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WO2023097854A1 - 一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体及其制备方法和应用 - Google Patents

一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体及其制备方法和应用 Download PDF

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WO2023097854A1
WO2023097854A1 PCT/CN2021/143135 CN2021143135W WO2023097854A1 WO 2023097854 A1 WO2023097854 A1 WO 2023097854A1 CN 2021143135 W CN2021143135 W CN 2021143135W WO 2023097854 A1 WO2023097854 A1 WO 2023097854A1
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ethyl
hydroxycamptothecin
prodrug
stirring reaction
bdp
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French (fr)
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郭正清
黄阳阳
纪丹丹
徐晗
何慧
艾丁丁
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苏州大学
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    • C07F5/02—Boron compounds
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    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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    • A61K49/0017—Fluorescence in vivo
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    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
    • C09K2211/1048—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms with oxygen
    • C—CHEMISTRY; METALLURGY
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
    • C09K2211/1055—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms with other heteroatoms

Definitions

  • the invention relates to the field of design and synthesis of antitumor drugs, in particular to a 7-ethyl-10-hydroxycamptothecin drug precursor with fluorescence activity and its preparation method and application.
  • SN38 7-Ethyl-10-hydroxycamptothecin
  • CPT-11 irinotecan
  • fluorescence imaging technology has the characteristics of high sensitivity, high specificity, short response time, and real-time monitoring. It has been widely used in the fields of body ion detection, biological imaging, and medical diagnosis.
  • the system based on small molecule fluorescent dyes can maintain high sensitivity and resolution in highly complex biological systems, and is an excellent tool for fluorescence imaging of biological tissues.
  • fluoroboron dipyrrole dye molecule BODIPY
  • BODIPY fluoroboron dipyrrole dye molecule
  • the present invention provides a fluorescently active 7-ethyl-10-hydroxycamptothecin prodrug and its preparation method and application. It is obtained by condensation reaction between the carboxyl group of the bispyrrole dye molecule BODIPY (abbreviated as BDP) and the hydroxyl group at the 10th position of 7-ethyl-10-hydroxycamptothecin (SN38). BDP-SN38 exhibits good solubility and stability in pharmaceutical solvents.
  • BDP bispyrrole dye molecule
  • SN38 7-ethyl-10-hydroxycamptothecin
  • BDP-SN38 exhibited comparable anti-tumor activity, high tumor uptake ability, and can produce strong green fluorescence under visible light excitation, which is convenient for the detection of residual tumors by fluorescence after drug treatment and further investigation. Treatment.
  • the present invention provides the following technical solutions:
  • the first aspect of the present invention provides a fluorescent active 7-ethyl-10-hydroxycamptothecin prodrug
  • the 7-ethyl-10-hydroxycamptothecin prodrug has the following general chemical structure :
  • n is an integer.
  • the second aspect of the present invention provides a method for preparing a fluorescently active 7-ethyl-10-hydroxycamptothecin prodrug described in the first aspect, mainly including method A and method B:
  • the method A comprises the following steps: under nitrogen protection,
  • the method B comprises the following steps: under nitrogen protection,
  • the solvent is N,N-dimethylformamide or/and dichloromethane.
  • the condensing agent includes dicyclohexylcarbodiimide, diisopropylcarbodiimide, (2-oximino-ethyl cyanoacetate)-N,N-di Methyl-morpholinourea hexafluorophosphate, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 1-ethyl- One or more of (3-dimethylaminopropyl) carbodiimide and its hydrochloride.
  • the condensing agent is preferably dicyclohexylcarbodiimide, diisopropylcarbodiimide and 1-ethyl-(3-dimethylaminopropyl) carbodiimide and One or more of its hydrochlorides.
  • the condensing agent is preferably (2-oximino-ethyl cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate and/or 2-(7-nitrogen Hexabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • the molar ratio of the condensing agent to fluorobodipyrrole is 1-5:1.
  • the molar ratio of 1-hydroxybenzotriazole to bodipyrrole is 1-3:1.
  • the molar ratio of 7-ethyl-10-hydroxycamptothecin to bodipyrrole is 2-3:1.
  • the stirring temperature is 20-30°C.
  • the stirring time is not less than 20 minutes.
  • the stirring reaction time is 10-24 hours.
  • the catalyst is 4-dimethylaminopyridine or 4-pyrrolidinylpyridine.
  • the organic base is selected from one of triethylamine, diisopropylamine and pyridine.
  • the temperature of the stirring reaction is 35-65° C., and the time of the stirring reaction is 10-30 minutes.
  • the temperature of the first stirring reaction is -10-0°C, and the time of the first stirring reaction is 10-60 minutes.
  • the second stirring reaction specifically includes: first stirring at -10-0°C for 2-4 hours, then transferring to 20-30°C and stirring for 6-24 hours.
  • the preparation method also includes the process of extracting the product obtained by the stirring reaction of S A2 or S B3 and performing column chromatography; wherein, the solvent used in the extraction process is dichloromethane and saturated sodium carbonate solution, and the process of column chromatography
  • the solvent used was a mixed solvent of dichloromethane and ethyl acetate.
  • the third aspect of the present invention provides the application of the fluorescent active 7-ethyl-10-hydroxycamptothecin prodrug and its drug combination in the diagnosis and treatment of tumors described in the first aspect.
  • the present invention provides two different preparation methods, the carboxyl of boron dipyrrole dye molecule BODIPY and the hydroxyl group of No. 10 position of 7-ethyl-10-hydroxycamptothecin (SN38) are obtained by condensation reaction.
  • Fluorescent active 7-ethyl-10-hydroxycamptothecin prodrug BDP-SN38.
  • BDP-SN38 shows good solubility and stability in pharmaceutical solvents, which improves the problem of poor solubility of SN38.
  • the BDP-SN38 compound exhibits antitumor activity comparable to that of SN38, and at the same time exhibits fluorescent properties consistent with BDP, and can produce strong green fluorescence under visible light excitation.
  • the BDP-SN38 compound prepared by the present invention as a combined drug of photosensitizer and chemotherapeutic drug, has a higher tumor uptake ability, and can realize the tracking of residual tumor after drug treatment. In addition, it can be used as a combination of chemotherapy and phototherapy. Synergistic drugs to increase the killing effect on tumors.
  • Fig. 1 is the synthetic route of the 1 H NMR spectrogram of 7-ethyl-10-hydroxycamptothecin prodrug BDP-SN38;
  • Fig. 2 is a 1 H NMR spectrogram of a 7-ethyl-10-hydroxycamptothecin prodrug BDP-SN38;
  • Fig. 3 is the absorption spectrum of 7-ethyl-10-hydroxycamptothecin prodrug BDP-SN38 and BDP;
  • Fig. 4 is the emission spectrum of 7-ethyl-10-hydroxycamptothecin prodrug BDP-SN38 and BDP;
  • Fig. 5 is the solubility test of 7-ethyl-10-hydroxycamptothecin prodrug BDP-SN38 in different pharmaceutical solvents
  • Fig. 6 is the ultraviolet-visible absorption spectrum of 7-ethyl-10-hydroxycamptothecin prodrug BDP-SN38 in different drug solvents;
  • Fig. 7 is the toxicity test of 7-ethyl-10-hydroxycamptothecin prodrug BDP-SN38, SN38 and irinotecan to 4T1 cells;
  • Figure 8 is a laser confocal fluorescence image of 7-ethyl-10-hydroxycamptothecin prodrug BDP-SN38 after being taken up by 4T1 cells;
  • Fig. 9 is a laser confocal fluorescence image of 7-ethyl-10-hydroxycamptothecin prodrug BDP-SN38 and SN38 taken up by MCF7 cells.
  • the BDP used in the following examples is prepared by the following method, and the specific preparation process is as follows:
  • the compound BODIPY was dissolved in 50 times the weight of N,N-dimethylformamide, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( The molar ratio of the added amount to BODIPY is 3:1) and 1-hydroxybenzotriazole, then stirred at room temperature for half an hour; then added 7-ethyl-10-hydroxycamptothecin (SN-38, added The molar ratio of the amount and BODIPY is 1:1) and 4-dimethylaminopyridine, stirred at room temperature for 12 hours. After the reaction was completed, the compound BODIPY-SN38 was obtained after extraction and column chromatography (dichloromethane: methanol), with a yield of 34%.
  • the compound BODIPY was dissolved in 50 times the weight of N,N-dimethylformamide, and then dicyclohexylcarbodiimide was added (the molar ratio of the added amount to BODIPY was 1.2:1) and 1- Hydroxybenzotriazole, then stirred at room temperature for half an hour; then add 7-ethyl-10-hydroxycamptothecin (the molar ratio of the amount added to BODIPY is 1:1) and 4-dimethylaminopyridine, in Stir at room temperature for 12 hours. After the reaction was completed, the compound BODIPY-SN38 was obtained after extraction and column chromatography (dichloromethane: methanol), with a yield of 20%.
  • the compound BODIPY was dissolved in 50 times the weight of N,N-dimethylformamide, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( The amount added is 5:1 with the mol ratio of BODIPY) and 1-hydroxybenzotriazole, then stirred at room temperature for half an hour; Then add 7-ethyl-10-hydroxycamptothecin (the amount added is the same as that of BODIPY The molar ratio is 2:1) and 4-dimethylaminopyridine, stirred at room temperature for 12 hours. After the reaction, the compound BODIPY-SN38 was obtained after extraction and column chromatography (dichloromethane:methanol), with a yield of 60%.
  • the compound BODIPY was dissolved in 50 times the weight of N,N-dimethylformamide, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( The mol ratio of the added amount and BODIPY is 5:1) and 1-hydroxybenzotriazole, then stirred at room temperature for half an hour; The molar ratio is 3:1) and 4-dimethylaminopyridine, stirred at room temperature for 12 hours. After the reaction, the compound BODIPY-SN38 was obtained after extraction with dichloromethane and saturated sodium carbonate solution and column chromatography (dichloromethane: ethyl acetate), with a yield of 65%.
  • compound BODIPY is dissolved in 50 times of weight of dichloromethane, then add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (the amount added is the same as that of BODIPY) The molar ratio is 5:1) and 1-hydroxybenzotriazole, then stir at room temperature for half an hour; Then add 7-ethyl-10-hydroxycamptothecin (the molar ratio of the amount added to BODIPY is 2:1 ) and 4-dimethylaminopyridine, stirred at room temperature for 12 hours. After the reaction, the compound BODIPY-SN38 was obtained after extraction and column chromatography (dichloromethane:methanol), with a yield of 56%.
  • the BODIPY-SN38 prepared in Example 4 was characterized by NMR, and the characterization results are shown in Figure 2.
  • BDP-SN38 BODIPY-SN38
  • the 4T1 cells in the logarithmic growth phase were spread on a 96-well plate at a seeding density of 6 ⁇ 10 cells/mL, 100 ⁇ L per well, and placed in a cell incubator for constant temperature cultivation for 12 hours. Wash 1-2 times with phosphate buffer, add BDP-SN38 solution, SN38 solution or irinotecan solution prepared with culture medium, 100 microliters per well, prepare blank group and corresponding compound solutions of different concentrations, in which BDP- The concentrations of SN38 solution and SN38 solution were set as: 0.16, 0.31, 0.63, 1.25, 2.5, 5.0, and 10.0 ⁇ M, and the concentrations of irinotecan solution were set as: 1.25, 2.5, 5, 10, 20, 40, and 80 ⁇ M.
  • the test results are shown in Figure 5.
  • the IC 50 value of the BDP-SN38 compound is comparable to that of SN38, far lower than that of the anticancer drug irinotecan, showing a stronger killing effect on tumor cells.
  • BDP-SN38 can be well taken up by 4T1 cells, and the distribution of cells can be observed through the fluorescent signal of BDP-SN38 under the laser confocal microscope.
  • the MCF-7 cells were cultured with the BDP-SN38 solution prepared by the above method and the medium, and the distribution of BDP-SN38 in the MCF-7 cells was observed using a laser microscope. As shown in Figure 7, BDP-SN38 can be absorbed by MCF -7 cells were well taken up, and the distribution of MCF-7 cells was further observed by the fluorescence signal of BDP-SN38.

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Abstract

本发明公开了一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体及其制备方法和应用，通过将氟硼二吡咯染料分子的羧基与7-乙基-10-羟基喜树碱10号位的羟基进行缩合反应，制备得到一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体(BDP-SN38)。BDP-SN38在绝大多数药用溶剂中表现出较好的溶解性和稳定性。与SN38相比，BDP-SN38表现出相当的抗肿瘤活性，具有较高的肿瘤摄取能力，并且在可见光激发下能产生强绿色荧光，便于药物治疗后通过荧光对残余肿瘤进行查找以及进一步的治疗，在诊疗一体化研究和肿瘤高效治疗方面具有良好的应用前景。

Description

一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体及其制备方法和应用 技术领域
本发明涉及抗肿瘤药物设计、合成领域，具体涉及一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体及其制备方法和应用。
背景技术
7-乙基-10-羟基喜树碱(SN38)是一种半合成的天然生物碱类抗癌药物，具有广谱高效的抗肿瘤活性。但由于存在溶解性差、内酯环不稳定、副作用大等问题，SN38的临床应用受到极大限制。为了克服上述问题，近年来大量研究集中于SN38前药的制备，其中以伊立替康(CPT-11)最具代表性。CPT-11被摄入后经体内的羧酸酯酶转化为更具活性的SN38，通过抑制DNA拓扑异构酶Ι(Topo I)来阻止肿瘤细胞生长。然而研究发现CPT-11在体内的生物利用率低，只有极少部分CPT-11(约2-8％)能有效转化为SN-38，其药效仅为SN38的1/1000～1/100。
另一方面，当前临床肿瘤诊断与治疗仍存在诸多问题亟待解决，如最佳治疗时间的选择、药物递送的实时监测、治疗状况的评估等。荧光成像技术作为重要的检测手段，具有灵敏性高、专一性高、响应时间短、实时监控等特点，已被广泛应用于在体离子检测、生物成像及医学诊断等领域。尤其是基于小分子荧光染料体系能够在高度复杂的生物系统中保持高灵敏度和分辨率，是优良的生物组织荧光成像工具。近年来，氟硼二吡咯染料分子(BODIPY)因其高摩尔消光系数、高荧光量子产率和出色的光稳定性，在医学诊断和治疗等领域被广泛关注。
发明内容
本发明为了克服现有技术存在的缺点和不足，提供了一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体及其制备方法和应用，所述药物前体由氟硼二吡咯染料分子BODIPY(简写BDP)的羧基与7-乙基-10-羟基喜树碱(SN38)10号位的羟基缩合反应得到。BDP-SN38在药用溶剂中表现出较好的溶解性和稳定性。此外，与SN38相比，BDP-SN38表现出相当的抗肿瘤活性，具有较高的肿瘤摄取能力，并且在可见光激发下能产生强绿色荧光，便于药物治疗后通过荧光对残余肿瘤进行查找以及进一步的治疗。
为解决上述技术问题，本发明提供以下技术方案：
本发明第一方面提供了一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体，所述7-乙基-10-羟基喜树碱药物前体具有以下化学结构通式：
Figure PCTCN2021143135-appb-000001
其中n＝1～19，n为整数。
通过具有荧光性质的BODIPY修饰SN38 10号位的羟基，获得了具有良好稳定性且具有荧光性质的BDP-SN38化合物，表现出与SN38相当的抗肿瘤活性，且具有较高的肿瘤摄取能力，可实现药物治疗后对残余肿瘤的追踪。
本发明第二方面提供了第一方面所述的一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体的制备方法，主要包括方法A及方法B：
所述方法A包括以下步骤：在氮气保护下，
S A1：将氟硼二吡咯、缩合剂、1-羟基苯并三唑加入溶剂中，搅拌后得到混合溶液；
S A2：向混合溶液中加入7-乙基-10-羟基喜树碱及催化剂，进行搅拌反应，得到所述7-乙基-10-羟基喜树碱药物前体；
所述方法B包括以下步骤：在氮气保护下，
S B1：将7-乙基-10-羟基喜树碱、有机碱加入溶剂中，进行搅拌反应；
S B2：将溶于溶剂中的氟硼二吡咯加至反应体系中，进行第一搅拌反应；再将溶于溶剂中的缩合剂加入反应体系中，进行第二搅拌反应，得到所述7-乙基-10-羟基喜树碱药物前体。
进一步地，方法A及方法B中，所述溶剂为N,N-二甲基甲酰胺或/和二氯甲烷。
进一步地，方法A及方法B中，所述缩合剂包含二环己基碳二亚胺、二异丙基碳二亚胺、(2-肟基-氰基乙酸乙酯)-N,N-二甲基-吗啉基脲六氟磷酸酯、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺及其盐酸盐中的一种或多种。
进一步地，方法A中，所述缩合剂优选二环己基碳二亚胺、二异丙基碳二亚胺和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺及其盐酸盐中的一种或多种。
进一步地，方法B中，所述缩合剂优选(2-肟基-氰基乙酸乙酯)-N,N-二甲基-吗啉基脲六氟磷酸酯和/或2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
进一步地，方法A及方法B中，所述缩合剂与氟硼二吡咯的摩尔比为1～5:1。
进一步地，方法A中，所述1-羟基苯并三唑与氟硼二吡咯的摩尔比为1～3:1。
进一步地，方法A及方法B中，所述7-乙基-10-羟基喜树碱与氟硼二吡咯的摩尔比为2～3:1。
进一步地，S A1及S A2中，所述搅拌的温度为20～30℃。
进一步地，S A1中，搅拌的时间不低于20分钟。
进一步地，S A2中，所述搅拌反应的时间为10-24小时。
进一步地，S A2中，所述催化剂为4-二甲氨基吡啶或4-吡咯烷基吡啶。
进一步地，S B1中，所述有机碱选自三乙胺、二异丙胺和吡啶中的一种。
进一步地，S B1中，所述7-乙基-10-羟基喜树碱与N,N-二异丙基乙胺的摩尔比为1:1～3。
进一步地，S B1中，所述搅拌反应的温度为35～65℃，搅拌反应的时间为10～30分钟。
进一步地，S B2中，所述第一搅拌反应的温度为-10～0℃，第一搅拌反应的时间为10～60分钟。
进一步地，S B2中，所述第二搅拌反应具体为：先在-10～0℃搅拌2～4小时，再转移至20～30℃搅拌6～24小时。
S B2中，将氟硼二吡咯和缩合剂先溶于溶剂中，再将相应的溶液加至反应体系中，有利于反应速率的提高。
进一步地，所述制备方法还包括将S A2或S B3搅拌反应得到的产物进行萃取、柱层析的过程；其中，萃取过程使用的溶剂为二氯甲烷和饱和碳酸钠溶液，柱层析过程使用的溶剂为二氯甲烷及乙酸乙酯的混合溶剂。
本发明第三方面提供了第一方面所述的一种具有荧光活性的7-乙基-10-羟 基喜树碱药物前体及其药物组合在肿瘤诊断和治疗方面的应用。
与现有技术相比，本发明的有益效果在于：
1.本发明提供了两种不同的制备方法，将氟硼二吡咯染料分子BODIPY的羧基与7-乙基-10-羟基喜树碱(SN38)10号位的羟基通过缩合反应得到一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体(BDP-SN38)。BDP-SN38在药用溶剂中表现出良好的溶解性和稳定性，改善了SN38溶解度差的问题。此外，BDP-SN38化合物表现出与SN38相当的抗肿瘤活性，同时表现出与BDP一致的荧光性质，在可见光激发下能产生强绿色荧光。
2.本发明制备得到的BDP-SN38化合物，作为光敏剂和化疗药的一种结合药物，具有较高的肿瘤摄取能力，可实现药物治疗后对残余肿瘤的追踪，此外，可作为化疗和光治疗协同药物以增加对肿瘤的杀伤作用。
附图说明
图1为7-乙基-10-羟基喜树碱药物前体BDP-SN38的 1H NMR谱图的合成路线；
图2为一种7-乙基-10-羟基喜树碱药物前体BDP-SN38的 1H NMR谱图；
图3为7-乙基-10-羟基喜树碱药物前体BDP-SN38及BDP的吸收光谱；
图4为7-乙基-10-羟基喜树碱药物前体BDP-SN38及BDP的发射光谱；
图5为7-乙基-10-羟基喜树碱药物前体BDP-SN38在不同药用溶剂中的溶解性测试；
图6为7-乙基-10-羟基喜树碱药物前体BDP-SN38在不同药物溶剂中的紫外-可见吸收光谱；
图7为7-乙基-10-羟基喜树碱药物前体BDP-SN38、SN38及伊立替康对4T1细胞的毒性测试；
图8为7-乙基-10-羟基喜树碱药物前体BDP-SN38被4T1细胞摄取后的激光共聚焦荧光图；
图9为7-乙基-10-羟基喜树碱药物前体BDP-SN38和SN38被MCF7细胞摄取后的激光共聚焦荧光图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本文所使用的术语“及/或”包括一个或多个相关的所列项目的任意的和所有的组合。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法，所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例中使用的BDP均通过以下方法制备得到，具体的制备过程如下所示：
①将对羟基苯甲醛、6-溴己酸和碳酸钾加入反应容器中，加入苯并-18-冠-6-醚、乙腈，加热回流反应24h后过滤，将得到的固体用乙腈冲洗；将固体溶于水后加入4mol/L的盐酸直至无气泡产生，过滤后得到白色滤渣即为6-(4-甲酰基苯氧基)己酸。
②将6-(4-甲酰基苯氧基)己酸和2,4-二甲基吡咯加入反应容器中，然后加入四氢呋喃和三氟乙酸，再加入溶于四氢呋喃的2,3-二氯-5,6-二氰对苯醌溶液，室温搅拌反应12小时后，加入三乙胺，在冰水浴的条件下逐滴加入三氟化硼乙醚反应过夜。反应结束后，用砂板布氏漏斗过滤，减压旋转浓缩后，加入少量稀盐酸搅拌3小时；再次浓缩后，用乙酸乙酯萃取，将萃取液经柱层析 (SiO 2；洗脱剂为石油醚/二氯甲烷)得到化合物BODIPY。
实施例一
在氮气保护下，将化合物BODIPY溶于50倍重量的N,N-二甲基甲酰胺，再加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(加入的量与BODIPY的摩尔比为3:1)和1-羟基苯并三唑，然后在室温下搅拌半小时；再加入7-乙基-10-羟基喜树碱(SN-38，加入的量与BODIPY的摩尔比为1:1)和4-二甲氨基吡啶，在室温下搅拌12小时。反应结束后经萃取、柱层析(二氯甲烷：甲醇)后得到化合物BODIPY-SN38，产率34％
实施例二
在氮气保护下，将化合物BODIPY溶于50倍重量的N,N-二甲基甲酰胺，再加入二环己基碳二亚胺(加入的量与BODIPY的摩尔比为1.2:1)和1-羟基苯并三唑，然后在室温下搅拌半小时；再加入7-乙基-10-羟基喜树碱(加入的量与BODIPY的摩尔比为1:1)和4-二甲氨基吡啶，在室温下搅拌12小时。反应结束后经萃取、柱层析(二氯甲烷：甲醇)后得到化合物BODIPY-SN38，产率20％
实施例三
在氮气保护下，将化合物BODIPY溶于50倍重量的N,N-二甲基甲酰胺，再加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(加入的量与BODIPY的摩尔比为5:1)和1-羟基苯并三唑，然后在室温下搅拌半小时；再加入7-乙基-10-羟基喜树碱(加入的量与BODIPY的摩尔比为2:1)和4-二甲氨基吡啶，在室温下搅拌12小时。反应结束后经萃取、柱层析(二氯甲烷：甲醇)后得到化合物BODIPY-SN38，产率60％。
实施例四
在氮气保护下，将化合物BODIPY溶于50倍重量的N,N-二甲基甲酰胺，再加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(加入的量与BODIPY 的摩尔比为5:1)和1-羟基苯并三唑，然后在室温下搅拌半小时；再加入7-乙基-10-羟基喜树碱(加入的量与BODIPY的摩尔比为3:1)和4-二甲氨基吡啶，在室温下搅拌12小时。反应结束后经二氯甲烷和饱和碳酸钠溶液萃取、柱层析(二氯甲烷：乙酸乙酯)后得到化合物BODIPY-SN38，产率65％。
实施例五
在氮气保护下，将化合物BODIPY溶于50倍重量的二氯甲烷，再加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(加入的量与BODIPY的摩尔比为5:1)和1-羟基苯并三唑，然后在室温下搅拌半小时；再加入7-乙基-10-羟基喜树碱(加入的量与BODIPY的摩尔比为2:1)和4-二甲氨基吡啶，在室温下搅拌12小时。反应结束后经萃取、柱层析(二氯甲烷：甲醇)后得到化合物BODIPY-SN38，产率56％。
实施例六
在氮气保护下，将7-乙基-10-羟基喜树碱(加入的量与BODIPY的摩尔比为1.5:1)溶于N,N-二甲基甲酰胺(加入的量与BODIPY的质量比为50:1)，再加入三乙胺(加入的量与BODIPY的摩尔比为3:1)，然后在50℃搅拌20分钟；之后再加入溶于DMF中的BODIPY(DMF与BODIPY的质量比为50：1)溶液，在-5℃搅拌30分钟；再加入溶于DMF中的(2-肟基-氰基乙酸乙酯)-N,N-二甲基-吗啉基脲六氟磷酸酯溶液，在-10～0℃搅拌3小时，再转移至室温下搅拌12小时；反应结束后经二氯甲烷和饱和碳酸钠溶液萃取、柱层析(二氯甲烷：乙酸乙酯)后得到化合物BODIPY-SN38，产率57％。
实施例七
在氮气保护下，将7-乙基-10-羟基喜树碱(加入的量与BODIPY的摩尔比为1.5:1)溶于N,N-二甲基甲酰胺(加入的量与BODIPY的质量比为50:1)，再加入N,N-二异丙基乙胺(加入的量与BODIPY的摩尔比为3:1)，然后在50℃搅拌20分钟；之后再加入溶于DMF中的BODIPY(DMF与BODIPY的质量 比为50：1)溶液，在-5℃搅拌30分钟；再加入溶于DMF中的(2-肟基-氰基乙酸乙酯)-N,N-二甲基-吗啉基脲六氟磷酸酯溶液，在-10～0℃搅拌3小时，再转移至室温下搅拌12小时；反应结束后经二氯甲烷和饱和碳酸钠溶液萃取、柱层析(二氯甲烷：乙酸乙酯)后得到化合物BODIPY-SN38，产率60％。
表征及性能测试
对实施例四制备得到的BODIPY-SN38进行核磁表征，表征结果如图2所示，核磁结果如下： 1H NMR(400MHz,CDCl 3):δ8.26(d,J＝9.2Hz,1H),7.84(d,J＝2.4Hz,1H),7.67(s,1H),7.57(dd,J＝9.2,2.5Hz,1H),7.17(d,J＝8.7Hz,2H),7.01(d,J＝8.7Hz,2H),5.97(s,2H),5.75(d,J＝16.3Hz,1H),5.31(d,J＝16.3Hz,1H),5.27(s,2H),4.07(t,J＝6.3Hz,2H),3.16(q,J＝7.7Hz,2H),2.74(t,J＝7.4Hz,2H),2.55(s,6H),1.81–2.00(m,6H),1.66–1.77(m,2H),1.44(s,4H),1.41(t,J＝7.8Hz,3H),1.04(t,J＝7.4Hz,3H)。
①光物理性质研究
分别称取1g的BDP和BODIPY-SN38(BDP-SN38)溶于10mL的DMF中，调节两种溶液的浓度，使最大吸收波长的吸光度值为0.2～0.8，测定两种材料的吸收光谱(如图3所示)，再测试调节浓度后的两种溶液的发射光谱，结果如图4所示；两种化合物的吸收光谱基本重合，且发射光谱完全重合，该现象也说明BDP-SN38化合物具有与BDP相似的荧光性质。
②溶解性和稳定性测试
分别称取1毫克BDP-SN38于1.5毫升离心管中，在每个离心管中加入300微升不同种类的溶剂(1,2-二氯乙烷、1,4-环氧六环、丙酮、氯仿、四氢呋喃、乙酸乙酯、乙腈、乙醇、正丁醇、异丙醇、乙二醇、甘油)，经震荡一分钟、离心三分钟后，观察各种BDP-SN38溶液中是否有沉淀以及溶液颜色并且记录，在不同溶剂中的溶解情况如图5所示，BDP-SN38在大多数药用溶剂中都是可溶的。
用分析天平分别记录两个离心管的重量，再称取BDP-SN38和SN38各2毫克置于离心管中。在上述离心管中分别加入300微升氯仿，经震荡、离心后，观察BDP-SN38和SN38在溶液中的溶解情况。通过减重法估算不同化合物在氯仿中的溶解度(具体操作为：移取溶液，将剩余固体经冻干处理后进行称重)，计算可得，BDP-SN38在氯仿溶液的溶解度大于6.7mg/mL，而SN38在氯仿溶液中几乎不溶解。
分别用移液枪量取不同BDP-SN38溶液中离心过后的上层清液12微升，加入相对应的溶剂(丙酮、氯仿、四氢呋喃、乙酸乙酯、乙腈、乙醇)，配置成600微升的稀溶液并装入微量石英皿中测定它们的吸收光谱，测试结果如图6所示，和图3对比可知，BDP-SN38在不同溶剂中紫外可见吸收光谱保持一致，这表明BDP-SN38在不同类型的溶剂中都具有较高的稳定性。
③细胞毒性测试
取对数生长期的4T1细胞铺96孔板，接种密度为6×10 3个/mL，每孔100μL，放入细胞培养箱恒温培养12小时，确定细胞贴壁后，倒掉培养液，用磷酸盐缓冲液洗1-2次，加入用培养基配好的BDP-SN38溶液、SN38溶液或伊利替康溶液，每孔100微升，配置空白组及不同浓度的相应化合物溶液，其中BDP-SN38溶液及SN38溶液的浓度设置分别为：0.16、0.31、0.63、1.25、2.5、5.0、10.0μM，伊利替康溶液的浓度设置为：1.25、2.5、5、10、20、40、80μM，每个浓度4个复孔；放入培养箱培养48小时后，更换培养液，加20μL浓度为5mg/mL溶于磷酸缓冲溶液中的3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐，4小时后弃去培养液，加入200μL的DMSO，振荡10分钟，酶标仪490nm处测定吸光度值。
测试结果如图5所示，BDP-SN38化合物的IC 50值与SN38相当，远低于抗癌药物伊利替康，对肿瘤细胞表现出更强的杀伤效果。
④细胞摄取测试
取对数生长期的4T1细胞铺在2个共聚焦皿，每皿1.0×10 4个细胞，放入细胞培养箱恒温培养12小时，确定细胞贴壁后，倒掉培养液，用磷酸盐缓冲液洗1-2次，分别加入用培养基配好的BDP-SN38溶液(1μM，1mL)、SN38溶液(1μM，1mL)，放入培养箱培养24小时后，用磷酸盐缓冲液洗1-2次，结束后使用激光显微镜观察BDP-SN38在4T1细胞内的分布情况。如图6所示，BDP-SN38能够被4T1细胞良好的摄取，在激光共聚焦显微镜下能通过BDP-SN38的荧光信号观察到细胞的分布。
将MCF-7细胞通过上述方法与培养基配好的BDP-SN38溶液进行培养，使用激光显微镜观察BDP-SN38在MCF-7细胞内的分布情况，如图7所示，BDP-SN38能够被MCF-7细胞良好的摄取，且通过BDP-SN38的荧光信号进一步观察到MCF-7细胞的分布。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例，本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换，均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。

Claims (10)

  1. 一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体，其特征在于，所述7-乙基-10-羟基喜树碱药物前体具有以下化学结构通式：
    Figure PCTCN2021143135-appb-100001
    其中n＝1～19，n为整数。
  2. 权利要求1所述的一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体的制备方法，其特征在于，所述制备方法包括方法A和方法B；
    所述方法A包括以下步骤：在氮气保护下，
    S A1：将氟硼二吡咯、缩合剂、1-羟基苯并三唑加入溶剂中，搅拌后得到混合溶液；
    S A2：向混合溶液中加入7-乙基-10-羟基喜树碱及催化剂，进行搅拌反应，得到所述7-乙基-10-羟基喜树碱药物前体；
    所述方法B包括以下步骤：在氮气保护下，
    S B1：将7-乙基-10-羟基喜树碱、有机碱加入溶剂中，进行搅拌反应；
    S B2：将溶于溶剂中的氟硼二吡咯加至反应体系中，进行第一搅拌反应；再将溶于溶剂中的缩合剂加入反应体系中，进行第二搅拌反应，得到所述7-乙基-10-羟基喜树碱药物前体。
  3. 根据权利要求2所述的一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体的制备方法，其特征在于，方法A及方法B中，所述溶剂为N,N-二甲基甲酰胺或/和二氯甲烷；所述缩合剂包含二环己基碳二亚胺、二异丙基碳二亚胺、(2-肟基-氰基乙酸乙酯)-N,N-二甲基-吗啉基脲六氟磷酸酯、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺及其盐酸盐中的一种或多种。
  4. 根据权利要求2所述的一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体的制备方法，其特征在于，S A1中，搅拌的时间不低于20分钟。
  5. 根据权利要求2所述的一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体的制备方法，其特征在于，S A2中，所述催化剂为4-二甲氨基吡啶或4-吡咯烷基吡啶；所述搅拌反应的时间为10-24小时。
  6. 根据权利要求2所述的一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体的制备方法，其特征在于，S B1中，所述有机碱选自三乙胺、二异丙胺和吡啶中的一种。
  7. 根据权利要求2所述的一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体的制备方法，其特征在于，S B1中，所述搅拌反应的温度为35～65℃，搅拌反应的时间为10～30分钟。
  8. 根据权利要求2所述的一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体的制备方法，其特征在于，S B2中，所述第一搅拌反应的温度为-10～0℃，第一搅拌反应的时间为10～60分钟；所述第二搅拌反应具体为：先在-10～0℃搅拌2～4小时，再转移至20～30℃搅拌6～24小时。
  9. 根据权利要求2所述的一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体的制备方法，其特征在于，所述制备方法还包括将S A2或S B3搅拌反应得到的产物进行萃取、柱层析的过程；其中，萃取过程使用的溶剂为二氯甲烷和饱 和碳酸钠溶液，柱层析过程使用的溶剂为二氯甲烷及乙酸乙酯的混合溶剂。
  10. 权利要求1所述的一种具有荧光活性的7-乙基-10-羟基喜树碱药物前体及其药物组合在肿瘤诊断和治疗方面的应用。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103755753A (zh) * 2014-01-25 2014-04-30 福州大学 一类糖基化氟硼二吡咯衍生物及其制备和应用
CN112047952A (zh) * 2020-08-28 2020-12-08 四川大学 一种喜树碱-光敏剂前药及其制备方法和应用
CN112920210A (zh) * 2021-02-01 2021-06-08 福州大学 一种红光可激活的光动力治疗-化疗联用前药及其制备和应用

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2690145C (en) * 2007-06-25 2016-04-12 Scinopharm Taiwan Ltd. Crystalline polymorph of 7-ethyl-10-hydroxycamptothecin
EP2197279B1 (en) * 2007-10-16 2017-01-18 Bionumerik Pharmaceuticals, Inc. C10-substituted camptothecin analogs
CN102060991B (zh) * 2010-11-26 2012-11-21 浙江大学 7-乙基-10-羟基喜树碱的两亲性药物前体及其制备方法
CN103251596A (zh) * 2013-05-06 2013-08-21 浙江大学 7-乙基-10-羟基喜树碱的两亲性聚合物药物前体及其制备方法和纳米颗粒
CN106519213B (zh) * 2016-09-26 2019-01-01 苏州大学 一种铂基化氟硼二吡咯类化合物及制备方法和应用
CN109303780B (zh) * 2017-07-28 2021-09-21 烟台药物研究所 一种还原响应型7-乙基-10-羟基喜树碱的两亲性聚合物药物前体及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103755753A (zh) * 2014-01-25 2014-04-30 福州大学 一类糖基化氟硼二吡咯衍生物及其制备和应用
CN112047952A (zh) * 2020-08-28 2020-12-08 四川大学 一种喜树碱-光敏剂前药及其制备方法和应用
CN112920210A (zh) * 2021-02-01 2021-06-08 福州大学 一种红光可激活的光动力治疗-化疗联用前药及其制备和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIU YANG, PEI QING, CHEN LI, LI ZHENSHENG, XIE ZHIGANG: "Reduction-responsive fluorescence off–on BODIPY–camptothecin conjugates for self-reporting drug release", JOURNAL OF MATERIALS CHEMISTRY. B, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 4, no. 13, 1 January 2016 (2016-01-01), GB , pages 2332 - 2337, XP093070361, ISSN: 2050-750X, DOI: 10.1039/C6TB00009F *

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