CN116332923A - 一类咔唑及吩嗪类化合物中位取代花菁染料及其制备方法和应用 - Google Patents
一类咔唑及吩嗪类化合物中位取代花菁染料及其制备方法和应用 Download PDFInfo
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- CN116332923A CN116332923A CN202310360159.3A CN202310360159A CN116332923A CN 116332923 A CN116332923 A CN 116332923A CN 202310360159 A CN202310360159 A CN 202310360159A CN 116332923 A CN116332923 A CN 116332923A
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- substituted
- phenazine
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Abstract
本发明公开了一类咔唑及吩嗪类化合物中位取代花菁染料及其制备方法和应用,通过使用咔唑及吩嗪类化合物对七甲川花菁染料进行中位取代,通过取代基团对其荧光发射、活性氧产生及放出热量的途径进行调控,从而提升染料分子的成像、光动力或光热效果,同时还具有良好的生物相容性和较低的细胞毒性,可以用于生物和医药领域当中。
Description
技术领域
本发明涉及有机染料技术领域,尤其涉及一类咔唑及吩嗪类化合物中位取代花菁染料及其制备方法和应用。
背景技术
癌症是世界上最常见的威胁生命的疾病之一,近几十年来,其发病率一直保持上升趋势。目前,应用最广泛的癌症治疗方法是手术切除、化学治疗和放射治疗。虽然这些治疗可以在一定程度上减缓癌症的进展,但它们对人体的危害极大,并导致患者的生活质量急剧下降。因此,研究有效的癌症治疗策略迫在眉睫。得益于光学器件和光学技术的进步,包括利用荧光成像、光声成像(PA)等成像手段以及光动力治疗(PDT)和光热治疗(PTT)等光疗手段在癌症的监测和治疗领域引起了广泛的关注。
七甲川花菁(Cy7)染料是一类重要的有机小分子染料。目前,七甲川花菁染料及其应用于生物识别成像、以及肿瘤光动力和光热治疗等方面的研究应用受到广泛重视。七甲川花菁染料不仅具有优秀的生物相容性,同时还具有高的摩尔消光系数、处于近红外区域的吸收和发射波长以及固有的光动力和光热能力。其中,吲哚菁绿(ICG)已经被美国食品和药物管理局(FDA)批准并广泛用于肿瘤成像和光疗。然而,这些基于七甲川花菁染料的光热试剂在光疗中并不令人满意,这主要是因为它们固有的光动力或光热转化能力较弱。
根据Jablonski能级图,有三种过渡途径可以衰减单线态激发物质的能量。第一种是发射荧光。第二个是通过系间窜越(ISC)形成三重态激发态并继而生成活性氧(ROS)用于光动力治疗。第三个是通过非辐射弛豫的途径产生热量并用于光热治疗。由于激发物质对一个分子的能量通常是固定的,因此三个激发能量耗散过程往往处于竞争关系中。因此,可以通过能量转化的角度研究设计具有优良的成像、光动力或光热效果的花菁染料。
发明内容
针对现有技术存在的基于七甲川花菁染料固有的光动力或光热转化能力较弱的问题,本发明提供一类咔唑及吩嗪类化合物中位取代花菁染料及其制备方法和应用,通过使用咔唑及吩嗪类化合物对七甲川花菁染料进行中位取代,通过取代基团对其荧光发射、活性氧产生及放出热量的途径进行调控,从而提升染料分子的成像、光动力或光热效果,同时还具有良好的生物相容性和较低的细胞毒性,可以用于生物和医药领域当中。
为了实现上述目的,本发明的技术方案是:一类咔唑及吩嗪类化合物中位取代花菁染料,具有通式I的结构:
式I中,R1选自一种如下结构式的基团:
R2选自具有1-18个碳的烷基、具有1-18个碳的羟基、具有1-18个碳的羧烷基、具有1-18个碳的烷基磺酸根或烷基磺酸盐、芳基、芳基磺酸根或芳基磺酸盐中的任意一种;
R3选自氢、卤素、具有1-8个碳的烷基、具有1-8个碳的羟基、具有1-8个碳的羧烷基、芳基、烷基磺酸根或烷基磺酸盐、芳基磺酸根或芳基磺酸盐中的任意一种。
更进一步地,R2选自具有1-18个碳的烷基、具有1-18个碳的羧烷基、具有1-18个碳的烷基磺酸根或烷基磺酸盐中的任意一种;优选地,R2选自具有1-18个碳的烷基、具有1-18个碳的烷基磺酸根或烷基磺酸盐;
R3选自氢、卤素、具有1-8个碳的羧烷基、烷基磺酸根或烷基磺酸盐中的任意一种;优选地,R3选自氢、卤素、羧基、磺酸基或磺酸盐。
进一步地,所述R1选自咔唑、吩噁嗪、吩噻嗪、吩硒嗪或吩碲嗪。
为了实现上述目的,本发明的还提供了如下技术方案:一类咔唑及吩嗪类化合物中位取代花菁染料的制备方法:
所述制备方法包括如下步骤:
(1)在第一有机溶剂中,将含R3取代的2,3,3-三甲基吲哚Y-1与N烷基化试剂反应,反应温度为60-90℃,反应时间为3-48h,得到含N-R2取代侧链的Y-2,Y-2经有机溶剂进行重结晶,得纯化后的Y-2;所述N烷基化试剂选自含R2取代的烷烃或卤代烷烃;
(2)将步骤(1)制得的Y-2和2-氯-3-(羟基亚甲基)-1-环己烯-1-甲醛与第二有机溶剂混合,在80-130℃下反应1-24h,反应结束后旋蒸除去溶剂,并经硅胶柱纯化,得到中间产物Y-3;
(3)将步骤(2)制得的中间产物Y-3、含有R1的化合物、醋酸钯、三叔丁基磷和叔丁醇钠、第三有机溶剂混合均匀,在50-120℃下反应24-72h,反应结束后旋蒸除去溶剂,并经高效液相制备色谱纯化得到咔唑及吩嗪类化合物中位取代花菁类荧光化合物I。
更进一步地,所述重结晶溶剂选自甲醇、乙醇、乙腈、乙酸乙酯、乙醚、丙酮和丙醇中的至少一种。
进一步地,在步骤(1)中,所述含R3取代的2,3,3-三甲基吲哚Y-1与N烷基化试剂的摩尔比为1:1-10;
第一有机溶剂选自丙酮、乙醇、乙腈、苯、甲苯和邻二氯苯中至少一种。
进一步地,在步骤(2)中,Y-2和2-氯-3-(羟基亚甲基)-1-环己烯-1-甲醛的摩尔比为1:1-3;
第二有机溶剂选自选自苯、甲苯、邻二氯苯、甲醇、乙醇、丙醇、丁醇、乙酸和乙酸酐中至少一种。
进一步地,在步骤(3)中,Y-3、含有R1的化合物、醋酸钯、三叔丁基磷和叔丁醇钠的摩尔比为1:1-2:0.1-0.5:0.3-0.5:1-2;
第三有溶剂选自苯、甲苯或邻二氯苯。
进一步地,在步骤(1)中,所述含R3取代的2,3,3-三甲基吲哚Y-1与N烷基化试剂的摩尔比为1:2-5。
为了实现上述目的,本发明的还提供了如下技术方案:一类咔唑及吩嗪类化合物中位取代花菁染料的应用,所述应用是在细胞/肿瘤成像、光动力及光热治疗中的用途。
进一步地,所述应用是用于生物体内荧光成像和肿瘤治疗。
综上所述,本发明具有以下有益效果:
第一、本发明所述的咔唑及吩嗪类化合物中位取代花菁类染料,通过在七甲川菁染料中位引入咔唑及吩嗪类化合物,实现优秀的成像、光动力或光热效果。
第二、采用本申请制备方法制备的染料具有近红外光吸收和发射,相比于未取代前的化合物,该类染料最大吸收和发射波长发生红移,且荧光量子产率有所增强,使该类染料可以很好的用于深层生物体内荧光成像和肿瘤治疗领域当中。
第三、采用本申请制备方法制备的染料具有近红外光吸收,相比于未取代前的化合物,该类染料荧光发生淬灭,且其活性氧产率及光热转化能力大幅提升,并能够在光照下有效杀死肿瘤细胞,这表明该类染料可以很好的用于深层生物体内光声成像和肿瘤治疗领域当中。
第四、本发明所述的染料具有良好的生物相容性,使用最大浓度为30μmol/L的化合物培养4T1细胞24h后,细胞仍然显具有较好的存活率,说明本申请提供的类咔唑及吩嗪类化合物中位取代花菁类染料具有非常好的生物相容性,在工作浓度范围内不会对细胞产生毒副作用。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作一简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其他的附图。
图1为本发明公开的化合物1、3和5在甲醇中的吸收光谱图;
图2为本发明公开的化合物1、3和5在甲醇中的发射光谱图;
图3是本发明公开的化合物3的活性氧效果图;
图4是本发明公开的化合物5的光热效果图;
图5是本发明公开的化合物1无光照条件下的MTT实验图;
图6是本发明公开的化合物3无光照条件下的MTT实验图;
图7是本发明公开的化合物3光照条件下的MTT实验图;
图8是本发明公开的化合物5光照条件下的MTT实验图;
图9是本发明公开的化合物5的小鼠肿瘤光声成像图;
图10是本发明公开的化合物5的小鼠光热治疗图。
具体实施方式
以下结合附图1-10和实施例1-7对本发明作进一步详细说明。
除另有说明外,本文中使用的术语具有以下含义。
本文中使用X表示术语“卤素”,包括氟、氯、溴和碘。
本发明中使用的术语“MTT”指的是一种检测细胞存活和生长的方法。
本发明中使用的术语“烷基”包括直链烷基和支链烷基。
实施例中所采用的仪器和设备:
本发明柱层析过程中,采用购于青岛美高集团有限公司的200-300目、100-200目柱色谱硅胶和购于天大化学试剂厂的20-40目分析纯石英砂。
在检测化合物过程中,核磁共振氢谱采用美国Bruker公司的Bruker Avance III500进行检测。
染料的吸收、发射光谱以及光稳定性用Agilent公司的Cary60紫外可见分光光度计和CaryEclipse荧光分光光度计测得。染料的绝对荧光量子产率使用滨松光子学商贸(中国)有限公司的C11347绝对荧光量子产率仪测得。
细胞毒性试验用美国Thermofisher公司的Varioskan LUX MultimodeMicroplate Reader仪器测得。
激光器输出功率由光纤耦合激光器系统(FCW-808-30W,长春新工光电科技有限公司)控制,功率计(CEL-NP2000,北京中焦金源科技有限公司)测量。
光声成像由InVision128MSOT系统(iTheraMedical,Germany)监测。
动物与肿瘤模型本工作所涉及的所有动物实验均经大连医科大学动物保护使用委员会批准。
一类咔唑及吩嗪类化合物中位取代花菁染料,具有通式I的结构:
式I中,R1选自一种如下结构式的基团:
R2选自具有1-18个碳的烷基、具有1-18个碳的烷基磺酸根或烷基磺酸盐;
R3选自氢、卤素、羧基、磺酸基或磺酸盐。
以下,举出由通式I所表示的化合物的具体例,但本发明并不限于这些具体例。
本发明由通式I所示的化合物可通过下述记载的方法合成。
实施例1
化合物1的合成路线:
S1:将2,3,3-三甲基-3H-吲哚(1g,6.28mmol)和1,3-丙烷磺酸内酯(1.70g,7.54mmol)加入含10mL乙腈的反应瓶中,在氮气气氛下回流反应24h,反应结束后冷却至室温,然后使用50ml乙酸乙酯洗涤、Na2SO4干燥,得到紫色固体粉末中间产物1-1(1.45g,5.15mmol,Y=82.06%);
S2:取步骤S1制得的中间产物1-1(1g,3.55mmol)、2-氯-3-(羟基亚甲基)-1-环己烯-1-甲醛(0.28g,1.62mmol)和乙酸钠(0.33g,4mmol)加入到10mL乙酸酐溶液中,在110℃回流反应4h,反应结束后旋蒸除去溶剂,并经硅胶柱纯化得到中间产物1-2(0.56g,0.8mmol,Y=49.64%);
S3:将醋酸钯(0.04g,0.16mmol)、三叔丁基磷(0.06g,0.31mmol)和叔丁醇钠(0.08g,0.79mmol)加入到10mL甲苯溶液中混合均匀,然后加入步骤S2制得的中间产物1-2(0.5g,0.69mmol)及咔唑(0.14g,0.83mmol)混合均匀,在100℃反应48h,反应结束后旋蒸除去溶剂,并经高效液相制备色谱纯化得到化合物1(0.054g,0.06mmol,Y=9.13%)。
使用1H NMR对其进行表征。
1H NMR(500MHz,DMSO-d6)δ7.80(dd,J=7.6,1.5Hz,2H),7.69(ddd,J=7.3,4.4,1.4Hz,2H),7.63–7.49(m,3H),7.49–7.35(m,4H),7.25(dd,J=8.0,1.3Hz,1H),7.16(ddd,J=7.7,6.5,1.3Hz,1H),7.11–6.96(m,2H),6.86(dd,J=6.5,1.5Hz,1H),6.74(d,J=8.4Hz,1H),6.27(dt,J=8.4,0.9Hz,1H),4.50(t,J=8.0Hz,2H),3.72(t,J=6.5Hz,2H),3.53(dt,J=14.8,11.0Hz,1H),3.42(dt,J=14.8,11.1Hz,1H),3.03(s,0H),2.72–2.57(m,4H),2.12(tt,J=11.4,8.0Hz,2H),1.95(tt,J=10.9,6.4Hz,2H),1.72(s,4H),1.58(s,4H),1.51(ttd,J=8.1,5.8,3.4Hz,2H).
实施例2
化合物2的合成路线:
S1:将5-溴-2,3,3-三甲基-3H-吲哚(1g,4.2mmol)和碘甲烷(2.23g,15.7mmol)加入含10mL丙酮的反应瓶中,在氮气气氛下回流反应24h。反应结束后冷却至室温,使用50mL乙酸乙酯洗涤、Na2SO4干燥,得到红棕色固体粉末中间产物2-1(1.49g,3.92mmol,Y=93.35%);
S2:向反应瓶中加入10ml正丁醇和4ml甲苯混合均匀,然后加入步骤S1制得的中间产物2-1(1g,2.63mmol)和2-氯-3-(羟基亚甲基)-1-环己烯-1-甲醛(0.22g,1.32mmol),在110℃回流反应2h,反应结束后采用旋蒸除去溶剂,并经硅胶柱纯化得到中间产物2-2(0.72g,0.94mmol,Y=35.59%);
S3:将醋酸钯(0.02g,0.09mmol)、三叔丁基磷(0.04g,0.18mmol)和叔丁醇钠(0.04g,0.44mmol)加入到5mL甲苯溶液中混合均匀,然后向其中加入步骤S2制得的中间产物2-2(0.3g,0.39mmol)和咔唑(0.08g,0.47mmol),在120℃下反应48h,反应结束后旋蒸除去溶剂,并经高效液相制备色谱纯化得到化合物2(0.032g,0.04mmol,Y=9.2%)。
使用1H NMR对其进行表征。
1H NMR(500MHz,DMSO-d6)δ7.87(dd,J=8.4,2.4Hz,1H),7.80(dd,J=7.6,1.5Hz,2H),7.71–7.64(m,2H),7.56(d,J=8.4Hz,1H),7.54–7.49(m,2H),7.47–7.35(m,5H),7.33(d,J=2.2Hz,1H),7.13(d,J=15.0Hz,1H),6.97(d,J=0.8Hz,1H),6.86(d,J=8.1Hz,1H),6.76(d,J=8.1Hz,1H),6.25(dt,J=8.2,1.1Hz,1H),4.24(s,2H),2.72–2.57(m,4H),1.71(s,4H),1.62(s,4H),1.51(ttd,J=8.1,5.8,3.4Hz,2H).
实施例3
化合物3的合成
和实施例1的区别仅在于,在步骤S3中,用吩噁嗪(0.15g,0.83mmol)替换咔唑(0.14g,0.83mmol),经高效液相制备色谱纯化得到化合物3(0.075g,0.09mmol,Y=12.45%)。
使用1H NMR对其进行表征。
1H NMR(500MHz,DMSO-d6)δ7.72–7.66(m,2H),7.66–7.58(m,1H),7.60–7.53(m,1H),7.37(ddd,J=6.9,3.0,1.8Hz,2H),7.28–7.22(m,3H),7.25–7.17(m,3H),7.16(ddd,J=7.7,6.5,1.3Hz,1H),7.07(d,J=8.6Hz,1H),7.02(td,J=7.7,1.5Hz,1H),6.97(dd,J=7.6,1.7Hz,2H),6.86(dd,J=6.5,1.5Hz,1H),6.23(dt,J=8.6,0.9Hz,1H),4.50(t,J=8.0Hz,2H),3.72(t,J=6.5Hz,2H),3.53(dt,J=14.8,11.0Hz,1H),3.42(dt,J=14.8,11.1Hz,1H),3.07(s,0H),3.03(s,0H),2.78–2.66(m,4H),2.12(tt,J=11.4,8.0Hz,2H),1.95(tt,J=10.9,6.4Hz,2H),1.72(s,4H),1.60–1.48(m,6H).
实施例4
化合物4的合成路线:
S1:将5-羧基-2,3,3-三甲基-3H-吲哚(1g,4.92mmol)和苄基溴(1.09g,6.4mmol)加入含10mL乙腈的反应瓶中,在氮气气氛下回流反应24h。反应结束后冷却至室温,使用50ml乙醚洗涤、Na2SO4干燥,得到中间产物4-1(0.73g,2.48mmol,Y=50.4%);
S2:将步骤S1制得的中间产物4-1(0.5g,1.34mmol)和2-氯-3-(羟基亚甲基)-1-环己烯-1-甲醛(0.16g,0.67mmol)加入到含有5mL甲醇的反应瓶内,在80℃回流反应24h,旋蒸除去溶剂,并经硅胶柱纯化得到中间产物4-2(0.2g,0.25mmol,Y=18.43%);
S3:将醋酸钯(0.01g,0.05mmol)、三叔丁基磷(0.02g,0.1mmol)和叔丁醇钠(0.02g,0.25mmol)加入到4mL甲苯溶液中混合均匀,然后向其中加入步骤S2制得的中间产物4-2(0.18g,0.22mmol)和吩噁嗪(0.05g,0.27mmol),在90℃反应48h,反应结束后旋蒸除去溶剂,并经高效液相制备色谱纯化得到化合物4(0.02g,0.02mmol,Y=9.42%)。
使用1H NMR对其进行表征。
1H NMR(500MHz,DMSO-d6)δ8.45(d,J=2.3Hz,1H),8.07–8.01(m,2H),7.94–7.85(m,2H),7.48–7.38(m,2H),7.38–7.31(m,2H),7.34–7.29(m,2H),7.31–7.27(m,5H),7.27(q,J=1.0Hz,3H),7.27–7.23(m,1H),7.25–7.18(m,1H),7.15(d,J=7.0Hz,1H),7.11–7.01(m,5H),6.33(dt,J=8.4,0.9Hz,1H),5.89(d,J=1.1Hz,2H),5.53(q,J=0.8Hz,1H),4.98(t,J=0.9Hz,2H),2.64–2.57(m,2H),2.60–2.52(m,2H),1.71(s,4H),1.61(s,4H),1.58–1.45(m,2H).
实施例5
化合物5的合成
和实施例1的区别仅在于,在步骤S3中:将醋酸钯(0.04g,0.16mmol)、三叔丁基磷(0.06g,0.31mmol)和叔丁醇钠(0.08g,0.79mmol)加入到10ml甲苯溶液中混合均匀,然后加入步骤S2制得的中间产物1-2(0.5g,0.69mmol)和吩噻嗪(0.17g,0.83mmol),在120℃下反应48h,反应结束后采用旋蒸除去溶剂,并经高效液相制备色谱纯化得到化合物5(0.08g,0.09mmol,Y=13.45%)。
使用1H NMR对其进行表征。
1H NMR(500MHz,DMSO-d6)δ7.72–7.66(m,1H),7.66–7.53(m,1H),7.46(ddd,J=7.2,6.1,1.3Hz,1H),7.35(td,J=6.8,2.5Hz,1H),7.28–7.13(m,3H),7.10–6.98(m,1H),4.50(t,J=8.0Hz,1H),3.72(t,J=6.5Hz,1H),2.78–2.65(m,2H),2.12(tt,J=11.4,8.0Hz,1H),1.95(tt,J=10.9,6.4Hz,1H),1.72(s,2H),1.60–1.49(m,3H).
实施例6
化合物6的合成路线:
S1:将5-羟基-2,3,3-三甲基-3H-吲哚(1g,5.71mmol)和8-溴辛酸(1.91g,8.56mmol)加入含10mL甲苯的反应瓶中,在氮气气氛下回流反应24h,反应完成后冷却至室温,然后使用50ml乙醚洗涤、Na2SO4干燥,得到中间产物6-1(0.91g,2.28mmol,Y=40.3%);
S2:将步骤S1制得的中间产物6-1(0.5g,1.26mmol)和2-氯-3-(羟基亚甲基)-1-环己烯-1-甲醛(0.12g,0.69mmol)加入到含有5mL乙醇的反应瓶内,在80℃回流反应16h,旋蒸除去溶剂,并经硅胶柱纯化得到中间产物6.2(0.19g,0.23mmol,Y=18.13%);
S3:将醋酸钯(0.01g,0.04mmol)、三叔丁基磷(0.02g,0.08mmol)和叔丁醇钠(0.02g,0.2mmol)加入到4mL甲苯溶液中混合均匀,然后向其中加入步骤S2制得的中间产物6-2(0.15g,0.18mmol)和吩噻嗪(0.04g,0.21mmol),在100℃反应48h,反应结束后旋蒸除去溶剂,并经高效液相制备色谱纯化得到化合物6(0.02g,0.02mmol,Y=11.75%)。
使用1H NMR对其进行表征。
1H NMR(500MHz,DMSO-d6)δ8.83(s,1H),8.67(s,1H),7.79(d,J=15.4Hz,1H),7.44–7.20(m,10H),7.11(dd,J=9.2,2.2Hz,1H),7.03(d,J=8.4Hz,1H),6.86(d,J=8.9Hz,1H),6.81(d,J=2.2Hz,1H),6.69(dd,J=8.9,2.3Hz,1H),6.30(dt,J=8.4,0.9Hz,1H),5.62(q,J=0.8Hz,1H),4.43(t,J=7.0Hz,2H),3.70(t,J=5.5Hz,2H),2.63–2.51(m,4H),2.26(d,J=17.8Hz,2H),2.04–1.85(m,2H),1.77(tt,J=6.9,5.5Hz,2H),1.72(s,4H),1.61(s,4H),1.59–1.45(m,8H),1.42–1.24(m,10H).
实施例7
化合物7的合成
和实施例1的区别仅在于,在步骤S3中,将醋酸钯(0.04g,0.16mmol)、三叔丁基磷(0.06g,0.31mmol)和叔丁醇钠(0.08g,0.79mmol)加入10ml甲苯溶液中混合均匀,然后加入步骤S2制得的中间产物1-2(0.5g,0.69mmol)和吩硒嗪(0.2g,0.83mmol),在100℃反应48h,反应结束后旋蒸除去溶剂,并经高效液相制备色谱纯化得到化合物7(0.06g,0.06mmol,Y=9.01%)。
使用1H NMR对其进行表征。
1H NMR(500MHz,DMSO-d6)δ7.88(dd,J=7.1,1.5Hz,2H),7.72–7.66(m,2H),7.66(d,J=15.4Hz,1H),7.63–7.58(m,1H),7.61–7.56(m,1H),7.58–7.50(m,2H),7.33(td,J=7.1,1.5Hz,2H),7.28(td,J=7.2,1.5Hz,2H),7.25(dd,J=8.0,1.3Hz,1H),7.22–7.13(m,2H),7.07(d,J=8.6Hz,1H),7.02(td,J=7.8,1.5Hz,1H),6.86(dd,J=6.5,1.5Hz,1H),6.23(dt,J=8.6,1.0Hz,1H),4.50(t,J=8.0Hz,2H),3.72(t,J=6.5Hz,2H),3.53(dt,J=14.8,11.0Hz,1H),3.42(dt,J=14.8,11.1Hz,1H),3.07(s,0H),3.03(s,1H),2.77–2.65(m,4H),2.12(tt,J=11.4,8.0Hz,2H),1.95(tt,J=10.9,6.4Hz,2H),1.72(s,5H),1.60–1.48(m,7H).
性能检测试验
用万分之一天平精确称量经过真空干燥后的染料,配制成2mmol/L的DMSO染料母液于棕色样品瓶中,在4℃冰箱中保存备用,对实施例1-7制备的化合物及中间产物进行如下性能测试:
1、对实施例1、3和5制备的化合物及实施例1的中间产物1-2进行光物理性能测试,测试结果参见图1-2。
使用移液枪量取6μL的染料母液,并将其溶于含有3mL待测溶剂的石英比色皿中,混合均匀,得到染料的浓度为4μmol/L,采用紫外可见分光光度计测出吸收光谱,采用荧光分光光度计测出荧光发射光谱,测试条件为:25℃。
图1为测试样品在甲醇中的吸收光谱图,由图1可以看出,化合物1、3和5的最大吸收波长分别为786nm、791nm和796nm,而中间产物1-2的最大吸收波长为783nm,化合物1、3和5的最大吸收波长相较于中间产物1-2发生红移,且化合物1、3和5的最大吸收波长均达到了近红外区(650-900nm)。
图2为测试样品在甲醇中的发射光谱图,由图2可以看出,化合物1的最大发射波长为816nm,达到了近红外区(650-900nm),相较于未经过取代的中间产物1-2的最大发射波长803nm而言,化合物1的发射光谱红移达到13nm。同时,可以观察到化合物3和5荧光发生淬灭,这表明化合物2和3可能具有较好的光动力或者光热性质。
2、对实施例1、3和5制备的化合物及实施例1的中间产物1-2进行绝对荧光量子产率的测定。
测试方法:用染料母液分别配置2μmol/L的化合物1-3的甲醇和水溶液,经绝对荧光量子产率仪(Hamamatsu,C11347)测得对应的绝对荧光量子产率,见表1。所有测试均在25℃下完成。
表1
甲醇/水中的激发波长(nm) | 甲醇 | 水 | |
化合物1 | 786/781 | 0.087 | 0.025 |
化合物3 | 791/787 | - | - |
化合物5 | 796/789 | - | - |
中间产物1-2 | 783/776 | 0.061 | 0.024 |
吲哚菁绿 | 781/779 | 0.059 | 0.019 |
由表1可以看出,化合物1在甲醇和水中的荧光量子产率较高,优于中间产物1-2及商业化的吲哚菁绿。这表明化合物1能够很好的应用于生物成像领域。同时,化合物3和5的荧光量子产率无法由仪器监测到,再次证明化合物3和5荧光发生淬灭,这表明化合物3和5可能具有较好的光动力或者光热性质。
3、对实施例3制备的化合物和实施例1的中间产物1-2进行活性氧测试
染料分子的活性氧通过1,3-二苯基异苯呋喃(DPBF)降解实验评估。DPBF是一款荧光探针,其可以特异性与单线态氧(1O2)、羟基自由基(HO·)等活性氧反应,并转化成1,2-二苯基苯(DBB)。发生反应后,DPBF被不可逆氧化,其在414nm处的吸收强度迅速降低。
用染料母液配置2μmol/L的化合物3的甲醇溶液,并加入适量DPBF使其吸光度为1,然后使用10mW/cm2、808nm激光照射含有溶液的石英比色皿,每1min测试溶液吸光度,测试共10min。所有测试均在25℃下完成,测试结果参见图3。
由图3可以看出,化合物3的DPBF降解速率优于中间产物1-2及商业化染料吲哚菁绿,这表明化合物3具有较好的光动力性质,可以将其用于光动力治疗。
4、对实施例5制备的化合物和实施例1的中间产物1-2进行光热效果测试
用染料母液配置30μmol/L的化合物5的水溶液,并封装入0.7ml离心管,然后使用500mW/cm2、808nm激光照射,每间隔30s使用红外相机记录其温度,测试共5.5min,测试结果参见图4。
由图4可知,化合物5的光热转换能力明显优于中间产物1-2及商业化染料吲哚菁绿,这表明化合物5具有较好的光热性质,可以将其用于光热治疗。
5、对实施例1、3、5制备的化合物进行细胞毒性测试
染料分子对细胞的毒性通过MTT测定评估。其原理为:活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性的蓝紫色结晶甲臜(Formazan)并沉积在细胞中,而死细胞无此功能。二甲基亚砜(DMSO)能溶解细胞中的甲臜,用酶标仪在490nm波长处测定其光吸收值,可间接反映活细胞数量。
在96孔板中接种4T1细胞,经过一段时间培养后分别向不同孔中加入一定浓度的化合物1和化合物3,使化合物浓度分别为0-30μmol/L,继续孵育细胞24h后通过MTT实验检测细胞活性并记录为细胞暗毒性,测试结果参见图5-6。
在96孔板中接种4T1细胞,经过一段时间培养后分别向不同孔中加入一定浓度的化合物1和化合物3,使化合物浓度分别为0μmol/L、1μmol/L、2μmol/L、5μmol/L、10μmol/L、15μmol/L、20μmol/L和30μmol/L,并在孵育细胞2h后使用500mW/cm2、808nm激光照射10min,然后继续孵育22h后通过MTT实验检测细胞活性并记录为细胞光毒性,测试结果参见图7-8。
图5为化合物1无光照条件下的MTT实验图;图6为化合物3无光照条件下的MTT实验图。
结合图5和图6可以看出,即使使用最大浓度30μmol/L的化合物1和3培养4T1细胞24h后,细胞仍然显示出良好的存活率,说明这类咔唑及吩嗪类化合物中位取代花菁类染料具有非常好的生物相容性,在工作浓度范围内不会对细胞产生毒副作用,因此可以应用于生物和医药领域中。
图7为化合物3光照条件下的MTT实验图;图8为化合物5光照条件下的MTT实验图。
结合图7和图8可以看出,在光照后,使用化合物3和5的各组细胞存活率明显下降,这表明化合物3和5在光照下具有明显的肿瘤细胞杀伤能力,可以将其用于肿瘤的光动力和光热治疗,而化合物1其荧光性质较强,所以其光毒性较低,无需进行光毒性实验。
6、对实施例5制备的化合物进行小鼠肿瘤光声成像测试
选用大连医科大学实验动物中心6周龄雌性BALB/c小鼠,建立乳腺癌小鼠模型。在右腋窝皮下注射1×104个4T1细胞,建立4T1荷瘤BALB/c小鼠模型。4T1荷瘤小鼠肿瘤体积计算为体积A=A*b2/2(A:长度;b:宽度)。肿瘤体积约200mm3后,对小鼠进行光声成像。
光声成像4T1荷瘤裸鼠经尾静脉注射浓度为30μmol/L的化合物5的生理盐水溶液。使用InVision128MSOT系统(iThermedical,Germany)在不同时间点监测小鼠肿瘤PA图像,测试结果参见图9。
由图9可以看出,由于化合物5具有明显的光声效应,化合物5拥有在生物体内进行光声成像的能力,且由此得到小鼠在尾静脉注射化合物5后其最佳光热治疗时间为8h。
7、对实施例5制备的化合物进行小鼠光热治疗测试
选用大连医科大学实验动物中心6周龄雌性BALB/c小鼠,分别注射生理盐水和浓度为30μmol/L的化合物5的生理盐水溶液。在8h后使用1W/cm2、808nm激光照射10min,每间隔1min使用红外相机记录其温度,测试结果参见图10。
由图10可以看出,化合物5即使在生物体内也具有理想的光热转化能力,这表明化合物5能够很好地用于生物体内的光热治疗。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (8)
2.根据权利要求1所述的一类咔唑及吩嗪类化合物中位取代花菁染料的制备方法,其特征在于,
所述制备方法包括如下步骤:
(1)在第一有机溶剂中,将含R3取代的2,3,3-三甲基吲哚Y-1与N烷基化试剂反应,反应温度为60-90℃,反应时间为3-48h,得到含N-R2取代侧链的Y-2;所述N烷基化试剂选自含R2取代的烷烃或卤代烷烃;
(2)将步骤(1)制得的Y-2和2-氯-3-(羟基亚甲基)-1-环己烯-1-甲醛与第二有机溶剂混合,在80-130℃下反应1-24h,得到中间产物Y-3;
(3)将步骤(2)制得的中间产物Y-3、含有R1的化合物、醋酸钯、三叔丁基磷和叔丁醇钠、第三有机溶剂混合均匀,在50-120℃下反应24-72h,得到咔唑及吩嗪类化合物中位取代花菁类荧光化合物I。
3.根据权利要求2所述的一类咔唑及吩嗪类化合物中位取代花菁染料的制备方法,其特征在于,在步骤(1)中,所述含R3取代的2,3,3-三甲基吲哚Y-1与N烷基化试剂的摩尔比为1:1-10;
第一有机溶剂选自丙酮、乙醇、乙腈、苯、甲苯和邻二氯苯中至少一种。
4.根据权利要求2所述的一类咔唑及吩嗪类化合物中位取代花菁染料的制备方法,其特征在于,在步骤(2)中,Y-2和2-氯-3-(羟基亚甲基)-1-环己烯-1-甲醛的摩尔比为1:1-3;
第二有机溶剂选自选自苯、甲苯、邻二氯苯、甲醇、乙醇、丙醇、丁醇、乙酸和乙酸酐中至少一种。
5.根据权利要求2所述的一类咔唑及吩嗪类化合物中位取代花菁染料的制备方法,其特征在于,在步骤(3)中,Y-3、含有R1的化合物、醋酸钯、三叔丁基磷和叔丁醇钠的摩尔比为1:1-2:0.1-0.5:0.3-0.5:1-2;
第三有溶剂选自苯、甲苯或邻二氯苯。
6.根据权利要求3所述的一类咔唑及吩嗪类化合物中位取代花菁染料的制备方法,其特征在于,在步骤(1)中,所述含R3取代的2,3,3-三甲基吲哚Y-1与N烷基化试剂的摩尔比为1:2-5。
7.权利要求1所述的一类咔唑及吩嗪类化合物中位取代花菁染料的应用,其特征在于,所述应用是在细胞/肿瘤成像、光动力及光热治疗中的用途。
8.根据权利要求7所述的一类咔唑及吩嗪类化合物中位取代花菁染料的应用,其特征在于,用于生物体内荧光成像和肿瘤治疗。
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