类线粒体靶向的吩噁嗪酮吡啶鎓盐类化合物暗毒性较低，具有强的光毒性，可以用于光动力抗肿瘤治疗，有望作为一类有效的光动力抗肿瘤药物。
表3实施例1-4制得的吩噁嗪酮吡啶鎓盐类化合物光动力效果评价表
L(-)表示没有光照；L(+)表示红光LED灯照射。
Claims (10)
1.通式(I)所示吩噁嗪酮吡啶鎓盐类化合物,
其中，R为C4-C8的烷基，苄基；X为Br，Cl，I。
2.根据权利要求1所述的吩噁嗪酮吡啶鎓盐类化合物，其特征在于，
所述R为正丁基，正戊基，正己基，正庚基，正辛基，苄基；X为Br，Cl，I。
3.根据权利要求1所述的吩噁嗪酮吡啶鎓盐类化合物，其特征在于，结构式如下：
4.权利要求1所述的吩噁嗪酮吡啶鎓盐类化合物的制备方法，其特征在于，包含如下步骤：
1)将2-氨基-7-(二乙氨基)-3H-吩噁嗪-3-酮溶于氢溴酸中，用亚硝酸钠发生重氮化反应，然后与溴化亚铜进行Sandmeyer反应得2-溴-7-(二乙氨基)-3H-吩噁嗪-3-酮；
2)将2-溴-7-(二乙氨基)-3H-吩噁嗪-3-酮、4-乙烯基吡啶、三苯基膦、三乙胺和有机溶剂混合，进行Heck反应得化合物(E)-7-(二乙氨基)-2-(2-(吡啶-4-基)乙烯基)-3H-吩噁嗪-3-酮；
3)化合物(E)-7-(二乙氨基)-2-(2-(吡啶-4-基)乙烯基)-3H-吩噁嗪-3-酮、卤代烷烃或卤化苄和有机溶剂反应得具有通式Ⅰ结构的吩噁嗪酮吡啶鎓盐类化合物；
反应式如下：
其中：R为C4-C8的烷基，苄基，X为氯、溴或碘。
5.根据权利要求4所述的吩噁嗪酮吡啶鎓盐类化合物制备方法，其特征在于，所述步骤1中，2-氨基-7-(二乙氨基)-3H-吩噁嗪-3-酮，亚硝酸钠，溴化亚铜的摩尔比为1：1：2；步骤2中2-溴-7-(二乙氨基)-3H-吩噁嗪-3-酮，4-乙烯基吡啶，醋酸钯，三苯基膦和三乙胺的摩尔比为1：1.1～3：0.08～0.3：0.2～0.6：1～2；步骤3中，(E)-7-(二乙氨基)-2-(2-(吡啶-4-基)乙烯基)-3H-吩噁嗪-3-酮和卤代烷试剂的摩尔比为1：3～15。
6.根据权利要求4所述吩噁嗪酮吡啶鎓盐类化合物的制备方法，其特征在于，所述步骤1)中，所述有机溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、二氧六环中的一种或多种；步骤2)中，所述有机溶剂为乙腈、甲醇、乙醇或甲苯中的一种或多种。
7.权利要求1所述的吩噁嗪酮吡啶鎓盐类化合物在制备靶向肿瘤细胞线粒体的荧光成像剂中的应用。
8.根据权利要求1所述的吩噁嗪酮吡啶鎓盐类化合物在制备光动力治疗光敏剂中的应用。
9.根据权利要求1所述的吩噁嗪酮吡啶鎓盐类化合物在制备具有光动力肿瘤治疗作用药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述肿瘤为乳腺癌、肝癌、肺癌、前列腺癌、头颈癌，结肠癌、食管癌或黑色素瘤。
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