CN105670334B - 一种葡萄糖基化近红外染料及其制备方法和应用 - Google Patents
一种葡萄糖基化近红外染料及其制备方法和应用 Download PDFInfo
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- CN105670334B CN105670334B CN201610111482.7A CN201610111482A CN105670334B CN 105670334 B CN105670334 B CN 105670334B CN 201610111482 A CN201610111482 A CN 201610111482A CN 105670334 B CN105670334 B CN 105670334B
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Classifications
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- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
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- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
- A61K49/0082—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion micelle, e.g. phospholipidic micelle and polymeric micelle
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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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
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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
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
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Abstract
本发明公开了一种葡萄糖基化近红外染料及其制备方法和应用，具体涉及一种通式I所示的染料；通过三个片段的分别合成以及取代、缩合反应最终得到该染料；该染料具有紫外吸收，且有近红外发射，易于检测，具有一个衍生化位点，可以用来连接具有不同靶向性的分子。另外，该染料还具有一个荧光开关，能够连接乏氧、pH、酶、氧化还原敏感的基团，以达到选择性发荧光的效果，其应用于可视化靶向给药中。
Description
技术领域
本发明涉及荧光探针的技术领域，特别涉及一种可衍生化的染料分子及其制备方法和应用。
背景技术
癌症是严重威胁人类生命和社会发展的重大疾病，是致人死亡的主要原因之一，其发病率呈逐年上升的趋势，严重危害人们的身体健康。癌症的预防和治疗是目前人类医学健康面临的最大挑战。早期的诊断与发现是治疗癌症的关键，但是很多肿瘤发病隐秘，早期无明显症状，同时对肿瘤发生、发展、转移的实时监控目前尚缺少特异性的医学手段。近年来发展起来的生物荧光成像技术可以实现在分子水平研究癌症的发病机理，实时跟踪病理过程，并且对机体不形成损害。荧光成像技术通过荧光分子与高特异性的活化基团结合，在到达肿瘤组织后特异地被肿瘤组织活化，从而发射荧光。荧光成像技术的关键在于设计高特异性的荧光探针，荧光分子是荧光探针的关键部分。因此，寻找合适的荧光分子来设计探针对于在分子水平研究肿瘤细胞具有重要意义。
近红外荧光是指发射波长在650-900nm的荧光。相比于紫外可见光区的荧光容易被生物大分子吸收，近红外荧光具有无创，背景干扰小，穿透力强的特点。因此近红外荧光技术常被用于活体检测。
近年来，许多具有特异性识别作用的分子，如糖、肽、叶酸等，被尝试用于癌症的靶向治疗。每设计出一个靶头，就需要将它连接在一个类药性染料上，以可视化地观察其靶向性效果。
长期以来近红外染料研究最多的是菁染料与罗丹明染料及其衍生物。与大多数药物不同，这两种染料都有一个季胺盐中心，溶解性差，且结构复杂不易合成。最近有文献报道了一种苯并吡喃结构的近红外染料(DCPO)，该染料发射波长在680nm左右，荧光强度高，而且结构简单，易于合成。更加重要的是，与绝大多数药物相同，该类染料结构中没有季铵盐中心，相对于其他染料具有更好的类药性，因此在靶向研究中更具有说服力。但美中不足的是，该染料中没有明确的可以连接靶头分子的位点，因此仍需努力研究，得到一个新型功能性染料。
发明内容
本发明的目的是提供一种葡萄糖基化近红外染料，以解决现有技术中类药性差、不方便衍生化等问题。
本发明的另一目的是提供一种葡萄糖基化近红外染料的制备方法。
本发明的再一目的在于提供一种葡萄糖基化近红外染料在可视化靶向给药中的应用。
本发明的目的是这样实现的：
一种葡萄糖基化近红外染料，特点在于具有通式I所示的结构：
上式中，R为具有靶向性的糖、多肽、氨基酸或叶酸靶头，苯环上裸露的羟基为该染料的开关，能够连接乏氧、pH、酶或氧化还原敏感的基团，以达到控制发荧光的效果。上述基团包括：硝基咪唑、二硫键、苯硫酚、乙缩醛、腙、顺式乌头酰基。当靶头为糖或PEG化的糖、氨基酸、叶酸、多肽的亲水性基团时，尤其是大小、长度合适的情况下，该分子可以在水中组装成胶束，提高其水中的溶解性和生物利用效率。
一种上述葡萄糖基化近红外染料的制备方法，该方法包括如下步骤:
ⅰ)化合物II与叠氮化钠在溶剂DMF、DMSO或水中，40-60℃下发生亲核取代反应，18-24h后得到化合物III，化合物II与叠氮化钠摩尔比为1：1.1-1.5；
ⅱ)化合物III与对甲苯磺酰氯在溶剂二氯甲烷或DMF中，加入有机碱三乙胺、吡啶或二异丙基乙胺，20-40℃下反应18-24h得到化合物IV，化合物III与对甲苯磺酰氯的摩尔比为1：1.1-1.5；
ⅲ)化合物V与氯甲基甲醚在溶剂丙酮中，加入无机碱碳酸钾或碳酸钠，20-40℃下反18-24h得到化合物VI，化合物V与氯甲基甲醚的摩尔比为1：1.1-1.5；
ⅳ)使化合物VI在溶剂DMF或THF中与化合物IV反应，加入NaH做碱，室温下反应18-24h得到化合物VII，化合物VI与化合物IV的摩尔比为1：1.1-1.5，化合物VI与NaH的摩尔比为1：1.1-1.5；
ⅴ)化合物VII在溶剂甲醇中，在氢离子交换树脂的作用下，20-40℃反应48-72h脱保护得到化合物VIII，离子交换树脂的用量是化合物VII质量的1.2-2倍；
vi)使化合物VIII与化合物X在溶剂乙腈或DCM中反应，体系中加入醋酸和哌啶，40-70℃下反应12-24h得到化合物IX，化合物VIII与化合物X的摩尔比为1：1.0-1.2，醋酸与哌啶体积比为1:1-5，醋酸哌啶混合物与溶剂体积比为1：20-60；
vii)在水和异丙醇的混合溶剂中，化合物IX与不同的带有炔基的化合物进行click反应，加入化合物IX摩尔量1-10％的抗坏血酸钠和等摩尔量的硫酸铜或化合物IX摩尔量1-10％的DIPEA和等摩尔量的碘化亚铜，40-70℃下反应0.5-2h得到终产物化合物I，化合物IX与不同的带有炔基的化合物的摩尔比为(0.8-1)：1。
一种上述葡萄糖基化近红外染料在可视化靶向给药中的应用。
与现有技术相比，本发明具有以下有益效果：
(a)本发明提供了一种新的功能性近红外染料，具有一个可衍生化的位点，能够连接具有靶向性的分子，实现功能性；有一个“开-关”位点，能实现荧光控制。
(b)本发明所述染料由于结构中不含有季铵盐中心，有更好的类药性；有近红外的荧光发射，更利于生物检测。
(c)本发明还将葡萄糖与该染料连接，提供了几个具有功能性的新型染料分子，能够以不同于原染料的方式摄取进入细胞。
附图说明
图1为本发明实施例8所配制溶液的紫外-可见吸收光谱图；
图2为本发明实施例8所配制溶液在579nm激发光下的荧光发射光谱；
图3为本发明实施例9所制得的胶束的粒径分布DLS图；
图4为本发明实施例10所描述的不同浓度的化合物XI在Hela细胞中的社区情况拍照。
具体实施方式
本发明的染料和制备方法与应用在如下实施例中更详细地叙述，但实施例不构成对本发明的限制。
实施例1
1.1化合物III的合成
将2.0g(16.1mmol)化合物II溶于20mLDMSO，向其中加入1.25g叠氮化钠(19.2mmol)，加热到50℃左右反应20h。用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压蒸馏去除溶剂。粗产物经柱层析(乙酸乙酯：石油醚＝1:4)得化合物III浅黄色液体1.54g，收率73.3％。
1H NMR(400MHz,CDCl3)δ3.69(t,J＝4Hz,2H),3.63(t,J＝4Hz,2H),3.55(t,J＝4Hz,2H),3.36(t,J＝6Hz,2H),2.67(s,1H)。
实施例2
1.2化合物IV的合成
1.0g(8.0mmol)化合物III，吡啶0.97mL(12.05mmol)，溶于20mL DCM，冰浴下加入TsCl 1.8g(9.6mmol)，升温至室温，反应20h。DCM萃取，稀盐酸洗，水洗，饱和NaCl洗，无水NaSO4干燥，减压蒸馏去除溶剂。粗产物经柱层析(乙酸乙酯：石油醚＝1:4)得化合物IV为浅黄色液体1.1g，收率48.0％。
1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),4.17(t,J＝5.4,4.1Hz,2H),3.70(t,J＝5.3,4.1Hz,2H),3.60(t,J＝5.0Hz,2H),3.32(t,J＝5.0Hz,2H),2.45(s,3H)。
实施例3
1.3化合物VI的制备
5.0g(36.2mmol)化合物V，溶于100mL无水丙酮中，氮气保护，分批加入6.5g(47.1mmol)碳酸钾固体，加毕，分批加入3.3mL(38.7mmol)MOMCl，室温反应20h。反应结束后，加水，乙酸乙酯萃取，饱和氯化钠溶液洗，无水硫酸钠干燥，减压蒸馏去除溶剂。粗产物经柱层析(乙酸乙酯：石油醚＝1:4)得化合物VI为白色固体4.2g，收率64.2％。
1H NMR(400MHz,CDCl3)δ6.12(s,2H),6.08–5.98(m,1H),5.96(s,1H),5.39(d,J＝17.3Hz,1H),5.28(d,J＝10.5Hz,1H),4.65(s,2H),4.52(d,J＝4.6Hz,2H),4.08(d,J＝11.2Hz,2H),3.92(s,2H),3.85-3.75(m,8H),2.37-2.29(m,4H),1.67-1.57(m,4H),1.28(m,24H),0.88(t,J＝5.9Hz,6H)。
实施例4
1.4化合物VII的制备
4.0g(27.4mmol)化合物VI，溶于80mL DMF中，氮气保护，冰浴下，分批加入1.0g(32.9mmol)NaH，加毕，冰浴下搅拌5min，分批加入化合物IV，室温反应20h。反应结束后，加水，用乙酸乙酯萃取，饱和氯化钠溶液洗，无水硫酸钠干燥，减压蒸馏去除溶剂。粗产物经柱层析(乙酸乙酯：石油醚＝1:8)得化合物VII为淡黄色液体3.3g，收率50.9％。
1H NMR(400MHz,CDCl3)δ10.35(s,1H),7.80(d,J＝8.6Hz,1H),6.69(d,J＝8.7Hz,1H),6.62(s,1H),5.22(s,2H),4.28–4.19(m,2H),3.96–3.88(m,2H),3.76(t,J＝4.8Hz,2H),3.48(s,3H),3.44–3.37(m,2H)。
实施例5
1.5化合物VIII的制备
750mg化合物VII溶于3mL甲醇中，加入氢离子交换树脂1.5g，反应30h。反应结束后，抽滤除去离子交换树脂，甲醇冲洗，减压蒸馏去除溶剂，粗产物经柱层析(乙酸乙酯：石油醚＝1:2)得化合物VIII淡黄色液体140mg，收率22.0％。
1H NMR(400MHz,CDCl3)δ10.29(s,1H),7.76(d,J＝8.5Hz,1H),6.95(d,J＝40.8Hz,1H),6.51(dd,J＝8.5,2.1Hz,1H),6.47(d,J＝2.1Hz,1H),4.26–4.18(m,2H),3.95–3.88(m,2H),3.80–3.71(m,2H),3.46–3.36(m,2H)。
实施例6
1.6化合物IX的制备
950mg(3.78mmol)化合物VIII用12mL乙腈溶解，将790mg(3.78mmol)化合物X加入两口瓶，换氮气后将化合物VIII的乙腈溶液加入体系中，分别缓慢加入哌啶0.6mL、冰醋酸0.6mL，投毕，升温至70℃反应20h。反应结束后减压蒸馏去除溶剂，加2mL DCM、10mL乙醚，滴加0.6mL三氟乙酸，析出红色固体，抽滤，水洗、乙醚洗，油泵抽干，得到产物化合物IX为红色固体1.12g，收率67.1％。
1H NMR(400MHz,DMSO)δ10.26(s,1H),8.71(t,J＝7.9Hz,1H),7.93–7.83(m,2H),7.70(t,J＝9.4Hz,1H),7.66–7.54(m,2H),7.29–7.17(m,1H),6.88–6.79(m,1H),6.47(d,J＝6.9Hz,2H),4.17(s,2H),3.91(s,2H),3.83–3.75(m,2H),3.51–3.44(m,2H)。
实施例7
1.7化合物XI的制备
化合物IX 55.9mg(0.13mmol)与化合物XII 41.6mg(0.11mmol)混合，加入水、叔丁醇各0.7mL，加入催化量无水硫酸铜1mg(5％)、抗坏血酸钠1.3mg(5％)，升温至50℃，2h后原料反应完全。减压蒸馏去除溶剂，粗产物经柱层析(二氯甲烷：甲醇＝10:1)得化合物XI红色蜡状物质57.8mg，收率66.6％。
1H NMR(400MHz,MeOD)δ8.66(d,J＝8.2Hz,1H),7.97(s,1H),7.74(t,J＝7.6Hz,1H),7.59(d,J＝16.0Hz,1H),7.47(d,J＝8.3Hz,1H),7.39(t,J＝7.6Hz,1H),7.32(d,J＝8.5Hz,1H),6.85(d,J＝16.0Hz,1H),6.48(s,1H),6.40(d,J＝8.5Hz,1H),6.34(s,1H),4.67(t,J＝4.5Hz,2H),4.51(s,2H),4.32(d,J＝7.7Hz,1H),4.11–3.97(m,5H),3.88(s,3H),3.77–3.57(m,16H),3.31(d,J＝6.8Hz,2H),3.22(t,J＝8.4Hz,1H)。
实施例8
将实施例8制备的化合物XI，分别检测其吸收波长和在该激发光下的荧光发射，取化合物112.0mg，溶于1mL THF，取出83.3uL，用4mL DMSO：PBS缓冲液1:1的混合溶剂(pH7.4)稀释，Varian Cary 100紫外-可见分光光度计检测其吸收波长，结果如附图1；在最大吸收波长579nm的激发下，用日立F-4500荧光分光光度计检测荧光发射，结果如附图2。
实施例9
将实施例8制备的化合物XI，在水相中制备成胶束，检测其粒径。取化合物XI2.0mg，溶解于1.0mL THF中，取0.1mL用THF稀释到0.5mL，再用Longerpump LSP02-18注射泵将该溶液缓慢、匀速用5min注射入5mL蒸馏水中，搅拌30min，减压蒸馏去除THF，使用nano-zs动态光散射仪检测粒径分布，得到平均粒径为185nm，PDI＝0.081，如附图3。
实施例10
将处于对数生长期的HELA细胞接种接种于96孔板内，密度为6×103个细胞/孔/180uL，经过细胞接种的96孔板放置在培养箱(37℃、5％CO2浓度的潮湿环境)中培养24h。24h后加入不同浓度实施例8制备化合物XI，最终浓度分别为50uM、25uM、12.5uM、6.25uM、3.125uM，每个浓度均为三个复孔。然后再次放入培养箱培养24h后，用移液枪吸出培液，用PBS缓冲液缓慢冲洗每个孔3次，在荧光电子显微镜下观察并拍照。结果显示，细胞对该化合物有着较好的吸收，并荧光强度随着浓度的下降而降低，如附图4。附图中，每个浓度下拍照两次，第一次为白光下拍照(白色背景)，第二次为绿光激发下拍照(黑色背景)，两次为同一视野，以做对比。
Claims (3)
1.一种葡萄糖基化近红外染料，其特征在于具有通式Ⅺ所示的结构：
2.一种权利要求1所述葡萄糖基化近红外染料，其特征在于，该近红外染料在可视化靶向给药中的应用。
3.一种权利要求1所述葡萄糖基化近红外染料的制备方法，其特征在于该方法包括如下步骤：
ⅰ)化合物II与叠氮化钠在溶剂DMF、DMSO或水中，40-60℃下发生亲核取代反应，18-24h后得到化合物III，化合物II与叠氮化钠摩尔比为1：1.1-1.5；
ⅱ)化合物III与对甲苯磺酰氯在溶剂二氯甲烷或DMF中，加入有机碱三乙胺、吡啶或二异丙基乙胺，20-40℃下反应18-24h得到化合物IV，化合物III与对甲苯磺酰氯的摩尔比为1：1.1-1.5；
ⅲ)化合物V与氯甲基甲醚在溶剂丙酮中，加入无机碱碳酸钾或碳酸钠，20-40℃下反18-24h得到化合物VI，化合物V与氯甲基甲醚的摩尔比为1：1.1-1.5；
ⅳ)使化合物VI在溶剂DMF或THF中与化合物IV反应，加入NaH做碱，室温下反应18-24h得到化合物VII，化合物VI与化合物IV的摩尔比为1：1.1-1.5，化合物VI与NaH的摩尔比为1：1.1-1.5；
ⅴ)化合物VII在溶剂甲醇中，在氢离子交换树脂的作用下，20-40℃反应48-72h脱保护得到化合物VIII，离子交换树脂的用量是化合物VII质量的1.2-2倍；
vi)使化合物VIII与化合物X在溶剂乙腈或DCM中反应，体系中加入醋酸和哌啶，40-70℃下反应12-24h得到化合物IX，化合物VIII与化合物X的摩尔比为1：1.0-1.2，醋酸与哌啶体积比为1:1-5，醋酸哌啶混合物与溶剂体积比为1：20-60；
vii)在水和异丙醇的混合溶剂中，化合物IX与化合物XII进行click反应，加入化合物IX摩尔量1-10％的抗坏血酸钠和等摩尔量的硫酸铜或化合物IX摩尔量1-10％的DIPEA和等摩尔量的碘化亚铜，40-70℃下反应0.5-2h得到终产物化合物Ⅺ，化合物IX与化合物XII的摩尔比为(0.8-1)：1。
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