CN113087703A - 一种能特异性标记脂滴的光敏剂及其制备方法 - Google Patents
一种能特异性标记脂滴的光敏剂及其制备方法 Download PDFInfo
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- CN113087703A CN113087703A CN202110386229.3A CN202110386229A CN113087703A CN 113087703 A CN113087703 A CN 113087703A CN 202110386229 A CN202110386229 A CN 202110386229A CN 113087703 A CN113087703 A CN 113087703A
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- Prior art keywords
- palladium
- photosensitizer
- bis
- lipid droplets
- triphenylphosphine
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- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
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- 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
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- C09K2211/1007—Non-condensed systems
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- 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
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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- C09K2211/1025—Heterocyclic compounds characterised by ligands
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- 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
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Abstract
本发明公开了一种能特异性标记脂滴的光敏剂及其制备方法，其制备方法包括以下步骤：将4‑(9H‑咔唑‑9‑基)苯硼酸与4‑氯‑7‑硝基苯并‑2‑氧杂‑1,3‑二唑进行Suzuki偶联反应，然后对反应产物分离纯化，制得光敏剂。本发明制得的光敏剂在水溶液中荧光很弱而在油脂中具有很强的荧光，可以特异性靶向到细胞内的脂质并在光照下高效产生单线态氧，适用于脂滴成像和肿瘤光动力治疗。
Description
技术领域
本发明属于光敏剂技术领域，尤其涉及一种能特异性标记脂滴的光敏剂及其制备方法。
背景技术
脂滴是细胞中性脂的主要储存场所，在细胞能量存储和信号传导中发挥着重要的作用。当细胞处于正常的生理状态时，其脂滴含量维持在较稳定的水平。而细胞衰老或者病变时往往伴随着脂滴的异常累积，因此脂滴也成为一些疾病诊断和治疗的靶点，如动脉粥样硬化、脂肪肝以及一些癌症。其中，在肾透明细胞癌、前列腺癌和结肠癌等癌症组织中发现大量的脂质堆积，这也为这些癌症的脂滴靶向诊疗提供了理论依据。然而，目前仍少有脂滴特异性诊疗剂的报道，发展新型的诊疗剂对诊断和治疗富含脂质的癌症具有重要的研究价值。
目前荧光成像由于其操作简单、灵敏度高、成像速度快以及可以实时观察等优点成为癌症诊断的新选择。传统有机荧光探针在聚集或者固体状态下常发生荧光猝灭的现象，这在很大程度上限制了传统有机荧光探针的生物医学应用。而目前取得商业化的脂滴荧光探针，如油红，尼罗红，Bodipy 493/503及Lipid Blue和Lipid Red等荧光探针，存在特异性不足、光稳定性较差等问题。此外，这些荧光探针除了荧光成像外并不具备治疗的功能。
近年来响应组织微环境使荧光点亮的策略为设计新型脂滴成像荧光探针提供了新的思路。在溶解和聚集状态下没有荧光，而在油或脂质里荧光显著增强的荧光探针成为发展脂滴荧光探针的首选。这样的荧光探针有利于提高信噪比，获得更好的成像效果。此外，具备一些特定结构的荧光探针在光照下还能产生具有治疗作用的单线态氧，开发在光照下能够产生单线态氧的脂滴靶向型荧光探针具有潜在的应用前景。
发明内容
本发明的目的在于：针对上述现有技术中存在的不足，提供一种能特异性标记脂滴的光敏剂及其制备方法,可有效解决传统有机荧光探针在聚集或者固体状态下常发生荧光猝灭以及并不具备治疗功能的问题。
本发明采用的技术方案如下：
本发明提供一种能特异性标记脂滴的光敏剂，化学结构如式I所示：
上述的能特异性标记脂滴的光敏剂的制备方法，具体步骤及合成路线如下：
将4-(9H-咔唑-9-基)苯硼酸与4-氯-7-硝基苯并-2-氧杂-1,3-二唑进行Suzuki偶联反应，然后对反应产物分离纯化，制得光敏剂。
进一步地，4-(9H-咔唑-9-基)苯硼酸和4-氯-7-硝基苯并-2-氧杂-1,3-二唑的摩尔比为1～3:1～3，优选为1:1.05。
进一步地，Suzuki偶联反应的反应过程为：将反应底物4-(9H-咔唑-9-基)苯硼酸和4-氯-7-硝基苯并-2-氧杂-1,3-二唑、碱和催化剂加入反应装置中，在惰性气体氛围下加入溶剂，于40～130℃温度下反应6～48小时。
进一步地，Suzuki偶联反应的反应温度为75～110℃，反应时间为24～30小时。
进一步地，碱为碳酸氢钠、碳酸钾、碳酸钠、碳酸铯、磷酸钠、醋酸铯或氟化铯。
进一步地，催化剂为醋酸钯、氯化钯、二(苯腈)二氯化钯、三(二亚苄基丙酮)二钯、四(三苯基膦)钯、二(三叔丁基膦)钯、二(乙腈)二氯化钯、二(三苯基膦)二氯化钯、双(二亚苄基丙酮)钯、氯化烯丙基钯(II)二聚物、(1,5-环辛二烯)二氯化钯(II)、乙酰丙酮三苯基膦羰基铑、三氯化铑、醋酸铑、二氯二羰基双(三苯基膦)钌、三苯基膦氯化钌、三苯基膦氯化铑、三氯化钌和双(2-甲基烯丙基)(1,5-环辛二烯)钌(II)中的至少一种。
进一步地，溶剂为甲苯、甲醇、乙醇、四氢呋喃、二甲苯、三氯甲烷、二氯甲烷、乙腈、苯、二甲基亚砜、1,4-二氧六环和N,N-二甲基甲酰胺中的至少一种。
上述的光敏剂在脂滴荧光成像中的应用。
上述的光敏剂在光动力治疗中的应用。
本发明的有益效果是：
1、本发明提供了一种能特异性标记脂滴的光敏剂，该光敏剂在油脂中具有强烈的荧光，而在水溶液中荧光很弱，并且本发明的光敏剂在低功率白光照射下便能高效产生单线态氧，可用于肿瘤的光动力治疗；同时具有优异的脂滴靶向成像能力，可实时脂滴荧光成像引导的光动力治疗；
2、本发明提供上述光敏剂的制备方法，以4-(9H-咔唑-9-基)苯硼酸与4-氯-7-硝基苯并-2-氧杂-1,3-二唑为原料，于特定温度和特定反应时间下通过Suzuki偶联反应制得光敏剂；具有原料廉价易得，且反应条件温和、产物收率高和操作简单的优点。
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1制得的光敏剂(式Ⅰ化合物)的核磁氢谱图；
图2为本发明实施例1制得的光敏剂(式Ⅰ化合物)在油酸和水溶液中的荧光发射图；
图3为单线态氧指示剂在本发明实施例1制得的光敏剂(式Ⅰ化合物)存在下指示剂紫外吸收随光照时间延迟的衰减图；
图4为本发明实施例1制得的光敏剂(式Ⅰ化合物)靶向786-O细胞中油脂成像的激光共聚焦图；
图5为细胞相对活性图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明，即所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。通常在此处附图中描述和示出的本发明实施例的组件可以以各种不同的配置来布置和设计。
因此，以下对在附图中提供的本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围，而是仅仅表示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。
需要说明的是，术语“第一”和“第二”等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。而且，术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含，从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素，而且还包括没有明确列出的其他要素，或者是还包括为这种过程、方法、物品或者设备所固有的要素。在没有更多限制的情况下，由语句“包括一个……”限定的要素，并不排除在包括所述要素的过程、方法、物品或者设备中还存在另外的相同要素。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
本发明较佳的实施例提供一种能特异性标记脂滴的光敏剂及其制备方法，具体步骤如下：
在氩气保护下，将4-(9H-咔唑-9-基)苯硼酸(2.00g，6.97mmol)，4-氯-7-硝基苯并-2-氧杂-1,3-二唑(1.32g，6.62mmol)，四(三苯基膦)钯(0.32g，0.28mol)以及碳酸钾(2.98g，21.57mmol)加入250mL三口瓶中，然后加入经过超声脱气处理的甲苯(100mL)，乙醇(30mL)和水(10mL)，混合体系在氩气保护下于110℃条件下反应30小时。停止反应，待体系冷却至室温，过滤并浓缩，用二氯甲烷溶解并再次过滤，滤液进一步浓缩后经柱层析分离出产物，得到1.97g红棕色产物(式Ⅰ化合物)，产率为69.59％。
本实施例1制得的的光敏剂(式Ⅰ化合物)的核磁氢谱图见图1，具体核磁表征数据：1H NMR(400MHz,CDCl3):δ＝7.32-7.37(t,2H),7.43-7.49(t,2H),7.54-7.58(d,2H),7.83-7.89(d,3H),8.15-8.19(d,2H),8.32-8.36(m,2H),8.63-8.66(d,1H)。
实施例2
本发明较佳的实施例提供一种能特异性标记脂滴的光敏剂及其制备方法，具体步骤如下：
4-(9H-咔唑-9-基)苯硼酸(1.00g，3.49mmol)，4-氯-7-硝基苯并-2-氧杂-1,3-二唑(0.66g，3.31mmol)，二(三叔丁基膦)钯(35.60mg，0.07mol)以及氟化铯(1.59g，10.49mmol)加入250mL三口瓶中，然后加入经过超声脱气处理的四氢呋喃(18mL)和水(2mL)，混合体系在氩气保护下于75℃条件下反应24小时。停止反应，待体系冷却至室温，浓缩，用二氯甲烷溶解并过滤，滤液进一步浓缩后经柱层析分离出产物，得到1.22g红棕色产物(光敏剂)，产率为86.22％。
实施例3
本实施例3与实施例1的区别仅在于：将四(三苯基膦)钯替换为乙酰丙酮三苯基膦羰基铑(0.28mol)，碳酸钾替换为氟化铯(21.57mmol)，最终红棕色产物收率为78.35％。
实施例4
本实施例4与实施例1的区别仅在于：将四(三苯基膦)钯替换为三苯基膦氯化钌(0.28mol)，碳酸钾替换为碳酸氢钠(21.57mmol)，其余步骤及参数均相同，最终红棕色产物收率为77.35％。
实施例5
本实施例5与实施例1的区别仅在于：将四(三苯基膦)钯替换为氯化烯丙基钯(II)二聚物(0.28mol)，溶剂为二甲基亚砜(120mL)和三氯甲烷(10mL)和(21.57mmol)，其余步骤及参数均相同，最终红棕色产物收率为80.35％。
实施例6
本实施例6与实施例1的区别仅在于：反应温度为100℃，反应时间为26小时，其余步骤及参数均相同，最终红棕色产物收率为75.35％。
实施例7
本实施例7与实施例1的区别仅在于：反应底物用量为4-(9H-咔唑-9-基)苯硼酸(2.85g，9.93mmol)，4-氯-7-硝基苯并-2-氧杂-1,3-二唑(1.32g，6.62mmol)，最终红棕色产物收率为70.35％。
对比例1
本对比例1与实施例1的区别仅在于：反应温度为50℃，反应时间为30小时，其余步骤及参数均相同，最终因反应未发生，导致未获得目标产物。
对比例2
本对比例2与实施例1的区别仅在于：反应温度为130℃，反应时间为30小时，其余步骤及参数均相同，最终因反应产物复杂，造成分离困难，未获得目标产物。
实验例
(1)荧光探针在油脂中荧光测试
将实施例1合成得到的光敏剂(式Ⅰ化合物)配置成5mM的DMSO储存液，用油酸或去离子水稀释荧光探针到10μM，测定荧光探针在油酸和去离子水中的荧光发射情况，比较探针在油酸和水中的荧光强度差异。如图2所示，式Ⅰ化合物在水溶液中基本没有荧光，而在油酸中荧光明显增强，且在605nm处荧光增强超过800倍。
(2)单线态氧指示剂9,10-蒽基-双(亚甲基)二丙二酸在实施例1制得的式Ⅰ化合物存在下指示剂紫外吸收随光照时间延迟的衰减情况如图3所示，图3中曲线由上至下依次为0～10。
(3)荧光探针脂滴标记
将786-O细胞接种到玻底皿中，将实施例3中的荧光探针母液用培养基稀释成1μM的染色液。细胞染色1小时，随后吸去染液，用BODIPY 493/503进一步染色以研究荧光探针脂滴靶向成像能力。如图4所示，786-O的细胞核用Hoechst 33342标记，式Ⅰ化合物的红色荧光信号与BODIPY 493/503的绿色荧光信号能很好地重叠，重合系数超过96％，说明本发明制得的光敏剂(式Ⅰ化合物)可以特异性标记细胞内的脂滴。
(4)荧光探针光动力研究
将786-O细胞以5 000每孔的密度种在96孔板里，培养24小时后，吸去培养基并加入200μL含有不同浓度的式Ⅰ化合物的新培养基，细胞进一步培养24小时。随后细胞用白光照射30分钟，光强为10毫瓦每平方厘米。随后用CCK8法测定细胞的相对活性。结果见图5，在黑暗条件下式Ⅰ化合物并没有明显的毒性，而在光照条件下，细胞的相对活性显著降低，在式Ⅰ化合物浓度为2μM的条件下，相对细胞活性已经低于20％，说明本发明制得的光敏剂(式Ⅰ化合物)具有优异的光动力能力。
以上所述仅为本发明的较佳实施例而已，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、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (9)
1.一种能特异性标记脂滴的光敏剂，其特征在于，其化学结构如式I所示：
2.根据权利要求1所述的能特异性标记脂滴的光敏剂的制备方法，其特征在于，包括以下步骤：
将4-(9H-咔唑-9-基)苯硼酸与4-氯-7-硝基苯并-2-氧杂-1,3-二唑进行Suzuki偶联反应，然后对反应产物分离纯化，制得光敏剂。
3.根据权利要求2所述的能特异性标记脂滴的光敏剂的制备方法，其特征在于，所述Suzuki偶联反应的反应过程为：将4-(9H-咔唑-9-基)苯硼酸、4-氯-7-硝基苯并-2-氧杂-1,3-二唑、碱和催化剂加入反应装置中，在惰性气体氛围下加入溶剂，于40～130℃温度下反应6～48小时。
4.根据权利要求2或3所述的能特异性标记脂滴的光敏剂的制备方法，其特征在于，所述4-(9H-咔唑-9-基)苯硼酸和4-氯-7-硝基苯并-2-氧杂-1,3-二唑的摩尔比为1～3:1～3。
5.根据权利要求2或3所述的能特异性标记脂滴的光敏剂的制备方法，其特征在于，所述4-(9H-咔唑-9-基)苯硼酸和4-氯-7-硝基苯并-2-氧杂-1,3-二唑的摩尔比为1:1.05。
6.根据权利要求3所述的能特异性标记脂滴的光敏剂的制备方法，其特征在于，所述催化剂为醋酸钯、氯化钯、二(苯腈)二氯化钯、三(二亚苄基丙酮)二钯、四(三苯基膦)钯、二(三叔丁基膦)钯、二(乙腈)二氯化钯、二(三苯基膦)二氯化钯、双(二亚苄基丙酮)钯、氯化烯丙基钯(II)二聚物、(1,5-环辛二烯)二氯化钯(II)、乙酰丙酮三苯基膦羰基铑、三氯化铑、醋酸铑、二氯二羰基双(三苯基膦)钌、三苯基膦氯化钌、三苯基膦氯化铑、三氯化钌和双(2-甲基烯丙基)(1,5-环辛二烯)钌(II)中的至少一种。
7.根据权利要求3所述的能特异性标记脂滴的光敏剂的制备方法，其特征在于，所述溶剂为甲苯、甲醇、乙醇、四氢呋喃、二甲苯、三氯甲烷、二氯甲烷、乙腈、苯、二甲基亚砜、1,4-二氧六环和N,N-二甲基甲酰胺中的至少一种。
8.根据权利要求3所述的能特异性标记脂滴的光敏剂的制备方法，其特征在于，所述碱为碳酸氢钠、碳酸钾、碳酸钠、碳酸铯、磷酸钠、醋酸铯或氟化铯。
9.根据权利要求3所述的能特异性标记脂滴的光敏剂的制备方法，其特征在于，所述反应温度为75～110℃，反应时间为24～30小时。
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