CN116144192A - 一类半花菁近红外二区染料及其制备方法与用途 - Google Patents
一类半花菁近红外二区染料及其制备方法与用途 Download PDFInfo
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Abstract
本发明属于生物医学材料技术领域,具体涉及一类半花菁近红外二区染料及其制备方法与用途。所述染料在骨架上引入苯并吲哚、噻吩和苯并氧杂蒽基延伸共轭,显示出位于近红外二区的荧光发射,荧光最大发射峰为750~1200nm,并且显著提高了穿透深度,降低了组织自发荧光的影响。摄入机体进行活体荧光成像时,受自发荧光和饮食代谢影响较少,肠道成像灵敏度较高;并且注射后表现出良好的生物相容性,无明显毒副作用,为疾病的早期诊断、术中导航以及药物的研发提供了一种更为直观、有效的方法,具有良好的应用前景。
Description
技术领域
本发明属于生物医学材料技术领域。更具体地,涉及一类半花菁近红外二区染料及其制备方法与用途。
背景技术
光学成像在分子水平上为可视化和量化多种生物分子在机体中代谢过程提供了一种实时和无创的方法,在生物医学研究中发挥着重要作用。目前,利用近红外一区(650~900nm)荧光染料的生物成像和检测得到了长足的发展,但这种技术仍存在一定的缺陷,如在近红外一区范围内,组织存在竞争性自发荧光和光衰减,影响了成像深度和灵敏度。
七甲川花菁染料是临床手术中常用的生物成像荧光团之一,例如ICG(VahrmeijerA L,Hutteman M,Van Der Vorst J R,et al.Image-guided cancer surgery usingnear-infrared fluorescence[J].Nature reviews Clinical oncology,2013,10(9):507-518.)、IRDye800CW(Nishio N,van den Berg N S,van Keulen S,et al.Opticalmolecular imaging can differentiate metastatic from benign lymph nodes inhead and neck cancer[J].Nature communications,2019,10(1):5044.)和ZW800-1(deValk KS,Handgraaf H J,Deken M M,et al.A zwitterionic near-infraredfluorophore for real-time ureter identification during laparoscopicabdominopelvic surgery[J].Nature communications,2019,10(1):3118.)分别在肝癌、神经母细胞瘤和术中输尿管实时识别中得到了应用。但是在实际应用中发现,大多数花菁染料存在从可见光(如Cy3)到近红外范围(如Cy5和Cy7)的发射跨度相对较短、组织穿透能力弱、信号-背景比率低等问题;并且这些半花菁染料的发射波长集中在近红外一区,造成成像深度有限和灵敏度低。近红外二区荧光(950~1700nm)依赖于更弱的光与组织之间的相互作用,极大地减少了组织的光子散射和自发荧光,具有更高的信号-背景比率、灵敏度和分辨率。因此,亟需开发具有更长发射波长的新型近红外二区染料用于生物医学成像。
发明内容
本发明要解决的技术问题是克服现有近红外一区荧光染料成像深度有限和灵敏度低的缺陷和不足,提供一类具有近红外二区荧光发射波长和高亮度、高穿透深度的半花菁近红外二区染料。
本发明的目的是提供所述半花菁近红外二区染料的制备方法。
本发明另一目的是提供所述半花菁近红外二区染料的用途。
本发明还有一个目的是提供一种半花菁近红外二区染料纳米颗粒。
本发明上述目的通过以下技术方案实现:
一类半花菁近红外二区染料,所述半花菁近红外二区染料具有以下任一结构:
其中,n为0~18的整数。
优选地,所述n为0~10的整数。更优选地,所述n为0~5的整数。
优选地,所述半花菁近红外二区染料具有以下任一结构:
另外的,本发明还提供了所述半花菁近红外二区染料的制备方法,具体包括以下步骤:
S1、化合物4与化合物5发生缩合反应(优选温度为30~120℃,时间为6~24h),即得到半花菁近红外二区染料式(Ⅰ)化合物;
或S2、化合物3与化合物6发生缩合反应(优选温度为0~120℃,时间为8~24h),即得到半花菁近红外二区染料式(Ⅱ)化合物;
或S3、化合物4与化合物14发生缩合反应(优选温度为0~120℃,时间为8~24h),即得到半花菁近红外二区染料式(Ⅲ)化合物;
或S4、化合物3与化合物14发生缩合反应(优选温度为0~120℃,时间为8~24h),即得到半花菁近红外二区染料式(Ⅳ)化合物;
或S5、化合物3与化合物17发生缩合反应(优选温度为0~120℃,时间为8~24h),即得到半花菁近红外二区染料式(Ⅴ)化合物;
其中所涉及化合物结构如下:
进一步地,所述化合物14通过如下步骤制备得到:
SI、化合物9发生取代反应(优选在碱存在,0~30℃条件下取代反应4~12h,所述碱选自氢氧化钠、氢化钠或碳酸钾中的一种或多种)得到化合物10,化合物10发生取代反应(优选在0~30℃条件下取代反应6~12h)得到化合物11,化合物11发生缩合反应(优选在-20~0℃条件下缩合反应6~12h)得到化合物12,化合物12发生还原反应(优选在酸存在,10~30℃条件下还原反应3~12h,所述酸选自盐酸、硫酸中的一种或两种)得到化合物13,备用;
SII、化合物7发生取代反应(优选在0~30℃条件下取代反应6~12h)得到化合物8,备用;
SIII、化合物13与化合物8发生成环反应(优选在缩合剂存在,10~30℃条件下成环反应4~12h,所述缩合剂选自醋酸钠,碳酸钾、碳酸铯和醋酸钾中的一种或多种)得到化合物14;
其中所涉及化合物结构如下:
更进一步地,所述化合物3通过如下步骤制备得到:
化合物1与R-X发生取代反应(优选在无机碱存在,30~120℃条件下取代反应6~24h,所述无机碱选自氢氧化钠、氢氧化钾、氢化钠、碳酸钾、碳酸铯、乙酸钠、乙醇钠中的一种或多种)得到化合物2,其中R-X中R为Cn+2的烷基,n的定义与上述一致,X为卤素原子;化合物2发生还原反应(优选在-20~0℃条件下还原反应6~24h)得到化合物3;
其中所涉及化合物结构如下:
进一步地,所述化合物17通过如下步骤制备得到:
化合物14发生还原反应(优选在10~30℃条件下还原反应4~12h)得到化合物15,化合物15发生取代反应(优选在活化剂存在,80~100℃条件下取代反应1~6h,所述活化剂选自三氯化铝、TMSI、硼氢化钠、三苯基磷溴化氢溶液中的一种或多种)得到化合物16,化合物16与2,5-噻吩二甲醛发生缩合反应(优选在缩合剂存在,10~30℃条件下缩合反应4~12h,所述缩合剂选自氢化钠,碳酸钾、碳酸铯中的一种或多种)得到化合物17;
其中所涉及化合物结构如下:
更进一步地,制备过程在有机溶剂存在条件下进行,所述有机溶剂选自甲醇、乙醇、乙腈、二氯甲烷、四氢呋喃、乙酸、乙酸酐、N,N-二甲基甲酰胺、乙醚、DMSO、甲苯中的一种或多种。
进一步地,步骤S1中,所述缩合反应还需要添加有机碱,所述有机碱选自三乙胺、吡啶、DIPEA中的一种或多种。
本发明的半花菁近红外二区染料在骨架上引入苯并吲哚、噻吩和苯并氧杂蒽基,这些分子的引入能够延长扩大π-共轭偶联,显示出位于近红外二区的荧光发射,荧光最大发射峰为750~1200nm,比现有的半花菁荧光团更长,并且显著提高了穿透深度,降低了组织自发荧光的影响。该半花菁近红外二区染料可制备成多种给药制剂(静脉注射、腹腔注射或者喷洒)进行给药。以静脉注射方式为例,本发明将半花菁近红外二区染料经静脉注射入后,进行活体荧光成像时,受自发荧光和饮食代谢影响较少,肠道成像灵敏度较高;同时,注射后表现出良好的生物相容性,无明显毒副作用。
因此,本发明还要求保护所述半花菁近红外二区染料及其药学上可接受的盐、溶剂化物、对映异构体、非对映异构体、互变异构体在制备荧光分子探针中的用途。
优选地,所述药学上可接受的盐为盐酸盐、氢溴酸盐、硝酸盐、甲基硝酸盐、硫酸盐、硫酸氢盐、氨基硫酸盐、磷酸盐、乙酸盐、羟基乙酸盐、苯基乙酸盐、丙酸盐、丁酸盐、异丁酸盐、戊酸盐、马来酸盐、羟基马来酸盐、丙烯酸盐、延胡索酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、水杨酸盐、对氨基水杨酸盐、乙醇酸盐、乳酸盐、庚酸盐、邻苯二甲酸盐、草酸盐、琥珀酸盐、苯甲酸盐、邻乙酰氧基苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟苯酸盐、甲氧基苯甲酸盐、扁桃酸盐、丹宁酸盐、甲酸盐、硬脂酸盐、抗坏血酸盐、棕榈酸盐、油酸盐、丙酮酸盐、双羟奈酸盐、丙二酸盐、月桂酸盐、戊二酸盐、谷氨酸盐、丙酸酯月桂硫酸盐(estolate)、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、对氨基苯磺酸盐、对甲苯磺酸盐(甲苯磺酸盐)和萘-2-磺酸盐等。
具体的,所述荧光分子探针可应用于组织成像、术前诊断、术中导航等领域。
进一步地,所述荧光分子探针的荧光发射波长为700~1200nm。
另外的,本发明还要求保护一种半花菁近红外二区染料纳米颗粒,以所述半花菁近红外二区染料或其药学上可接受的盐、溶剂化物、对映异构体、非对映异构体、互变异构体作为主要成分。
进一步地,所述纳米颗粒为在两亲性DSPE-PEG链存在的情况下,利用纳米共沉淀法将半花菁近红外二区染料或其药学上可接受的盐、溶剂化物、对映异构体、非对映异构体、互变异构体转化为水溶性纳米颗粒。
更进一步地,所述纳米颗粒的粒径为20~200nm。
进一步地利用两亲性聚合物包裹半花菁近红外二区染料可制备成水溶性纳米颗粒,用于活体淋巴结成像,可以呈现出更高的信噪率;在深层组织上通过荧光成像可实时监测荧光信号,实现不同部位肿瘤组织实时检测和肿瘤手术引导以及转移淋巴结可视化识别,可更为精准地指导肿瘤及微小转移灶可视化切除,提高手术疗效和患者预后,有望为人类疾病诊断和治疗中提供一种新的辅助方法。
本发明具有以下有益效果:
本发明提供了一类半花菁近红外二区染料,其在骨架上引入苯并吲哚、噻吩和苯并氧杂蒽基延伸共轭,显示出位于近红外二区的荧光发射,荧光最大发射峰为750~1200nm,并且显著提高了穿透深度,降低了组织自发荧光的影响。摄入机体进行活体荧光成像时,受自发荧光和饮食代谢影响较少,肠道成像灵敏度较高;并且注射后表现出良好的生物相容性,无明显毒副作用,为疾病的早期诊断、术中导航以及药物的研发提供了一种更为直观、有效的方法,具有良好的应用前景。
附图说明
图1为半花菁近红外二区荧光染料紫外吸收光谱图。
图2为半花菁近红外二区荧光染料荧光发射光谱图。
图3为半花菁近红外二区荧光染料在不同厚度的肌肉组织中穿透深度检测的荧光图。
图4为半花菁近红外二区荧光染料在活体小鼠肠道中的成像图。
图5为静脉注射半花菁近红外二区荧光染料后获得粪便样本的荧光信号图。
图6为半花菁近红外二区荧光染料水溶性纳米颗粒的信噪率数据统计图。
图7为半花菁近红外二区荧光染料水溶性纳米颗粒在活体小鼠的淋巴结中荧光成像图。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
实施例1化合物2’的合成
化合物1(640mg,4mmol)、无水碳酸钾(1104mg,8mmol)置于含有DMF(10mL)的烧瓶中,在室温下搅拌15min;加入碘甲烷(1.136g,8mmol),在室温下搅拌反应12h,在真空条件下除去溶剂,所得混合物加入乙醚(100mL)中,过滤,收集固体,并用乙醚洗涤三次,得到化合物2’(529mg,产率76%)。在下一个步骤中使用,无需进一步纯化。
ESI-MS(m/z):计算值:183.21,谱图显示:183.03。
实施例2化合物3’的合成
将化合物2’(300mg,2mmol)和甲基氯化镁(5ml)的混合物置于含有5ml四氢呋喃溶剂的25ml圆底烧瓶中,0℃条件下搅拌反应12h;向反应液中加入水进行淬灭,用二氯甲烷进行萃取,有机相用无水硫酸钠进行干燥后,在减压下蒸发溶剂,用PE/EA=1/1作为洗脱剂通过硅胶柱层析纯化粗产物,得到化合物3’(200mg,产率80%)。
1H NMR(400MHz,Methanol-d4)δ8.88(d,J=7.2Hz,1H),8.74(d,J=8.1Hz,1H),8.40(t,J=7.9Hz,2H),8.18–8.11(m,1H),7.99(dd,J=8.3,7.4Hz,1H),4.83(s,3H),4.29(s,3H).ESI-MS(m/z):计算值:183.25,谱图显示:183.10。
实施例3化合物8的合成
将N,N-二甲基甲酰胺(500mg,8mmol)溶解在20ml二氯甲烷中,加入三溴化磷(PBr3)(850g,3.0mmol),在25℃下搅拌30min后,缓慢滴加环己酮(780mg,8mmol,化合物7)溶液,在25℃下搅拌反应8h,反应结束后用饱和碳酸氢钠溶液中和,真空下浓缩,用水和二氯甲烷进行萃取,有机相干燥后,减压蒸发溶剂,无需进一步纯化,得到淡黄色油状化合物8(820mg,产率80%)。
1H NMR(400MHz,Chloroform-d)δ10.02(s,1H),2.75(td,J=3.8,1.9Hz,2H),2.28(dd,J=5.5,3.1Hz,2H),1.78–1.74(m,2H),1.69(dd,J=5.8,2.0Hz,2H).ESI-MS(m/z):计算值:189.05,谱图显示[m+H]+:190.55。
实施例4化合物10的合成
2,7-二羟基萘(6.4g,40mmol,化合物9)、无水碳酸钾(5.53g,40mmol)置于含有DMF(25mL)的烧瓶中,在室温下搅拌15min,加入碘甲烷(5.64g,40mmol),在室温下搅拌反应12h,除去溶剂,用水(50mL)洗涤,用乙酸乙酯(3×50mL)萃取,有机层用无水硫酸钠干燥并浓缩,粗产物采用硅胶柱层析(洗脱液:PE/EA=30/1~5/1)进行纯化,得到白色固体化合物10(3.62g,产率52%)。
1H NMR(400MHz,Chloroform-d)δ7.66(dd,J=8.7,2.7Hz,2H),7.05(d,J=2.5Hz,1H),7.03–6.97(m,2H),6.95(dd,J=8.8,2.5Hz,1H),3.91(s,3H).ESI-MS(m/z):计算值:175.20,谱图显示:174.99。
实施例5化合物11的合成
化合物10(3.62g,21mmol)和NaH(60%含矿物油,2.48g,62mmol)置于干燥烧瓶中,加入无水THF(40.0mL),在冰浴的氩气气氛下搅拌30min,缓慢地加入(氯甲基)甲基醚(1.7g,21mmol),在室温下搅拌反应12h,在真空条件下缓慢加入无水乙醇(60.0mL)并进行浓缩,加入水(50mL),用乙酸乙酯(3×50mL)提取混合物,真空干燥并浓缩,采用硅胶柱层析(洗脱液:PE/EA=15/1)对粗产物进行纯化,得到微黄色油液化合物11(3.71g,产率81%)。
1H NMR(400MHz,Chloroform-d)δ7.66(t,J=9.3Hz,2H),7.31(d,J=2.5Hz,1H),7.06(dd,J=8.9,2.5Hz,2H),7.01(dd,J=8.9,2.6Hz,1H),5.28(s,2H),3.90(s,3H),3.52(s,3H).ESI-MS(m/z):计算值:219.25,谱图显示:219.09。
实施例6化合物12的合成
化合物11(3.71g,17mmol)放置在含有乙醚(20mL)的干燥烧瓶中,在氩气气氛下缓慢加入正丁基锂(2.5mol/L,在己烷中,5.0mL),在-20℃搅拌30min,慢慢加入无水DMF(10mL),直到颜色由红褐色变为淡黄色,在0℃下搅拌反应过夜;用饱和的氯化铵水溶液淬灭,用乙酸乙酯(3×50ml)萃取,将有机层在减压条件下进行干燥和浓缩,粗产物采用硅胶柱层析(洗脱液:PE/EA=30/1~10/1)进行纯化,得到黄色固体化合物12(1.76g,产率42%)。
ESI-MS(m/z):计算值:247.26,谱图显示:247.12。
实施例7化合物13的合成
化合物12(1.76g,7.14mmol)置于含有2-丙醇(10.0mL)的干燥烧瓶中,缓慢滴加浓缩的盐酸(3.0mL),在室温下搅拌反应3h,加入饱和的碳酸氢钠水溶液(20mL)使反应淬灭,用乙酸乙酯(3×50mL)萃取,有机层用水和饱和的氯化钠水溶液洗涤,用无水硫酸钠干燥,并在真空下浓缩,采用硅胶柱层析(洗脱液:PE/EA=30/1)对粗产物进行纯化,得到黄色固体化合物13(1.15g,产率80%)。
ESI-MS(m/z):计算值:203.21,谱图显示:202.95。
实施例8化合物14的合成
将化合物13(1.15g,5.71mmol),2-溴环己烯-1-甲醛(1.29g,6.85mmol)和碳酸铯(3.72g,11.42mmol)置于含有DMF(20mL)的干燥烧瓶中,在室温下搅拌反应12h,减压浓缩,所得固体溶于水中(50mL),用乙酸乙酯(3×50mL)提取,有机层用无水硫酸钠干燥,过滤和浓缩,采用硅胶柱层析(洗脱液:PE/EA=15/1~5/1)对粗产物进行纯化,得到橙色固体化合物14(1.08g,产率65%)。
1H NMR(400MHz,Chloroform-d)δ10.44(s,1H),7.67(d,J=8.6Hz,1H),7.53(s,1H),7.36(s,1H),7.07–7.01(m,2H),6.80(s,1H),3.92(s,3H),2.62(d,J=6.1Hz,2H),2.48(t,J=6.4Hz,2H),1.76(t,J=6.5Hz,2H).ESI-MS(m/z):计算值:293.33,谱图显示:293.43。
实施例9化合物15的合成
化合物14(292.2mg,1mmol)和硼氢化钠(114mg,3mmol)置于含有无水乙醇(10mL)的干燥烧瓶中,在室温氩气气氛下搅拌反应4h,用饱和氯化铵水溶液淬灭,用二氯甲烷(3×20mL)萃取,有机层用无水硫酸钠干燥,并在减压下浓缩,采用硅胶柱层析(洗脱液:PE/EA=1/1~DCM:MeOH=10/1)进行纯化,得到黄色固体化合物15(213.68mg,产率73%)。
1H NMR(400MHz,Chloroform-d)δ7.55(d,J=8.5Hz,1H),7.26(d,J=2.1Hz,1H),7.07(s,1H),6.99–6.89(m,2H),6.24(s,1H),4.40(d,J=5.9Hz,2H),3.89(s,3H),2.50–2.47(m,2H),2.39(d,J=6.2Hz,2H),1.77(t,J=6.0Hz,2H).ESI-MS(m/z):计算值:295.35,谱图显示:295.23。
实施例10化合物16的合成
化合物15和三苯基膦氢溴酸盐(686mg,2mmol)置于干燥烧瓶中,加入无水乙腈(10mL),在氩气气氛回流下搅拌反应1.5h,用乙酸乙酯(3×50mL)萃取混合物,有机层用水和饱和的氯化钠水溶液洗涤,用无水硫酸钠干燥,并浓缩,得到粗品化合物16,在下一个步骤中使用,无需进一步纯化。
实施例11化合物17的合成
将粗品化合物16(358.4mg,0.58mmol)、NaH(60%矿物油,69.6mg,1.74mmol)和2,5-噻吩二甲醛(97.44mg,0.696mmol)置于干燥的烧瓶中,通过注射器加入无水THF(10mL),在室温氩气气氛下搅拌反应12h;缓慢加入无水乙醇(5.0mL),减压浓缩,所得固体溶于水中(20mL),用乙酸乙酯(3×20mL)提取,有机层用无水硫酸钠干燥,过滤和浓缩,采用硅胶柱层析(洗脱液:PE/EA=5/1)进行纯化,得到红色固体化合物17(144.77mg,产率62%)。
1H NMR(400MHz,Chloroform-d)δ9.83(s,1H),7.78(d,J=15.9Hz,1H),7.64–7.57(m,2H),7.35(s,1H),7.29(s,1H),7.07–6.97(m,3H),6.60(d,J=15.9Hz,1H),6.44(s,1H),3.92(s,3H),2.55(t,J=6.3Hz,2H),2.49(t,J=6.3Hz,2H),1.83(t,J=6.1Hz,2H).ESI-MS(m/z):计算值:401.49,谱图显示:401.17。
实施例12化合物HBC1的合成
将化合物4’(550mg,2mmol)溶解在20ml二氯甲烷中,加入醋酸钠(278.7mg,3.4mmol)和化合物5(600mg,2mmol)在25℃下搅拌反应8h;向反应液中加入水溶解固体,用乙酸乙酯进行萃取,有机相用无水硫酸钠进行干燥后,在减压下蒸发溶剂,并使用DCM:MeOH=15/1作为洗脱剂通过硅胶柱层析纯化粗产物,得到绿色固体HBC1(282mg,产率40%)。
1H NMR(400MHz,Methanol-d4)δ8.47–8.31(m,1H),8.11(d,J=7.9Hz,1H),7.71(s,1H),7.62(s,1H),7.49–7.44(m,1H),7.40(d,J=7.5Hz,1H),7.26(m,2H),7.10(d,J=9.5Hz,1H),7.04–6.91(m,1H),6.75(m,1H),6.59(d,J=7.8Hz,1H),4.22(s,3H),2.88–2.66(m,2H),2.08–1.97(m,2H),1.64–1.54(m,2H),1.28(s,6H).ESI-MS(m/z):计算值:435.56,谱图显示:435.31。
实施例13化合物HBC2的合成
将化合物4’(496.8mg,1.7mmol),化合物14(296.6mg,1.7mmol)和无水乙酸钠(278.7mg,3.4mmol)置于含有无水DCM(10mL)的烧瓶中,在氩气气氛下回流反应12h,通过注射器缓慢加入三溴化硼(426.4mg,1.7mmol),在0℃下搅拌反应8h,加入饱和的碳酸氢钠水溶液(10mL)使反应淬灭,用二氯甲烷(3×50mL)萃取,有机层用水和饱和的氯化钠水溶液洗涤,再用无水硫酸钠干燥并浓缩,粗产物采用硅胶柱层析(洗脱液:PE/EA=1/1~DCM/MeOH=20/1~10/1)进行纯化,得到蓝色固体HBC2(236.6mg,产率32%)。
1H NMR(400MHz,Methanol-d4)δ8.81(d,J=15.1Hz,1H),8.48(s,1H),7.86(s,1H),7.80(d,J=9.0Hz,1H),7.71(d,J=8.5Hz,1H),7.63(d,J=7.4Hz,1H),7.60–7.56(m,1H),7.52(s,1H),7.36(s,1H),7.13(d,J=2.4Hz,1H),7.08(m,1H),6.59(d,J=15.3Hz,1H),3.93(s,3H),2.80–2.78(m,2H),2.73–2.68(m,2H),1.93–1.89(m,2H),1.88(s,6H).ESI-MS(m/z):计算值:435.56,谱图显示:434.92。
实施例14化合物HBC3的合成
将化合物3’(597.1mg,2.05mmol),化合物6(496.1mg,2.05mmol)和无水乙酸钠(340.44mg,4.10mmol)置于含有无水DCM(20mL)的烧瓶中,在氩气气氛下搅拌反应12h,通过注射器缓慢加入三溴化硼(513.57mg,2.05mmol),在0℃下搅拌反应8h;加入饱和的碳酸氢钠水溶液(10mL)使反应淬灭,用二氯甲烷(3×50mL)萃取,有机层用水和饱和的氯化钠水溶液洗涤,再用无水硫酸钠干燥,并浓缩,采用硅胶柱层析(洗脱液:PE/EA=1/1~DCM/MeOH=20/1)纯化,得到绿色固体HBC3(326.8mg,产率41%)。
1H NMR(400MHz,DMSO-d6)δ8.88(d,J=14.0Hz,1H),8.60(d,J=7.4Hz,1H),8.33(d,J=8.2Hz,1H),8.01(dd,J=7.1Hz,7.7Hz,1H),7.85(dd,J=4.0Hz,4.2Hz,1H),7.75–7.66(m,3H),7.54(d,J=8.5Hz,1H),7.12(s,1H),6.91(d,J=6.0Hz,1H),6.72(d,J=14.3Hz,1H),4.39(s,3H),1.83(m,4H),1.50(m,2H).ESI-MS(m/z):计算值:393.48,谱图显示:392.20。
实施例15化合物HBC4的合成
将化合物14(584.5mg,2mmol),化合物3’(364.4mg,2mmol)和无水乙酸钠(327.6mg,4mmol)置于含有无水DCM(10mL)的烧瓶中,在氩气气氛下搅拌反应12h,通过注射器缓慢加入三溴化硼(500.54mg,2mmol),在0℃下搅拌反应8h,加入饱和的碳酸氢钠水溶液(10mL)使反应淬灭,用二氯甲烷(3×30mL)萃取,有机层用水和饱和的氯化钠水溶液洗涤,然后用无水硫酸钠干燥并浓缩,采用硅胶柱层析(洗脱液:PE/EA=1/1~DCM/MeOH=20/1~5/1)纯化,得到深绿色固体HBC4(247.8mg,产率28%)。
1H NMR(400MHz,Methanol-d4)δ10.21(d,J=8.2Hz,1H),8.54(d,J=8.0Hz,1H),8.28(d,J=8.6Hz,1H),8.11(d,J=8.1Hz,1H),8.02(m,2H),7.77(m,2H),7.71(dd,J=7.7,6.6Hz,1H),7.62(m,2H),7.57–7.48(m,3H),7.10(d,J=7.0Hz,1H),3.45(s,3H),2.19(m,2H),2.03(m,2H),1.58(m,2H).ESI-MS(m/z):计算值:442.54,谱图显示:442.31。
实施例16化合物HBC5的合成
将化合物17(144.77mg,0.362mmol),化合物3’(65.96mg,0.362mmol)和无水乙酸钠(59.37mg,0.724mmol)置于含有无水DCM(10mL)的烧瓶中,在氩气气氛下搅拌反应12h,通过注射器缓慢加入三溴化硼(90.6mg,0.362mmol),在0℃下搅拌反应8h,加入饱和的碳酸氢钠水溶液(10mL)使反应淬灭,用二氯甲烷(3×20mL)萃取,有机层用水和饱和的氯化钠水溶液洗涤,再用无水硫酸钠干燥并浓缩,采用硅胶柱层析(洗脱液:PE/EA=1/1~DCM/MeOH=10/1~5/1)进行纯化,得到黑色固体HBC5(69.69mg,产率35%)。
1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.94(d,J=7.2Hz,1H),8.62(d,J=15.2Hz,1H),8.47(d,J=8.1Hz,1H),8.08(d,J=8.3Hz,1H),8.02–7.92(m,2H),7.81(d,J=7.1Hz,1H),7.75(d,J=8.6Hz,1H),7.47(d,J=15.7Hz,1H),7.33(d,J=3.8Hz,1H),7.24(s,1H),7.08(d,J=21.0Hz,3H),6.96(s,1H),6.72(d,J=15.7Hz,1H),6.60(d,J=8.8Hz,1H),6.49(s,1H),3.97(s,3H),2.36(m,4H),1.72(m,2H).ESI-MS(m/z):计算值:552.69,谱图显示:551.37。
化合物性能测试
1、光谱测试:
10μM的新型半花菁近红外二区荧光染料置于二氯甲烷中,测定溶液的紫外吸收可见光谱和荧光发射光谱。
紫外吸收可见光谱参见图1,由图可见,本申请制备所得新型半花菁近红外二区荧光染料在二氯甲烷中的紫外吸收最大值在700~850nm之间。
荧光发射光谱参见图2,由图可见,本申请制备所得新型半花菁荧光染料表现出强烈的荧光,其中HBC4和HBC5染料在NIR-II区域表现出强烈的荧光,最大发射峰在1000~1300nm之间。
2、穿透深度测试:
以化合物HBC4染料为例对化合物染料的性能进行测试,其他二区荧光染料效果类似。
将HBC4(50μM,100μL)放置在不同厚度(0、0.5、1、2、3和4cm)的鸡胸肉组织下,在1100nm和800nm激发0.1s的NIR-ll荧光图像。
测试结果参见图3,由图可见,即使在4cm厚的鸡肉组织,HBC4染料的信号仍然可见,穿透性较好。
3、活体小鼠NIRF-II成像:
将HBC4(0.1mg/mL,200μL)或生理盐水对活体小鼠进行尾静脉注射。采用IVIS系统采集荧光图像,激发波长为650±10nm,发射波长为720±10nm,采集时间为0.1s。期间收集小鼠粪便样本的荧光信号,然后对小鼠实施安乐死,并对切除的器官进行成像。
注射本发明化合物后,小鼠无明显不适症状,机体能完全接受注入的化合物HBC4,表现出良好的生物相容性,也说明本发明的化合物无明显毒副作用。静脉注射半花菁近红外二区荧光染料的活体小鼠肠道和器官肝脏中的成像测试结果参见图4(活体小鼠背侧(左列)、切除肠道(右列)),由图可见,注射新型半花菁近红外二区荧光染料HBC4后2h,小鼠肠道和肝脏中观察到强烈的NIRF-II信号,成像灵敏度高。
静脉注射半花菁近红外二区荧光染料的活体小鼠获得粪便样本的荧光信号图参见图5,由图可见,静脉注射HBC4染料后获得粪便样本的荧光信号与体内成像数据一致,NIRF-II信号仅在注射了HBC4的小鼠的粪便中检测到。
4、半花菁近红外二区荧光染料水溶性纳米颗粒成像效果
制备纳米颗粒:将含有HBC4(1mg/mL)和DSPE-PEG(2mg/mL)的混合THF溶液(1mL)连续超声后快速注入蒸馏去离子水(9mL,Milli-Q水3min)中,超声处理后,用压力吹扫浓缩器在氮气气氛下蒸发THF,制备得到纳米颗粒NPHBC4。
将NPHBC4(0.1mg/mL,50μL)或生理盐水注射到2%异氟醚麻醉的活体小鼠后爪,用IVIS光谱成像系统在注射后20min、40min、60min、80min、100min和120min采集荧光图像;激发波长为800±10nm,发射波长为1100±10nm,采集时间为0.1s。
半花菁近红外二区荧光染料水溶性纳米颗粒的信噪率测试结果参见图6,由图可见,利用两亲性聚合物包裹新型半花菁近红外二区荧光染料可制备成水溶性纳米颗粒NPHBC4,用于活体淋巴结成像后,呈现出了更高的信噪率,成像灵敏度高。
半花菁近红外二区荧光染料水溶性纳米颗粒在活体小鼠的淋巴结中荧光成像参见图7,由图可见,向活体小鼠后爪注射水溶性纳米颗粒NPHBC4后40分钟,NIRF-II成像清晰勾画出腹股沟淋巴结,信号逐渐增强,成像灵敏度高,并在注射后80min达到最大值,然后下降。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述半花菁近红外二区染料,其特征在于,所述n为0~10的整数。
3.根据权利要求2所述半花菁近红外二区染料,其特征在于,所述n为0~5的整数。
5.根据权利要求4所述制备方法,其特征在于,制备过程在有机溶剂存在条件下进行,所述有机溶剂选自甲醇、乙醇、乙腈、二氯甲烷、四氢呋喃、乙酸、乙酸酐、N,N-二甲基甲酰胺、甲苯中的一种或多种。
6.权利要求1~3任一所述半花菁近红外二区染料及其药学上可接受的盐、溶剂化物、对映异构体、非对映异构体、互变异构体在制备荧光分子探针中的用途。
7.根据权利要求6所述用途,其特征在于,所述荧光分子探针的荧光发射波长为700~1200nm。
8.一种半花菁近红外二区染料纳米颗粒,其特征在于,以权利要求1~3任一所述半花菁近红外二区染料或其药学上可接受的盐、溶剂化物、对映异构体、非对映异构体、互变异构体作为主要成分。
9.根据权利要求8所述半花菁近红外二区染料纳米颗粒,其特征在于,所述纳米颗粒为在两亲性DSPE-PEG链存在的情况下,利用纳米共沉淀法将半花菁近红外二区染料或其药学上可接受的盐、溶剂化物、对映异构体、非对映异构体、互变异构体转化为水溶性纳米颗粒。
10.根据权利要求8或9所述半花菁近红外二区染料纳米颗粒,其特征在于,所述纳米颗粒的粒径为20~200nm。
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