CN109456304A - 易修饰近红外二区有机小分子染料及其合成方法和应用 - Google Patents
易修饰近红外二区有机小分子染料及其合成方法和应用 Download PDFInfo
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- CN109456304A CN109456304A CN201811479005.1A CN201811479005A CN109456304A CN 109456304 A CN109456304 A CN 109456304A CN 201811479005 A CN201811479005 A CN 201811479005A CN 109456304 A CN109456304 A CN 109456304A
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- ether
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Classifications
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Abstract
本发明提供一种易修饰近红外二区有机小分子染料及其合成方法和应用。本发明的此类近红外二区荧光染料属于多甲川吡喃或多甲川噻喃盐类有机小分子,由多甲川苯胺盐与吡喃或噻喃盐通过缩合反应制成。合成原料易得,成本低廉,制备过程简单,产率高,可大量合成。并通过改变分子内多甲川链及杂原子种类,达到调节荧光发射光谱的目的。此类小分子染料的最大发射波长范围1000‑1200nm,荧光量子产率高,光稳定性好,非常适用于活体成像。该类小分子染料可通过点击化学与具有特定功能的基团连接,实现多种生物成像应用。其近红外二区荧光活体成像背景噪音低,荧光信号强,信噪比高。
Description
技术领域
本发明属于生物荧光成像领域,具体涉及一种易修饰近红外二区有机小分子染料及其合成方法和应用。
背景技术
光学荧光成像使用荧光对生物体进行成像,作为一种非侵入式无放射性的成像手段,拥有检测疾病及追踪疾病治疗效果的强大能力。与其他成像手段相比,光学成像同时具有高时间分辨率及空间分辨率,能轻松实现对病理过程的实时动态长时间持续观察。其研究成本远低于MRI或者PET成像,具有极高的研究价值,已被广泛应用于多种生物成像应用。
光学成像这种利用荧光进行成像的方式固然拥有明显的不足之处,但是通过增加荧光发射波长可在一定程度上改善这一缺点,并且能够极大地提高成像信噪比。光学成像根据所用的荧光波长将荧光成像划分为三类,可见光成像(400-650nm)、近红外I区成像(NIR-I,650-950nm)、近红外II区成像(NIR-II,1000-1700nm)。众所周知,荧光的波长越长,穿透能力越强。通常近红外II区光学成像穿透机体深度可大于5mm。其荧光的散射损失也会减少九成以上,同时生物组织在近红外二区的自发荧光几乎为零,尤其在1300nm以上,成像信噪比得到大大提高,可达100。因此近红外二区光学成像已成为当下光学荧光成像的热点。NIR-II区又进一步划分出两个子区间,NIR-IIa(1300-1400nm)和NIR-IIb(1500-1700)。相比于~1000nm区间,子区间内的光散射及生物自荧光进一步降低,信噪比得到进一步提高。NIR-IIb由于荧光波长更长,比NIR-IIa更具有优势。
近红外二区成像于近几年,随着InGaAs CCD检测器的普及,才开始广泛研究。目前有报道的具有1000nm以上荧光的近红外二区成像材料种类较少,尤其是生物相容性好且安全无毒的小分子染料种类更少,极大限制了近红外光学成像的发展和临床应用。原因是有机小分子染料的合成步骤多,难度大,并且多数染料水溶性差。第一个近红外二区小分子染料是以苯并噻二唑为核心的D-A-D结构,随后的染料大多基于此结构加以修饰改造。这类分子的合成运用大量suzuki耦联的方法,合成难度大,产率低。此类小分子染料的最大发射波长通常在在1000-1100nm,其最大吸收在700-800nm亦不在NIR-II区。为延伸近红外二区成像的荧光波长,提高成像效果。亟需开发新型结构的小分子染料,使其发射波长更长,激发波长亦达到近红外二区。
发明内容
针对现有技术的不足,本发明的目的是提供一种易修饰近红外二区有机小分子染料及其合成方法和应用。具体是指一种具有近红外二区荧光及吸收的多甲川有机小分子染料及其合成方法,以及由该有机小分子染料制备而成的纳米颗粒及靶向探针在血管及肿瘤成像中的应用。该小分子染料荧光量子产率高,光稳定性好。
为实现上述目的,本发明提供的易修饰近红外二区有机小分子染料,其化学结构式如下:
其中:R选自氯或者氢;
n=1时X为硫;
n=2时X为氧。
本发明还提供一种有机小分子荧光染料的制备方法,具体步骤如下:
(1)1-(4-羟基苯基)-3-苯基-2-烯-1-酮(化合物1)的合成:
取4-羟基苯乙酮溶于甲醇溶液中,冰水浴条件下加入50%氢氧化钾水溶液,搅拌混匀。另取苯甲醛溶于甲醇中,置于恒压滴液漏斗中滴加至上述反应液中。然后室温搅拌过夜。旋蒸除去甲醇溶剂,向剩余溶液中滴加3M盐酸溶液至pH=7,由大量黄色固体析出。过滤取滤渣,甲醇重结晶得淡黄色结晶,为1-(4-羟基苯基)-3-苯基-2-烯-1-酮。其中4-羟基苯乙酮、苯甲醛与氢氧化钾的投料摩尔比为1:1:5~1:1.5:10;
(2)3-苯基-1-(4–(丙基-2-炔-1-氧基)苯基)丙基-2-烯-1-酮(化合物2)的合成:
将3-苯基-1-(4–(丙基-2-炔-1-氧基)苯基)丙基-2-烯-1-酮,3-溴丙炔与碳酸钾溶于丙酮,加热回流反应4h。冷却至室温,过滤除去碳酸钾固体。滤液旋蒸除去溶剂,得粗品,甲醇重结晶得白色固体。3-苯基-1-(4–(丙基-2-炔-1-氧基)苯基)丙基-2-烯-1-酮、3-溴丙炔与碳酸钾的投料摩尔比为1:1:3~1:2:6;
(3)2-(3-氧代-1-苯基-3-(4-(丙基-2-炔-1-氧基)苯基)丙基)环己酮-1-酮(化合物3b)的合成:
取环己酮和四氢吡咯溶于苯中于25mL圆底烧瓶,上接Dean-Stark分水器,回流反应4h。旋蒸除去溶剂,残渣溶解于1,4-二氧六环中,加入化合物2,回流反应2h。将反应冷却至室温,加水30mL,乙酸乙酯萃取。合并有机相,无水硫酸钠干燥。旋干过柱得白色固体。环己酮、四氢吡咯与化合物2的投料摩尔比为1.2:1.2:1~2:2:1;
(4)4-苯基-2-(4–(丙基-2-炔-1-氧基)苯基)-5,6,7,8-四氢苯并[b]吡喃四氟硼酸盐(化合物4b)的合成:
将化合物3b溶于4mL乙酸酐中,加入三氟化硼乙醚,加热回流反应3h。冷却至室温,加入少量水淬灭反应至无气泡产生,再加入大量乙醚析出沉淀。过滤,乙醚洗涤,取滤渣,干燥,得黄色粉末化合物4b。化合物3b与三氟化硼乙醚的投料摩尔比为1:1~1:3;
(5)3-(苯基氨基)烯丙基苯胺盐酸盐(化合物5a)的合成:
将1,1,3,3-四甲氧基丙烷与苯胺溶于乙醇中。零度冰水浴下滴加2mL浓盐酸,搅拌15min再转至室温搅拌反应1h。旋转蒸发除去溶剂,浓缩至10mL,倒入100mL水中,大量黄色固体析出,过滤,水洗,真空干燥,得黄色固体3-(苯基氨基)烯丙基苯胺盐酸盐。产率53%。1,1,3,3-四甲氧基丙烷与苯胺的投料摩尔比为1:2.2~1:3;
(6)化合物6H6的合成:
化合物4b,化合物5a和乙酸钠溶于乙酸酐中,70度反应2h。冷却至室温,将反应液倒入乙醚(80mL)中。析出固体,过滤,乙醚洗涤得粗品。HPLC纯化(乙腈/水;70/30;v/v)得深绿色固体。化合物4b、化合物5a与乙酸钠的投料摩尔比为2:1:2~2.5:1:2.5;
(7)2-氯-3-(苯基氨基)烯丙基苯胺盐酸盐(化合物5b)的合成:
糠氯酸溶于乙醇中。苯胺溶于乙醇中,通过恒压滴液漏斗滴入上述溶液中,室温下搅拌反应5h。旋蒸浓缩反应液倒入醚中,析出大量金色固体,过滤,冰乙醇洗涤,收集滤渣,真空干燥得金色固体化合物5b。糠氯酸与苯胺的投料摩尔比为1:2.2~1:3;
(8)化合物6L6的合成:
化合物4b,化合物5b和乙酸钠(0.02mmol,1.6mg)溶于乙酸酐中,70度反应2h。冷却至室温,将反应液倒入乙醚中。析出固体,过滤,乙醚洗涤得粗品。HPLC纯化(乙腈/水;70/30;v/v)得深绿色固体。化合物4b、化合物5b与乙酸钠的投料摩尔比为2:1:2~2.5:1:2.5;
(9)2-(3-氧代-1-苯基-3-(4-(丙基-2-炔-1-氧基)苯基)丙基)环戊酮-1-酮(化合物3a)的合成:
取环戊酮和四氢吡咯溶于苯中于25mL圆底烧瓶,上接Dean-Stark分水器,回流反应4h。旋蒸除去溶剂,残渣溶解于1,4-二氧六环中,加入化合物2回流反应2h。将反应冷却至室温,加水60mL,乙酸乙酯萃取。合并有机相,无水硫酸钠干燥。旋干过柱得化合物3a,为无色油状液体。环戊酮、四氢吡咯与化合物2的投料摩尔比为1.2:1.2:1~2:2:1;
(10)4-苯基-2-(4–(丙基-2-炔-1-氧基)苯基)-6,7-二氢-5H-环戊[b]噻喃四氟硼酸盐(化合物4a)的合成:
将化合物3a溶于10mL乙醚中,加入硫代乙酸,搅拌至完全溶解,再加入三氟化硼乙醚,加热回流反应6h。冷却至室温,加入少量水淬灭反应至无气泡产生,再加入大量乙醚析出沉淀。过滤,乙醚洗涤,取滤渣,干燥,得黄色粉末4a。化合物3a、硫代乙酸与三氟化硼乙醚的投料摩尔比为1:2:3~1:3:6;
(11)化合物5H5的合成:
化合物4a,化合物5a和乙酸钠溶于乙酸酐中,70度反应2h。冷却至室温,将反应液倒入乙醚中。析出固体,过滤,乙醚洗涤得粗品。HPLC纯化(乙腈/水;70/30;v/v)得色固体。化合物4b、化合物5b与乙酸钠的投料摩尔比为2:1:2~2.5:1:2.5;
(12)化合物5L5的合成:
化合物4a,化合物5b和乙酸钠溶于乙酸酐中,70度反应2h。冷却至室温,将反应液倒入乙醚中。析出固体,过滤,乙醚洗涤得粗品。HPLC纯化(乙腈/水;70/30;v/v)得深绿色固体。化合物4a、化合物5b与乙酸钠的投料摩尔比为2:1:2~2.5:1:2.5;
本发明还提供一种易修饰近红外二区有机小分子染料在活体血管造影剂中的应用,将该有机小分子染料制备成纳米颗粒后用于活体血池成像应用,所述有机小分子染料制备成纳米颗粒的方法是:
将DSPE-mPEG2K溶于一级水中配置成浓度为1.1mg/mL的溶液冰水浴保温备用。另取小分子染料溶于四氢呋喃中,在超声条件下滴加至上步溶液中,并保持超声2min。然后约50度温水浴下氮气流吹干有机溶剂。将溶液过0.22微米滤膜,再使用30K Millipore超滤离心管,10000r/min离心10min,再水洗三次,浓缩制得。
将该有机纳米颗粒作为血池成像探针,应用于小鼠腹部,背部,脑部及肿瘤四周的血管成像。该类有机小分子染料的纳米颗粒直径60nm,最大吸收1069nm,最大发射1125nm。
本发明还提供一种近红外二区有机小分子染料在肿瘤成像中的应用,将该有机小分子染料使用靶向多肽修饰制备成靶向肿瘤的分子影像探针,应用于靶向整合素的肿瘤成像,所述有机小分子染料制备成靶向探针的方法是:
将有机小分子染料,靶向多肽,三[(1-苄基-1H-1,2,3-三唑-4-基)甲基]胺,抗坏血酸钠和硫酸铜溶解于DMF中,氮气保护下室温搅拌1h。反应完全后,加入1mL乙醚析出沉淀,弃掉溶液,将沉淀重新溶解,高效液相色谱纯化。使用有机小分子染料制备的靶向探针分子量小于5KDa,激发光波长为808nm和1064nm。荧光检测波长范围为1000-1700nm和1300–1400nm。
本发明的优点在于:本发明采用一种杂原子取代的多甲川化合物同时具有近红外二区的吸收和发射,可作为新一代的近红外二区染料,此类染料的合成较为简单,原料方便易得,但是其溶解性差,化学修饰难度大。本发明的类近红外二区荧光染料属于杂原子取代多甲川类有机小分子,将该小分子染料使用两亲聚乙二醇包载成纳米颗粒,实现1064nm激发的NIR-IIa血池成像。又将该类小分子染料通过点击化学使用靶向整合素的多肽c(RGD)fk修饰,实现在近红外二区激发的近红外IIa区肿瘤成像。解决其修饰问题增加其生物相容性将使这类染料具有极大的应用前景。
本发明近红外二区荧光染料属于多甲川吡喃或多甲川噻喃盐类有机小分子,由多甲川苯胺盐与吡喃或噻喃盐通过缩合反应制成。合成原料易得,成本低廉,制备过程简单,产率高,可大量合成。并通过改变分子内多甲川链及杂原子种类,达到调节荧光发射光谱的目的。此类小分子染料的最大发射波长范围1000-1200nm,荧光量子产率高,光稳定性好,非常适用于活体成像。该类小分子染料可通过点击化学与具有特定功能的基团连接,实现多种生物成像应用。其近红外二区荧光活体成像背景噪音低,荧光信号强,信噪比高。
附图说明
图1为实施例1制备的近红外二区小分子染料5H5的核磁氢谱。
图2为实施例1制备的近红外二区小分子染料5H5的吸收(实线)和发射(虚线)光谱。
图3为实施例2制备的近红外二区小分子染料5L5的核磁氢谱。
图4为实施例2制备的近红外二区小分子染料5L5的吸收(实线)和发射(虚线)光谱。
图5为实施例3制备的近红外二区小分子染料6H6的核磁氢谱。
图6为实施例3制备的近红外二区小分子染料6H6的吸收(实线)和发射(虚线)光谱。
图7为实施例4制备的近红外二区小分子染料6L6的核磁氢谱。
图8为实施例4制备的近红外二区小分子染料6L6的吸收(实线)和发射(虚线)光谱。
图9为实施例5所示纳米颗粒的DLS粒径。
图10为实施例6所示的靶向探针5H5-PEG8-cRGDfk的Maldi-tof质谱图。
图11为应用例中小鼠腹部近红外二区血管显像。
图12为应用例中近红外二区小鼠肿瘤新生血管成像。
图13为应用例中近红外二区小鼠肿瘤成像。
具体实施方式
下面结合具体实施例对本发明作进一步说明,但本发明并不限于以下实施例。
实施例1
近红外二区小分子染料5H5的合成路线如下:
1)在500mL圆底烧瓶中,取对羟基苯乙酮(100mmol,13.6g)溶于200mL甲醇中,0℃冰水浴条件下加入氢氧化钾溶液(50%W/W,70mL),搅拌混匀使其充分溶解。另取苯甲醛(100mmol,10.6g)溶于30mL甲醇中,置于恒压滴液漏斗中滴加至上述反应液中。0℃搅拌1h,然后转至室温搅拌反应过夜。停止反应,使用旋转蒸发仪除去甲醇,向剩余溶液中滴加3M盐酸溶液至pH=7,由大量黄色固体析出。过滤取滤渣,甲醇重结晶得18.8g淡黄色结晶,为1-(4-羟基苯基)-3-苯基-2-烯-1-酮(化合物1)。产率为84%。
2)将化合物1(20mmol,4.48g),80%3-溴丙炔的甲苯溶液(30mmol,3.34mL)与碳酸钾(60mmol,4.15g)加入40mL丙酮中,60℃加热回流反应5h。冷却至室温,过滤除去碳酸钾固体。滤液使用旋蒸除去溶剂,得粗品,。醋瓶用甲醇重结晶得白色固体4.85g,为3-苯基-1-(4–(丙基-2-炔-1-氧基)苯基)丙基-2-烯-1-酮(化合物2)。产率为92%。
3)取环戊酮(20mmol,1.7mL)和四氢吡咯(20mmol,1.65mL)溶于20mL苯中于一25mL圆底烧瓶,上接Dean-Stark分水器,80℃回流反应4h。停止反应,冷却至室温,旋蒸除去溶剂,残渣溶解于1,4-二氧六环(10mL)中,加入化合物2(10mmol,2.62g),120℃回流反应2h。将反应冷却至室温,加水60mL,乙酸乙酯萃取(3x20mL)。合并有机相,无水硫酸钠干燥。旋干过柱(200-300目硅胶柱,正己烷/乙酸乙酯,5/1,v/v)。得2.2g2-(3-氧代-1-苯基-3-(4-(丙基-2-炔-1-氧基)苯基)丙基)环戊酮-1-酮(化合物3a),为无色油状液体。产率为64%。
4)将化合物3a(5.8mmol,2.0g)溶于10mL乙醚中,加入硫代乙酸(12.7mmol,0.9mL),室温搅拌至完全溶解,再加入三氟化硼乙醚(34.7mmol,4.4mL),45℃加热回流反应6h。停止反应,冷却至室温,加入少量水(约1mL)淬灭反应至无气泡产生,再加入大量乙醚(100mL),析出沉淀。过滤,乙醚洗涤,取滤渣,干燥,得黄色粉末1.69g,为4-苯基-2-(4–(丙基-2-炔-1-氧基)苯基)-6,7-二氢-5H-环戊[b]噻喃四氟硼酸盐(化合物4a)。产率69%。
5)将1,1,3,3-四甲氧基丙烷(10mmol,1.64g)与苯胺(22mmol,2mL)溶于25mL乙醇中。零度冰水浴下滴加2mL浓盐酸,搅拌15min再转至室温搅拌反应1h。旋转蒸发除去溶剂,浓缩至10mL,倒入100mL水中,大量黄色固体析出,过滤,水洗,真空干燥,得1.37g3-(苯基氨基)烯丙基苯胺盐酸盐(化合物5a),为黄色固体。产率53%。
6)化合物4a(0.2mmol,86mg),化合物5a(0.1mmol,25.9mg)和乙酸钠(0.2mmol,16.4mg)溶于10mL乙酸酐中,70℃加热反应2h。停止反应,冷却至室温,将反应液倒入乙醚(100mL)中。析出固体,过滤,乙醚洗涤得粗品。HPLC纯化(乙腈/水;70/30;v/v)得34mg红褐色固体5H5。产率42%。
实施例1所示的小分子染料5H5的结构检测结果如下:
1HNMR(400MHz,Acetonitrile-d3)δ7.29(d,J=8.6Hz,4H),7.20(2H),7.13(6H),7.07(2H),7.02(1H),7.00(2H),6.70(d,J=8.6Hz,4H),4.43(d,J=2.2Hz,4H),2.68(t,J=6.8Hz,4H),2.53(t,J=2.2Hz,2H),2.50(t,J=6.8Hz,4H).
MS(MALDI-TOF)C49H37O2S2 +:m/z721.42.
实施例1所示的小分子染料5H5的核磁氢谱如图1所示。
实施例1所示的小分子染料5H5的吸收发射光谱如图2所示。
实施例2
近红外二区小分子染料5L5的合成路线如下:
1)在一100mL圆底烧瓶中,加入糠氯酸(10mmol,1.68g)溶于10mL乙醇中。苯胺(22mmol,2mL)溶于10mL乙醇中,0.5h内通过恒压滴液漏斗滴入上述溶液中,室温下搅拌反应5h。旋蒸浓缩反应液至5mL,再将反应液倒入100mL乙醚中,析出大量金色固体,过滤,10mL冰乙醇洗涤两次,收集滤渣,真空干燥得1.6g金色固体,为化合物5b。产率62%。
2)化合物4a(0.02mmol,8.6mg),化合物5b(0.01mmol,2.9mg)和乙酸钠(0.02mmol,1.6mg)溶于1mL乙酸酐中,70度反应2h。冷却至室温,将反应液倒入乙醚(20mL)中。析出固体,过滤,乙醚洗涤得粗品。HPLC纯化(乙腈/水;70/30;v/v)得5mg深绿色固体5L5。产率59%。
实施例2所示的小分子染料5L5的结构检测结果如下:
1HNMR(400MHz,Acetonitrile-d3)δ7.60(d,J=8.8Hz,4H),7.49(q,J=5.3Hz,6H),7.44–7.40(m,4H),7.36(s,2H),7.31(s,2H),6.95(d,J=8.8Hz,4H),4.70(d,J=2.2Hz,4H),3.18(d,J=5.9Hz,4H),3.01(d,J=6.8Hz,4H),2.89(t,J=2.2Hz,2H);13CNMR(101MHz,CD3CN)δ160.13,160.05,146.96,145.68,145.60,138.03,136.32,135.00,129.79,128.93,128.20,128.17,127.85,127.78,125.86,115.63,77.96,76.61,55.96,30.92,30.28.
MS(MALDI-TOF)m/zC49H36ClO2S2 +:m/z755.10。
实施例2所示的小分子染料5L5的核磁氢谱如图3所示。
实施例2所示的小分子染料5L5的吸收发射光谱如图4所示。
实施例3
近红外二区小分子染料6H6的合成路线如下:
1)取环己酮(10mmol,1.03mL)和四氢吡咯(10mmol,0.84mL)溶于20mL苯中于一25mL圆底烧瓶,上接Dean-Stark分水器,回流反应4h。旋蒸除去溶剂,残渣溶解于1,4-二氧六环中,加入化合物2(5mmol,1.31g),回流反应2h。将反应冷却至室温,加水30mL,乙酸乙酯萃取(3x10mL)。合并有机相,无水硫酸钠干燥。旋干过柱(200-300目硅胶柱,正己烷/乙酸乙酯,5/1,v/v)。得1.23g化合物3b,为白色固体。产率68%。进一步高效液相制备分离纯化出两个异构体,仅用于核磁表征。
2)将化合物3b(2mmol,0.36g)溶于4mL乙酸酐中,加入三氟化硼乙醚(2mmol,0.25mL),加热回流反应4h。冷却至室温,加入少量水淬灭反应至无气泡产生,再加入大量乙醚(50mL),析出沉淀。过滤,乙醚洗涤,取滤渣,干燥,得黄色粉末192mg,为化合物4b。产率43%。
3)化合物4b(0.1mmol,42.8mg),化合物5a(0.05mmol,13.0mg)和乙酸钠(0.1mmol,8.2mg)溶于5mL乙酸酐中,70度反应2h。冷却至室温,将反应液倒入乙醚(80mL)中。析出固体,过滤,乙醚洗涤得粗品。HPLC纯化(乙腈/水;70/30;v/v)得31mg深绿色固体。产率77%。
实施例3所示的小分子染料5L5的结构检测结果如下:
1HNMR(400MHz,Acetonitrile-d3)δ7.98(d,J=9.0Hz,4H),7.94(d,J=13.2Hz,2H),7.57–7.51(m,6H),7.49–7.44(m,4H),7.10(d,J=9.0Hz,4H),7.06(s,2H),6.60(t,J=13.1Hz,1H),4.83(d,J=2.4Hz,4H),2.90(t,J=2.4Hz,2H),2.64(dt,J=16.4,5.9Hz,8H),1.78–1.71(m,4H);13CNMR(101MHz,CD3CN)δ162.77,160.47,158.96,150.04,144.56,144.53,136.42,133.01,129.86,128.76,128.56,128.11,127.15,123.84,115.46,109.38,78.00,76.73,56.12,27.02,24.65,20.35.
MS(MALDI-TOF)m/zC51H41O4 +:717.20。
实施例3所示的小分子染料6H6的核磁氢谱如图5所示。
实施例3所示的小分子染料6H6的吸收发射光谱如图6所示。
实施例4
近红外二区小分子染料6L6的合成路线如下:
化合物4b(0.02mmol,8.6mg),化合物5b(0.01mmol,2.9mg)和乙酸钠(0.02mmol,1.6mg)溶于1mL乙酸酐中,70度反应2h。冷却至室温,将反应液倒入乙醚(20mL)中。析出固体,过滤,乙醚洗涤得粗品。HPLC纯化(乙腈/水;70/30;v/v)得3mg深绿色固体。产率36%。
实施例4所示的小分子染料6L6的结构检测结果如下:
1HNMR(400MHz,Acetonitrile-d3)δ8.07(d,J=8.8Hz,4H),7.76(s,2H),7.60–7.48(m,10H),7.19(s,2H),7.10(d,J=8.9Hz,4H),4.83(d,J=2.2Hz,4H),2.84(t,J=2.3Hz,2H),2.84–2.76(m,4H),2.70–2.61(m,4H),1.80–1.71(m,4H).
实施例4所示的小分子染料6L6的核磁氢谱如图7所示。
实施例4所示的小分子染料6L6的吸收发射光谱如图8所示。
实施例5:
小分子荧光染料5H5使用DSPE-mPEG2K包载形成纳米颗粒5H5NPs的制备方法,具体步骤如下:
将5.5mgDSPE-mPEG2K溶于一级水中配置成浓度为1.1mg/mL的溶液冰水浴保温备用。另取0.5mg 5H5溶于0.5mL四氢呋喃中,在超声条件下滴加至上步溶液中,并保持超声2min。然后约50度温水浴下氮气流吹干有机溶剂。将溶液过0.22微米滤膜,再使用30KMillipore超滤离心管,10000r/min离心10min,再水洗三次,浓缩至0.5mL。
实施例5所示纳米颗粒的DLS粒径如图9所示。
实施例6:
有机小分子染料5H5使用靶向多肽c(RGD)fk修饰成靶向探针5H5-PEG8-cRGDfk的制备方法,合成路线如下:
1)将c(RGD)fk(0.01mmol,6.0mg)溶于1mLDMSO中,加入DIPEA(0.2mmol,30μL)搅拌混匀,再加入N3-PEG8-NHS(0.012mmol,6.8mg)室温搅拌4h。加水稀释反应,以乙腈和水作为流动相,高效液相色谱纯化得7.5mg白色固体。产率71%。
2)取5H5(0.001mmol,0.81mg),N3-PEG8-cRGDfk(0.002mmol,1.05mg),TBTA(0.0002mmol,0.10mg),抗坏血酸钠(0.001mmol,0.2mg)和CuSO4·5H2O(0.001mmol,0.25mg)溶解于0.2mLDMF中,氮气保护下室温搅拌1h。反应完全后,加入1mL乙醚析出沉淀,弃掉溶液,将沉淀重新溶解,高效液相色谱纯化得1.3mg棕色固体。产率46%。
实施例6所示的靶向探针5H5-PEG8-cRGDfk的结构检测结果如下:
MS(MALDI-TOF)m/zC141H189N24O34S2 +:2826.1。
实施例6所示的靶向探针5H5-PEG8-cRGDfk的质谱图如图10所示。
应用例:
有机小分子纳米颗粒5H5NPs对小鼠腹部血管成像。具体步骤如下:
使用异氟烷将小鼠麻醉,通过尾静脉注射150微克5H5NPs,使用功率密度0.1W/cm2的1064nm激光器照射小鼠腹部。相机镜头前加1320nm长通滤光片。对小鼠腹部采集荧光图像(参见图11)。
有机小分子纳米颗粒5H5NPs对荷瘤小鼠肿瘤周围血管成像。具体步骤如下:
使用异氟烷将小鼠麻醉,通过尾静脉注射150微克5H5NPs,使用功率密度0.1W/cm2的1064nm激光器照射小鼠腹部。相机镜头前加1320nm长通滤光片。对荷瘤小鼠肿瘤周围采集荧光图像(参见图12)。
有机小分子靶向探针5H5-PEG8-cRGDfk对荷瘤小鼠肿瘤成像。具体步骤如下:
使用异氟烷将小鼠麻醉,通过尾静脉注射150微克5H5NPs,使用功率密度0.1W/cm2的1064nm激光器照射小鼠腹部。相机镜头前加1320nm长通滤光片。对荷瘤小鼠采集荧光图像(参见图13)。
Claims (4)
1.一种易修饰近红外二区有机小分子染料,其特征在于:它具有如下结构式:
其中:R选自氯或者氢;
n=1时,X为硫;
n=2时,X为氧。
2.一种制备如权利要求1所述易修饰近红外二区有机小分子染料的制备方法,其特征在于:它的具体步骤如下:
(1)化合物1的合成,所述化合物1为1-(4-羟基苯基)-3-苯基-2-烯-1-酮:
取4-羟基苯乙酮溶于甲醇溶液中,冰水浴条件下加入50%氢氧化钾水溶液,搅拌混匀;另取苯甲醛溶于甲醇中,置于恒压滴液漏斗中滴加至上述反应液中;然后室温搅拌过夜,旋蒸除去甲醇溶剂,向剩余溶液中滴加3M盐酸溶液至pH=7,由大量黄色固体析出;过滤取滤渣,甲醇重结晶得淡黄色结晶,为1-(4-羟基苯基)-3-苯基-2-烯-1-酮;其中4-羟基苯乙酮、苯甲醛与氢氧化钾的投料摩尔比为1:1:5~1:1.5:10;
(2)化合物2的合成,所述化合物2为3-苯基-1-(4–(丙基-2-炔-1-氧基)苯基)丙基-2-烯-1-酮:
将3-苯基-1-(4–(丙基-2-炔-1-氧基)苯基)丙基-2-烯-1-酮,3-溴丙炔与碳酸钾溶于丙酮,加热回流反应4h;冷却至室温,过滤除去碳酸钾固体;滤液旋蒸除去溶剂,得粗品,甲醇重结晶得白色固体;3-苯基-1-(4–(丙基-2-炔-1-氧基)苯基)丙基-2-烯-1-酮、3-溴丙炔与碳酸钾的投料摩尔比为1:1:3~1:2:6;
(3)化合物3b的合成,所述化合物3b为2-(3-氧代-1-苯基-3-(4-(丙基-2-炔-1-氧基)苯基)丙基)环己酮-1-酮:
取环己酮和四氢吡咯溶于苯中于25mL圆底烧瓶,上接Dean-Stark分水器,回流反应4h;旋蒸除去溶剂,残渣溶解于1,4-二氧六环中,加入化合物2,回流反应2h;将反应冷却至室温,加水30mL,乙酸乙酯萃取;合并有机相,无水硫酸钠干燥,旋干过柱得白色固体;环己酮、四氢吡咯与化合物2的投料摩尔比为1.2:1.2:1~2:2:1;
(4)化合物4b的合成,所述化合物4b为4-苯基-2-(4–(丙基-2-炔-1-氧基)苯基)-5,6,7,8-四氢苯并[b]吡喃四氟硼酸盐:
将化合物3b溶于4mL乙酸酐中,加入三氟化硼乙醚,加热回流反应3h;冷却至室温,加入少量水淬灭反应至无气泡产生,再加入大量乙醚析出沉淀;过滤,乙醚洗涤,取滤渣,干燥,得黄色粉末化合物4b;化合物3b与三氟化硼乙醚的投料摩尔比为1:1~1:3;
(5)化合物5a的合成,所述化合物5a为3-(苯基氨基)烯丙基苯胺盐酸盐:
将1,1,3,3-四甲氧基丙烷与苯胺溶于乙醇中;零度冰水浴下滴加2mL浓盐酸,搅拌15min再转至室温搅拌反应1h;旋转蒸发除去溶剂,浓缩至10mL,倒入100mL水中,大量黄色固体析出,过滤,水洗,真空干燥,得黄色固体3-(苯基氨基)烯丙基苯胺盐酸盐,产率53%;1,1,3,3-四甲氧基丙烷与苯胺的投料摩尔比为1:2.2~1:3;
(6)化合物6H6的合成:
化合物4b,化合物5a和乙酸钠溶于乙酸酐中,70度反应2h;冷却至室温,将反应液倒入乙醚中;析出固体,过滤,乙醚洗涤得粗品,HPLC纯化得深绿色固体;化合物4b、化合物5a与乙酸钠的投料摩尔比为2:1:2~2.5:1:2.5;
(7)化合物5b的合成,所述化合物5b为2-氯-3-(苯基氨基)烯丙基苯胺盐酸盐:
糠氯酸溶于乙醇中,苯胺溶于乙醇中,通过恒压滴液漏斗滴入上述溶液中,室温下搅拌反应5h;旋蒸浓缩反应液倒入醚中,析出大量金色固体,过滤,冰乙醇洗涤,收集滤渣,真空干燥得金色固体化合物5b;糠氯酸与苯胺的投料摩尔比为1:2.2~1:3;
(8)化合物6L6的合成:
化合物4b,化合物5b和乙酸钠溶于乙酸酐中,70度反应2h;冷却至室温,将反应液倒入乙醚中;析出固体,过滤,乙醚洗涤得粗品,HPLC纯化得深绿色固体;化合物4b、化合物5b与乙酸钠的投料摩尔比为2:1:2~2.5:1:2.5;
(9)化合物3a的合成,所述化合物3a为2-(3-氧代-1-苯基-3-(4-(丙基-2-炔-1-氧基)苯基)丙基)环戊酮-1-酮:
取环戊酮和四氢吡咯溶于苯中于25mL圆底烧瓶,上接Dean-Stark分水器,回流反应4h;旋蒸除去溶剂,残渣溶解于1,4-二氧六环中,加入化合物2回流反应2h;将反应冷却至室温,加水60mL,乙酸乙酯萃取;合并有机相,无水硫酸钠干燥;旋干过柱得化合物3a,为无色油状液体;环戊酮、四氢吡咯与化合物2的投料摩尔比为1.2:1.2:1~2:2:1;
(10)化合物4a的合成,所述化合物4a为4-苯基-2-(4–(丙基-2-炔-1-氧基)苯基)-6,7-二氢-5H-环戊[b]噻喃四氟硼酸盐:
将化合物3a溶于10mL乙醚中,加入硫代乙酸,搅拌至完全溶解,再加入三氟化硼乙醚,加热回流反应6h;冷却至室温,加入少量水淬灭反应至无气泡产生,再加入大量乙醚析出沉淀;过滤,乙醚洗涤,取滤渣,干燥,得黄色粉末4a;化合物3a、硫代乙酸与三氟化硼乙醚的投料摩尔比为1:2:3~1:3:6;
(11)化合物5H5的合成:
化合物4a,化合物5a和乙酸钠溶于乙酸酐中,70度反应2h;冷却至室温,将反应液倒入乙醚中;析出固体,过滤,乙醚洗涤得粗品;HPLC纯化得深绿色固体;化合物4b、化合物5b与乙酸钠的投料摩尔比为2:1:2~2.5:1:2.5;
(12)化合物5L5的合成:
化合物4a,化合物5b和乙酸钠溶于乙酸酐中,70度反应2h;冷却至室温,将反应液倒入乙醚中;析出固体,过滤,乙醚洗涤得粗品;HPLC纯化得深绿色固体;化合物4a、化合物5b与乙酸钠的投料摩尔比为2:1:2~2.5:1:2.5。
3.如权利要求1所述的易修饰近红外二区有机小分子染料在活血管造影剂中的应用,其特征在于:将该有机小分子染料制备成纳米颗粒后用于活体血池成像应用,所述有机小分子染料制备成纳米颗粒的方法是:将DSPE-mPEG2K溶于一级水中配置成浓度为1.1mg/mL的溶液冰水浴保温备用;另取小分子染料溶于四氢呋喃中,在超声条件下滴加至上步溶液中,并保持超声2min;然后约50度温水浴下氮气流吹干有机溶剂;将溶液过0.22微米滤膜,再使用30K Millipore超滤离心管,10000r/min离心10min,再水洗三次,浓缩制得;所述纳米颗粒的直径范围为20—100nm;将该有机纳米颗粒作为血池成像探针,应用于小鼠腹部,背部,脑部及肿瘤四周的血管成像。
4.如权利要求1所述的易修饰近红外二区有机小分子染料在肿瘤成像中的应用,其特征在于:将该有机小分子染料使用靶向多肽修饰制备成靶向肿瘤的分子影像探针,通过Click反应制成靶向多肽修饰的小分子探针,将该探针应用于靶向整合素的肿瘤成像,所述有机小分子染料制备成靶向探针的方法是:将有机小分子染料,靶向多肽,三[(1-苄基-1H-1,2,3-三唑-4-基)甲基]胺,抗坏血酸钠和硫酸铜溶解于DMF中,氮气保护下室温搅拌1h;反应完全后,加入1mL乙醚析出沉淀,弃掉溶液,将沉淀重新溶解,高效液相色谱纯化;使用有机小分子染料制备的靶向探针分子量小于5KDa,激发光波长为808nm和1064nm;荧光检测波长范围为1000-1700nm和1300–1400nm。
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