CN115073438A - 一种off-on型近红外二区荧光探针及其制备方法和用途 - Google Patents
一种off-on型近红外二区荧光探针及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及有机化合物探针领域,特别是涉及一种off‑on型近红外二区荧光探针及其制备方法和用途。本发明提供一种化合物或其盐,所述化合物的结构式如式I所示。本发明所提供的化合物或其盐,具有结构新颖、稳定性好、生物安全性高且可生物识别等特点。
Description
技术领域
本发明涉及有机化合物探针领域,特别是涉及一种off-on型近红外二区荧光探针及其制备方法和用途。
背景技术
癌症(又成为恶性肿瘤)严重威胁着人类健康。由于医疗技术水平的限制,目前缺乏对晚期癌症的有效治疗手段,所以早期的诊断和检测对患者来说更为重要。更早的监测并采取及时治疗,可以显著提高癌症患者的存活率。
全世界的科学家、医疗工作者等都迫切开发出对疾病早期监测和诊断的方法。尤其是利用灵敏度高、特异性强、渗透性好、低毒性、高稳定性的监测手段来实时、原位监测生物标志物。相较于传统的光学成像技术例如超声、CT、MRI等等,荧光成像技术因其非侵入式、高时空分辨率、实时性的显著优势,已经受到了医学界、材料界、仪器设备领域等广泛关注。目前,近红外一区(NIR-I,650-900nm)荧光染料(FDA批准药物吲哚菁绿ICG等)已被广泛应用于基础和临床指导。但是NIR-I的缺点在于组织渗透性太差,几乎可以预见无法在实际应用手术指导和深层组织成像中发挥作用。相比之下,近红外二区(NIR-II,1000-1700nm)的荧光信号能保持在微米级成像精度的同时,兼有高信噪比和更低的组织自发荧光、更深的穿透力的特点。综上,发展具有新颖结构的NIR-II染料将在疾病早期监测、特异性诊断、癌症指导手术等领域展现极大的应用潜力和市场价值。在商业上有巨大的盈利空间。
苯并二噻二唑类和花菁类染料及其延伸物是已知的典型的NIR-II染料(Nat.Mater.2016,15,235-242),通常基于共轭体系的修饰实现长波长的荧光发射。然而,以上两类染料往往需要复杂的合成,并且很难进一步引入功能识别单元,对生物标志物的特异性响应。此外,由于较大的π共轭体系,使得该类染料化学稳定性、光稳定性差,实际应用时具有很多瓶颈。
发明内容
鉴于以上所述现有技术的缺点,本发明的目的在于提供一种off-on型近红外二区荧光探针及其制备方法和用途,用于解决现有技术中的问题。
为实现上述目的及其他相关目的,本发明一方面提供一种化合物或其盐,所述化合物的结构式如下所示:
其中,R1为特异性可离去酚羟基保护基团;
R3选自取代或未取代的芳基、取代或未取代的杂芳基;
R4选自取代或未取代的芳基、取代或未取代的杂芳基。
本发明另一方面提供上述的化合物或其盐的制备方法,包括:将化合物SHT1030与保护试剂反应,以提供上述化合物或其盐。
本发明另一方面提供上述的化合物或其盐在制备NIR-II荧光探针中的用途。
本发明另一方面提供一种缀合物,包括上述的化合物或其盐。
附图说明
图1显示为本发明所提供的化合物SHT1030的吸收发射谱示意图。
具体实施方式
为了使本发明的发明目的、技术方案和有益技术效果更加清晰,以下结合实施例对本发明进行进一步详细说明,熟悉此技术的人士可由本说明书所揭露的内容容易地了解本申请发明的其他优点及功效。
本发明发明人经过大量实践研究,提供了一种可用于NIR-II荧光探针的制备的化合物,该化合物具有结构新、稳定性好、安全性高等特点,并具有特异性的响应,具有良好的产业化前景。
本发明第一方面提供一种化合物或其盐,所述化合物的结构式如下所示:
其中,R1为特异性可离去酚羟基保护基团;
R3选自取代或未取代的芳基、取代或未取代的杂芳基;
R4选自取代或未取代的芳基、取代或未取代的杂芳基。
在本发明一具体实施例中,R3选自取代或未取代的噻吩基、取代或未取代的苯基,它们的取代基各自独立地选自C1~C10烷基、卤素、-NR’R”、-OR”’,其中,R’、R”各自独立地选自H、C1~C10烷基,R”’独立地选自H,C1~C10烷基、C1~C10烯基。
在本发明一具体实施例中,R4选自取代或未取代的噻吩基、取代或未取代的苯基,它们的取代基各自独立地选自C1~C10烷基、卤素、-NR’R”、-OR”’,其中,R’、R”各自独立地选自H,C1~C10烷基,R”’独立地选自H、C1~C10烷基、C1~C10烯基。
本发明中,“烷基”通常指饱和脂肪族基团,它们可以是直链或支链。例如,C1-C10烷基通常指包括1个、2个、3个、4个、5个、6个、7个、8个、9个、10个碳原子的烷基基团,烷基基团具体可以是包括但不限于甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基等。
本发明中,“烯基”包含在任意位置具有1个以上双键的直链或支链状烃基。例如,C2-C10烯基通常指包括2个、3个、4个、5个、6个、7个、8个、9个、10个碳原子的烃基基团,烯基基团具体可以是包括但不限于乙烯基、烯丙基、丙烯基、异丙烯基、丁烯基、异丁烯基、异戊二烯基(prenyl)、丁二烯基、戊烯基(pentenyl)、异戊烯基、戊二烯基、己烯基、异己烯基、己二烯基、庚烯基、辛烯基、壬烯基、癸烯基等。
本发明中,“芳基”通常指具有至少一个芳环但没有杂原子的基团。芳基基团具体可以是包括但不限于苯基、萘基、荧蒽基、芴基、四氢萘基、茚满基或蒽基等基团。在本发明一具体实施例中,芳基可以是5或6元环体系。
本发明中,“杂芳基”通常指具有至少一个芳族环并且可以任选地含有一个或多个选自N、O的杂原子的杂环体系。杂芳基具体可以是包括但不限于呋喃、苯并呋喃、吡咯、吡啶、嘧啶、哒嗪、吡嗪、喹啉、异喹啉、酞嗪、三唑、吡唑、异恶唑、吲哚、苯并三唑、苯并二氧戊环、苯并二恶烷、苯并咪唑、咔唑和喹唑啉等基团。在本发明一具体实施例中,杂芳基可以是5或6元环体系。
本发明中,“卤素”或“卤代”通常指氟、氯、溴或碘。
在本发明另一具体实施例中,R3选自如下之一所示的基团:
在本发明另一具体实施例中,R4选自如下之一所示的基团:
本发明中,式I化合物在近红外二区(即1100~2526nm、1100~1200nm、1200~1300nm、1300~1400nm、1400~1500nm、1500~1600nm、1600~1700nm、1700~1800nm、1800~1900nm、1900~2000nm、2000~2100nm、2100~2200nm、2200~2300nm、2300~2400nm、或2400~2526nm的波长范围)相对于其脱除R1基团后的状态通常基本没有明显的荧光,例如,可以是基本没有荧光或者相对较弱的荧光(相对于其脱除R1基团后的状态)。R1为特异性可离去酚羟基保护基团,在特异性响应物存在的条件下,式I化合物中的-OR1基团可以脱除R1基团,而-OR1基团在脱除R1基团后通常可以在对应位置形成酚羟基,从而使得整个化合物在脱除R1基团后在近红外二区具有明显增强的荧光。例如,其荧光强度可以被增强几倍到几十倍,具体例如2~3倍、3~4倍、4~6倍、6~8倍、8~10倍、10~15倍、15~20倍、20~30倍、30~40倍、40~50倍、或达到50倍以上。R1对于特异性响应物的响应通常是具有特异性的,即在没有特异性响应物存在的条件下,-OR1基团不会发生脱除R1基团的反应,而仅在特异性响应物存在的条件下,式I化合物中的-OR1基团可以脱除R1基团。
本发明中,特异性响应物通常指-OR1基团敏感的物质,如上所述,在这些物质存在的条件下,式I化合物中的-OR1基团可以脱除R1基团、并在脱除R1基团后可以在对应位置形成酚羟基。合适的-OR1基团敏感的物质对于本领域技术人员来说应该是已知的。例如,可以是-OR1基团敏感的酶、活性氧(ROS)、铜离子等中的一种或多种的组合。再例如,这些酶可以是碱性磷酸酶(ALP)、β-半乳糖苷酶(β-galactosidase)、酪氨酸酶(Tyrosinase)、羧酸酯酶(Carboxylesterase)、硝基还原酶(Nitroreductase)等中的一种或多种的组合。
在本发明一具体实施例中,R1选自如下之一所示的基团:
在本发明另一具体实施例中,上述化合物选自如下之一所示的化合物:
本发明中,式I化合物作为阳离子基团,通常可以与合适的阴离子或酸形成盐。例如,所形成的盐通常为有机盐。再例如,阴离子可以是BF4 -、F-、Cl-、Br-、I-、ClO4 -等。再例如,可选的酸可以是上述阴离子所对应的有机酸或无机酸等。
本发明第二方面提供本发明第一方面所提供的化合物或其盐的制备方法,包括:将化合物SHT1030与保护试剂反应,以提供上述化合物或其盐。通常来说,保护试剂的种类、以及化合物SHT1030与保护试剂之间的反应类型,通常与R1基团是相对应的。本领域技术人员可根据R1基团选择合适的保护试剂以及反应条件。例如,保护试剂可以是双(频哪醇合)二硼、三氯氧磷、四乙酰基-α-D-溴代半乳糖、三氟甲磺酸酐、烯丙酰氯、甲酸、双(频哪醇合)二硼、吡啶甲酰氯、4-溴甲基苯硼酸频哪醇酯、4-溴甲基苯硼酸、4-溴甲基磷酸、4-溴甲基苯基四乙酰基-β-D-溴代半乳糖苷、(4-溴甲基)苯基邻吡啶甲酸酯等,分别可以从左至右、从上至下对应如下所示的基团,保护试剂的用量相对于化合物SHT1030来说通常是基本等量或者过量的。再例如,反应可以在碱存在的条件下进行,碱的用量相对于化合物SHT1030来说通常是基本等量或者过量的。再例如,反应可以在室温至溶剂沸点的温度条件下进行,可选用的溶剂可以是醚类溶剂(例如,四氢呋喃等)等。
本发明第三方面提供本发明第一方面所提供的化合物或其盐在制备NIR-II荧光探针中的用途。如上所述,式I化合物在近红外二区通常没有明显的荧光,而-OR1基团在脱除R1基团后通常可以在对应位置形成酚羟基,从而使得整个化合物在脱除R1基团后在近红外二区具有明显的荧光,从而使得上述化合物或其盐可以用于制备NIR-II(近红外二区)荧光探针,这一探针通常可以是off-on型探针。
本发明第四方面提供一种缀合物,包括本发明第一方面所提供的化合物或其盐。上述缀合物通常指式I化合物或其盐与其他分子(例如,蛋白质、多肽、脂质、核酸和抗体等分子)以共价键相互连结而形成的化合物。例如,可以是PEG、多肽等。
上述缀合物中,式I化合物通常可以通过R3基团进一步与其他分子连接。例如,在上述缀合物中,式I化合物可以对应地形成如下所示的基团结构。
上述缀合物中,式I化合物与其他分子(例如,蛋白质、多肽、脂质、核酸和抗体等分子)之间,还可以包括合适的连接基团。例如,在上述缀合物中,式I化合物可以通过连接基团R2对应地形成如下所示的基团结构。
在本发明一具体实施例中,式I化合物或其盐与其他分子之间的连接基团R2可以选自如下之一所示的基团:
其中,n可以为0~18、且n为正整数,例如,可以为0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、或18;
m可以为1~200、且m为正整数,例如,可以为1~2、2~4、4~6、6~8、8~10、10~15、15~20、20~30、30~40、40~50、50~60、60~80、80~100、100~120、120~140、140~160、160~180、或180~200;
X可以选自F、Cl、Br、I、N3等。
上述缀合物的制备方法对于本领域技术人员来说应该是已知的。例如,可以通过点击反应和/或缩合反应等方法制备获得。
本发明所提供的化合物或其盐,具有结构新颖、稳定性好、生物安全性高且可生物识别等特点。该探针可以在无特异性响应物的环境下,激光激发无荧光发射,处于off状态,而在有特异性响应物的环境下,激光激发可以发射很强的荧光,处于on的状态。因此,上述化合物或其盐可以特异性识别生物体系中的待测物分子,能够特异性地用于生物体内成像,其在活体肿瘤、肿瘤微环境微小血管成像中表现出高信噪比、深组织渗透性、实时示踪等优点,从而可以应用于荧光成像等领域,具有良好的产业化前景。
下面通过实施例对本申请予以进一步说明,但并不因此而限制本申请的范围。
本申请实施例中的具体合成路线如下:
实施例1
化合物3的合成
冰浴条件下,在250mL圆底烧瓶中将苯乙酮(12.0g,100.0mmol)溶解在200mL甲醇中同时加入KOH水溶液(50%w/w)70mL,。搅拌10分钟后,加入在溶解在30mL甲醇中的苯甲醛(10.6g,100.0mmol)并在恒压滴液漏斗中,于1小时内逐滴滴下。然后,将反应混合物在室温搅拌过夜。次日减压旋蒸除去甲醇。用3M HCl水溶液中和,析出沉淀物过滤并用水洗涤。从甲醇中重结晶。得到浅黄色结晶固体(18.8g,90.4mmol),产率90.4%。
MS m/z(ESI):209.3[M+H]+
1H NMR(500MHz,Chloroform-d)δ8.02(d,2H),7.82(d,J=15.7Hz,1H),7.67–7.63(m,2H),7.59(t,J=7.4Hz,1H),7.57–7.48(m,3H),7.45–7.41(m,3H).
实施例2
化合物4的合成
室温条件下,环戊酮(1.7mL,20.0mmol)和吡咯烷(1.65mL,20.0mmol)溶解在甲苯溶液20mL中。并于装有Dean-Stark的圆底烧瓶中70℃回流4小时。除去溶剂,剩余的混合物为溶于1,4-二氧六环。将化合物3(4.16g,20.0mmol,)添加至反应体系,60℃回流2小时。加入水(60mL)淬灭。冷却至室温后,用乙酸乙酯(3×20mL)萃取。合并的有机层为并用无水硫酸钠干燥并浓缩。产物经快速色谱纯化得到无色油状化合物4(4.68g,16.0mmol),产率80.0%。
MS m/z(ESI):293.3[M+H]+
1H NMR(400MHz,chloroform-d):δ7.98(d,J=9.0Hz,2H),7.31-7.17(m,4H),7.00(m,4H),3.84-3.68(m,2H),3.41(dd,J=18.8,9.3Hz,1H),2.55(m,1H),2.29-2.19(m,1H),2.17-2.08(m,1H),1.98-1.86(m,1H),1.82-1.74(m,2H),1.69-1.59(m,1H)
实施例3
化合物5的合成
室温条件下,将化合物4(1.7g,5.8mmol)溶解在10mL无水乙醚中,加入硫代乙酸(0.9Ml,12.7mmol)完全溶解后将三氟化硼醚化物(4.4mL,34.7mmol)滴加到混合物中,然后回流6小时。然后,将反应混合物冷却至室温并用水(1mL)淬灭。然后将其倒入乙醚(100mL),出现大量黄色固体。过滤并用乙醚洗涤,干燥后得黄色固体(1.44g,3.83mmol),产率66.0%。
MS m/z(ESI):289[M-BF4]+
1H NMR(500MHz,Chloroform-d)δ8.42(s,1H),7.86(d,J=7.6Hz,2H),7.73–7.60(m,8H),3.88–3.76(m,2H),3.46–3.35(m,2H),2.50–2.39(m,2H).
实施例4
化合物7的合成
冰浴条件下,取DMF(22.4mL,290mmol)和氯仿100mL于250ml圆底烧瓶。缓慢滴加PBr3(24.8mL,261mmol),45分钟后,加入环己酮(10mL,96.8mmol),25℃搅拌16小时。反应结束后,将红色的反应体系倒入冰中,并用固体碳酸氢钠调节pH=7,并用二氯甲烷萃取,无水硫酸钠干燥,过滤后旋蒸得到黄色油状物质15.4g,无需纯化,直接下一步。
实施例5
化合物9的合成
室温条件下,取化合物7(204mg,1.08mmol)溶解在6mL DMF中,加入2-羟基-4-甲氧基-苯甲醛(137mg,0.90mmol),碳酸铯(880mg,2.7mmol)与25℃下搅拌16小时,TLC监测会看到黄色带有荧光的点。将不溶物除去以后,用二氯甲烷从体系中萃取出反应物,并用水洗涤。有几层用无水硫酸钠干燥,柱层析得到深黄色固体(164mg,0.68mmol),产率75.6%。
MS m/z(ESI):243.2[M+H]+.
1H NMR(500MHz,Chloroform-d)δ10.30(d,J=2.2Hz,1H),7.15–7.03(m,1H),6.78–6.59(m,3H),3.84(s,3H),2.60–2.53(m,2H),2.47–2.41(m,2H),1.75–1.67(m,2H).
实施例6
化合物10的合成
冰浴条件下,取化合物9(100mg,0.41mmol)溶解在20mL DCM中,加入滴加三溴化硼的二氯甲烷溶液(1~2mL,17%),于35℃下搅拌16小时,TLC监测反应完毕。饱和碳酸氢钠溶液淬灭反应,用二氯甲烷从体系中萃取出反应物,有几层用无水硫酸钠干燥,柱层析得到深黄色固体(50mg,0.22mmol),产率53.7%。
MS m/z(ESI):229.2[M+H]+.
实施例7
化合物SHT1030的合成
化合物10(500mg,2.19mmol)和化合物5(823mg,2.19mmol)溶于正丁醇中,加热至85℃反应2小时。冷却至室温,加入大量乙醚,析出固体,过滤。所得滤饼柱层析得到棕黑色固体(420mg,0.72mmol),产率32.9%。
MS m/z(MALDI-TOF):499.2[M-BF4]+.
1H NMR(500MHz,Chloroform-d)δ7.91–7.81(m,1H),7.72–7.66(m,2H),7.60–7.55(m,2H),7.52–7.46(m,3H),7.46–7.40(m,3H),7.32–7.29(m,1H),7.25–7.22(m,1H),7.17–6.95(m,3H),3.17–2.98(m,4H),2.92–2.85(m,2H),2.70–2.61(m,2H),1.85(d,J=12.3Hz,2H).
精确称量制备获得的SHT1030 0.586mg(molar weight:586g/mol)溶于1ml甲醇溶液配成1mmol/L的母液后,再次稀释100倍得最终浓度为10-5mol/L的SHT1030溶液。取上述溶液2ml,以甲醇为参比,使用型号为Agilent Gary 5000紫外可见近红外分光光度计测定吸收曲线,扫描范围为600-1200nm得最终的吸收曲线。
精确称量制备获得的SHT1030 0.586mg(molar weight:586g/mol)溶于1ml甲醇溶液配成1mmol/L的母液后,再次稀释100倍得最终浓度为10-5mol/L的SHT1030溶液。取上述溶液2ml,以甲醇为参比、激发光为808nm、使用型号为复享NIR1700的近红外荧光光谱仪测定发射曲线,测定范围为900-1700nm得最终的发射曲线。
化合物SHT1030的吸收发射谱示意图如图1所示,其中,深色线条为吸收曲线,浅色线条为发射曲线。
实施例8
化合物SHT1030-P的合成
化合物SHT1030(100mg,0.171mmol)溶于THF(15mL)中,加入三乙胺(173mg,1.71mmol),滴加POCl3(260mg,1.71mmol),于室温下搅拌2小时。加入冰水搅拌30分钟。过滤,用冰水洗涤滤饼,干燥,柱层析,得黑色固体(30mg,0.045mmol),产率26.3%。
MS m/z(MALDI-TOF):579[M-BF4]+.
综上所述,本发明有效克服了现有技术中的种种缺点而具高度产业利用价值。
上述实施例仅例示性说明本发明的原理及其功效,而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下,对上述实施例进行修饰或改变。因此,举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变,仍应由本发明的权利要求所涵盖。
Claims (12)
2.如权利要求1所示的化合物或其盐,其特征在于,R3选自取代或未取代的噻吩基、取代或未取代的苯基,它们的取代基各自独立地选自C1~C10烷基、卤素、-NR’R”、-OR”’,其中,R’、R”各自独立地选自H、C1~C10烷基,R”’独立地选自H,C1~C10烷基、C1~C10烯基。
3.如权利要求1所示的化合物或其盐,其特征在于,R4选自取代或未取代的噻吩基、取代或未取代的苯基,它们的取代基各自独立地选自C1~C10烷基、卤素、-NR’R”、-OR”’,其中,R’、R”各自独立地选自H,C1~C10烷基,R”’独立地选自H、C1~C10烷基、C1~C10烯基。
4.如权利要求1所示的化合物或其盐,其特征在于,在特异性响应物存在的条件下,式I化合物中的-OR1基团可以脱除R1基团,优选的,在脱除R1基团后形成酚羟基。
5.如权利要求1所示的化合物或其盐,其特征在于,所述式I化合物相对于其脱除R1基团后的状态在近红外二区基本没有荧光,所述式I化合物在脱除R1基团后在近红外二区具有荧光。
6.如权利要求4所示的化合物或其盐,其特征在于,所述特异性响应物选自-OR1基团敏感的物质,优选选自-OR1基团敏感的酶、活性氧、铜离子中的一种或多种的组合,所述酶优选选自碱性磷酸酶、β-半乳糖苷酶、酪氨酸酶、羧酸酯酶、硝基还原酶中的一种或多种的组合。
9.如权利要求1所示的化合物或其盐,其特征在于,所述盐中,阴离子选自BF4 -、F-、Cl-、Br-、I-、ClO4 -。
10.如权利要求1~9任一权利要求所述的化合物或其盐的制备方法,包括:将化合物SHT1030与保护试剂反应,以提供上述化合物或其盐。
11.如权利要求1~9任一权利要求所述的化合物或其盐在制备NIR-II荧光探针中的用途。
12.一种缀合物,包括如权利要求1~9任一权利要求所述的化合物或其盐。
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