CN102796094B - 二卤荧光素衍生物及其用途 - Google Patents
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N C1OCCOC1 Chemical compound C1OCCOC1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JHGCXCKEILJXLO-UHFFFAOYSA-N C=CCc(c(O1)c(cc2Cl)C(c3ccccc3C(O)=O)=C(C=C3Cl)C1=CC3=O)c2O Chemical compound C=CCc(c(O1)c(cc2Cl)C(c3ccccc3C(O)=O)=C(C=C3Cl)C1=CC3=O)c2O JHGCXCKEILJXLO-UHFFFAOYSA-N 0.000 description 1
- ZGJPSUVUGBVRSC-UHFFFAOYSA-N C=CCc(c(O1)c(cc2Cl)C(c3ccccc3C(OCC=C)=O)=C(C=C3Cl)C1=CC3=O)c2O Chemical compound C=CCc(c(O1)c(cc2Cl)C(c3ccccc3C(OCC=C)=O)=C(C=C3Cl)C1=CC3=O)c2O ZGJPSUVUGBVRSC-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及一种二卤荧光素衍生物及其用途。所述的二卤荧光素衍生物为式I所示化合物或其在药理上能接受的盐,本发明所揭示的二卤荧光素衍生物用于制备非标记型碳酸酐酶IX荧光探针。式I中,R1和R2分别独立选自Cl或Br中一种,X为NH或O。
Description
技术领域
本发明涉及一种空间光诱导电子转移(SPET)的荧光探针及其用途,具体地说,涉及一种二卤荧光素衍生物及其在碳酸酐酶IX(Carbonic Anhydrase IX,CA IX)检测中的应用。
背景技术
CA IX是碳酸酐酶家族的一种亚型。碳酸酐酶家族在人体内主要作用是催化一个非常简单的反应:水合CO2生成碳酸氢盐和氢离子。由于该反应涉及CO2的吸收,氢离子浓度的调节,因此在体内很多的生理和病理过程,例如CO2的呼吸、运输,碳酸氢盐在组织和肺中的代谢,各种组织器官中的电解质分泌,糖、脂肪以及尿素等生物合成反应,骨骼的吸收、钙化以及肿瘤的生,都需要碳酸酐酶参与,可以说碳酸酐酶对于人的正常生理活动是必须。近段时间的研究表明,CA IX会在很多乏氧肿瘤中有异常高位的表达。到目前为止,在食道癌、肺癌、肾癌、结肠癌、直肠癌、乳腺癌、宫颈癌和膀胱癌中都有相应的文献报道CA IX的过量表达。正是由于CAIX在天然实体瘤的乏氧环境中过度表达,因此CAIX就可以很好的作为一个内源性的靶标,用于预测或者治疗癌症(Carbonic anhydrase-Its inhibitors and activators;CRC Press:Boca Raton,FL,2004;1-376)。
目前,用于检测碳酸酐酶的荧光探针主要是采用标记型的,该类标记型的在结合靶标前后荧光强度或者波长都没有变化,不利于排除干扰实现选择性检测。另外,非标记型探针的设计主要集中在对CA I和CA II的检测(Chemical Communications 2007,2723-5),基本没有报道对于CAIX选择性检测的非标记型荧光探针。因此研究简便、高效、快捷的非标记型CAIX荧光探针有着十分重要的意义。
发明内容
本发明对二卤荧光素和糖精通过哌嗪基团进行对接,合成出一个基于空间光诱导电子转移(SPET)的新型一个探针Z1,经体外酶体系和体内细胞系统测试表明对CA IX有很高的选择性和快速响应能力。此外,光谱测试表明:本发明的一个探针Z1在和CA IX结合后,用511nm激发,可以发现在534nm出的一个发射有明显的增强。生物测试表明,本发明的荧光探针Z1对CA IX有着很好的专一性、高灵敏性和快速响应的能力,CA I和CA II对其基本没有干扰,因此可以很好的利用该探针的特性对体内的CA IX含量进行跟踪,从而预防和检测癌症。
本发明所述的二卤荧光素衍生物为式I所示化合物或其在药理上能接受的盐:
式I中,R1和R2分别独立选自Cl或Br中一种,X为NH或O。
附图说明
图1:式I所示化合物在pH值为7.2的Tris-HCl(含1%DMSO,10mM的ZnCl2)缓冲液中的吸收谱图和发射光谱图:
其中:(a)为吸收光谱图;(b)为发射光谱图。
图2:式I所示化合物在pH值为7.2的Tris-HCl(含1%DMSO,10mM的ZnCl2)缓冲液中与CAIX结合前后的荧光光谱图;
其中:上曲线为式I所示化合物+CA IX,下上曲线为式I所示化合物。
图3:式I所示化合物在pH值为7.2的Tris-HCl(含1%DMSO,10mM的ZnCl2)缓冲液中与CAI结合前后的荧光光谱图;
其中:上曲线为式I所示化合物,下上曲线为式I所示化合物+CAI
图4:式I所示化合物在pH值为7.2的Tris-HCl(含1%DMSO,10mM的ZnCl2)缓冲液中与CAII结合前后的荧光光谱图;
其中:上曲线为式I所示化合物,下上曲线为式I所示化合物+CAII。
图5:式I所示化合物在SiHa细胞中的荧光成像图。
图6:不同条件下,式I所示化合物在SiHa细胞中的荧光成像图。
具体实施方式
在本发明一个优选的技术方案中,R1和R2分别独立选自Cl或Br中一种,X为NH;
更优选的技术方案是:R1和R2均为Cl,X为NH
下面通过实施例对本发明作进一步阐述,其目的仅在于更好理解本发明的内容。因此,所举之例并不限制本发明的保护范围。在下列实施例中,所述的室温是20℃~25℃。
实施例1
将22.0g(160mmol)的对硝基甲苯加入到53.0mL的氯磺酸中,60℃反应48h。反应结束后冷却到室温,然后缓慢倒入碎冰中,并用1L的乙醚萃取。有机相用饱和食盐水(500mL×3)洗涤,合并有机相后加入300mL的浓氨水,加热至50℃直到乙醚全部挥发完毕。反应液冷到到室温,过滤,粗产品用水重结晶两次,得到淡黄色针状晶体12.1g,产率35%,m.p.182-183℃.
将9.0g(900mmol)的三氧化铬溶解于84.0mL浓硫酸和67.0mL去离子水的混合溶剂中,冰浴搅拌至冷却到室温。然后分批将4.3g(20mmol)化合物1加入到反应液中,室温搅拌24h。反应结束后,将反应液倒入至碎冰中,过滤,得到白色粗产品粉末。粗产品再用10%的NaHCO3水溶液溶解,过滤除去不溶性杂质,滤液再用5%的HCl酸化,过滤得到白色粉末1.8g,产率40%,mp 209-210℃。
1H NMR(400MHz,DMSO-d6,20℃):δ=8.45(t,J=1.6,2.0Hz,1H),8.42(s,1H),7.85(d,J=8Hz,1H),EI MS(m/e)228(M+,100)。
将5.7g(20mmol)化合物2溶解与50mL的甲醇中,缓慢加入570mg的10%Pd/C,氢气条件下室温搅拌4h。反应液用硅藻土过滤除去Pd/C,然后将滤液真空旋干,得到淡黄色粉末4.0g,产率80%,m.p.263-264℃。
1H NMR(400MHz,DMSO-d6,20℃):δ=7.24(s,1H),7.22(s,1H),6.69(s,2H),6.66(d,J=2.0Hz,1H),6.64(d,J=1.6,1H).EI MS(m/e)198(M+,100)。
将1.0g(5mmol)化合物3,1.3gNaHCO3溶于30mL水中,室温条件下缓慢滴加1.2g(10mmol)的2-氯乙酰氯,滴加完毕后室温搅拌2h。随后,反应液用2M的HCl调至pH为2-3,并有白色沉淀产生。过滤得到灰白色沉淀1.1g,产率80%,mp>300℃。
1H NMR(400MHz,DMSO-d6,20℃):δ=10.85(s,1H),8.07(s,1H),7.71(d,J=8.0Hz,1H),7.67(dd,J=4.0,8.4Hz,1H),4.33(s,2H).EI MS(m/e)274(M+,36)and 198(100)。
将1.0g(2.5mmol)2’,7’-二氯荧光素,2.1g(2.5mmol)K2CO3溶于15mL DMF中,冰浴下缓慢滴加0.9mL(10mmol)的溴丙烯,滴加完毕后室温反应3.5h。随后将反应液倒入到400mL去离子水中,用100mL ×3的乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,真空旋干滤液,得到橙色固体粗产品。粗产品柱层析分离(乙酸乙酯∶石油醚=1∶2(v/v)),得到亮橙色固体粉末1.0g,产率84%。
1H NMR(400MHz,CDCl3,20):δ=8.29(d,J=7.6Hz,1H),7.79(t,J=7.2,6.8Hz,1H),7.73(d,J=7.2Hz,1H),7.36(t,J=7.6,9.6Hz,1H),6.97-6.82(m,3H),6.69(t,J=7.6,9.2Hz,1H),6.11-6.04(m,1H),5.66-5.58(m,1H),5.49(dd,J=7.2,7.2Hz,1H),5.38(d,J=10.4Hz,2H),4.72(dd,J=4.4,4.8Hz,2H),4.48(s,2H).
13C NMR(100MHz,CDCl3,20℃):δ=178.67,164.76,158.59,153.25,150.48,149.30,133.79,132.87,131.48,131.34,130.86,130.59,130.10,129.08,129.03,126.74,119.49,118.88,118.14,115.94,111.97,111.09,109.93,101.16,70.32,66.14.EI MS(m/e)480(M+,100)。
240mg(0.5mmol)的化合物5至于2.0mL的二苯基醚中,油浴加热至200℃,反应2h。随后冷却至室温,将反应液直接柱层析分离(乙酸乙酯∶石油醚=2∶5(v/v)),得到155mg橙色固体,产率65%。
1H NMR(400MHz,CDCl3,20℃):δ=8.29(d,J=7.6Hz,1H),7.79(t,J=7.6Hz,6.4Hz,1H),7.72(t,J=7.6Hz,7.6Hz,1H),7.37(t,J=7.6Hz,10.8Hz,1H),7.13(s,1H),6.91-6.83(m,3H),6.69(d,J=10.0Hz,1H),6.12-6.03(m,1H),5.68-5.58(m,1H),5.49(dd,J=5.6Hz,5.6Hz,1H),5.39(dd,J=5.2Hz,5.2Hz,1H),5.16(s,1H),5.12(d,J=6.0Hz,1H),4.74(d,J=5.2Hz,1H),4.71(d,J=5.6Hz,1H),4.49(t,J=5.6Hz,3.2Hz,2H).
13C NMR(100MHz,CDCl3,20℃):δ=178.82,164.77,158.50,154.35,153.22,150.14,149.26,133.83,132.86,131.49,131.35,130.85,130.59,130.07,129.18,129.06,126.65,119.52,119.34,118.89,118.17,115.92,109.82,101.28,70.30,66.15,29.71.EI MS(m/e)480(M+,100)。
将96mg(0.2mmol)的化合物6,5.3mg(0.3mmol)氢氧化锂,0.2mL水溶于8mL的1,4-二氧六环中,加热至回流2.5h。反应结束后冷却至室温,用1M的HCl中和,再用乙酸乙酯萃取(20mL),合并有机相。有机相分别用饱和食盐水,饱和NaHCO3溶液洗涤,无水MgSO4干燥,过滤,真空旋干滤液。粗产品用柱层析分离(乙酸乙酯∶石油醚=2∶1(v/v)),得到亮橙色固体79mg,产率90%。
1H NMR(400MHz,CDCl3,20℃):δ=8.06(d,J=7.6Hz,1H),δ=7.75-7.66(m,2H),δ=7.19(d,J=7.2Hz,1H),δ=6.98(s,1H),δ=6.72(s,1H),6.62(s,1H),δ=6.07-5.98(m,1H),δ=5.17(d,J=17.2Hz,1H),δ=3.69(d,J=6Hz,1H),δ=3.50(s,1H),δ=2.98(s,2H).EIMS(m/e)441(M+1,100)。
将127mg(0.68mmol)的N-Boc-哌嗪,41mg的多聚甲醛至于10mL的无水乙腈中回流0.5h。然后将溶于3mL无水乙腈的100mg(0.2mmol)的化合物7加入到反应液中,继续回流4.5h。反应结束后冷却到室温,直接真空旋干溶剂,柱层析分离(乙酸乙酯∶二氯甲烷=1∶6(v/v)),得到橙红色的固体110mg,产率76%。
1H NMR(400MHz,CDCl3,20℃):δ=8.08(d,J=7.2Hz,1H),δ=7.69-7.78(m,2H),δ=7.22(d,J=7.2Hz,1H),δ=6.67(s,1H),δ=6.63(s,1H),δ=6.08-5.98(m,1H),δ=5.16-5.10(m,2H),δ=4.13(dd,J=14.8Hz,15.2Hz,2H),δ=3.70-3.68(m,1H),δ=3.81-3.35(br,4H),δ=2.82-2.52(br,4H),δ=2.33(d,J=3.6Hz,1H),δ=2.28(s,1H),1.15(s,9H).
13C NMR(100MHz,CDCl3,20℃):δ=168.70,156.00,154.42,151.56,150.84,148.14,135.36,134.53,130.32,129.56,128.91,127.56,126.87,126.02,125.78,125.52,125.33,123.93,117.14,115.88,115.16,112.41,110.37,108.64,82.59,80.38,54.57,52.63,28.38.
将化合物8溶于0.5mL的三氟乙酸中,室温搅拌过夜,旋干溶剂,得到橙色固体,无需纯化直接用于下步反应。
将20mg(0.04mmol)化合物9,33mg(0.3mmol)三乙胺溶于5mL的无水DMF中,室温搅拌0.5h。然后加入溶于0.5mL无水DMF的51mg(0.2mmol)的化合物4,室温继续搅拌12h。反应结束后真空除去溶剂,HPLC分离(5%-100%CH3CN),得到15mg橙红色固体,产率53%.HRMS(ESI):[M-H-]C37H29Cl2N4O9S计算值775.1038,检测值775.1035.
1H NMR(400MHz,CD3OD,20℃):δ=8.79(s,1H),δ=8.27(s,1H),δ=8.14(d,J=7.2Hz,1H),δ=7.81-7.92(m,1H),δ=7.73(d,J=8.0Hz,1H),δ=7.70-7.63(m,2H),δ=7.24(d,J=7.2Hz,1H),δ=7.14(d,J=9.6Hz,2H),δ=6.13-6.03(m,1H),δ=5.12(d,J=17.2Hz,1H),δ=5.04(d,J=9.6Hz,1H),δ=4.55(s,2H),δ=3.74(d,J=5.2Hz,2H),δ=3.63-3.59(m,1H),δ=3.56-3.50(m,1H),δ=3.42(s,4H),δ=3.38(s,2H),δ=2.93(s,3H).
13C NMR(100MHz,CD3OD,20℃):δ=169.43,169.01,168.93,168.85,163.224,154.04,147.69,145.30,141.97,135.99,134.02,131.25,129.76,129.72,129.53,129.22,128.86,128.79,128.35,127.12,123.59,123.17,114.11,113.80,110.61,110.24,104.53,62.96,60.50,51.79,50.19,27.45.
实施例2
式I所示化合物的光谱性能测试
1)紫外及荧光光谱的测定:
将式I所示化合物(以下简记为Z1)真空干燥后,天平上精确称量样品(精确到0.0001克),用二甲基亚砜定容,配成10-3M的溶液并定容于10mL容量瓶中,以此为母液,配制不同浓度的Z1溶液用于吸收光谱和激发-发射光谱的测试,结果见表1(Z1在Tris-HCl(含0.01%DMSO,0.1mM ZnCl2)缓冲液的光谱数据):
表1
2)Z1分别对碳酸酐酶I,II和IX的荧光响应:
将1×10-3mol/L的标准探针母液用Tris-HCl缓冲液稀释到0.1μM的溶液(包含0.01%的DMSO和0.1mM ZnCl2),然后将配置好的酶母液滴加到探针的缓冲液体系中,检测体系的荧光变化。测试所用的碳酸酐酶I和II(购自Sigma公司),碳酸酐酶IX由大肠杆菌表达(根据以下相关文献:J.Med.Chem.2005,48,1941-1947;Biochem.Bioph.Res.Co.2001,288,666-669;J.Med.Chem.2007,50,1651-1657.),所有的测试都在40μL的微量荧光比色皿中进行。在测试中,酶加入的浓度从0增加到2μM,每次加入酶混合均匀后,在37℃下稳定3min后测试。从图2-4我们可以看出,碳酸酐酶I和II会导致Z1的荧光发射降低,而碳酸酐酶IX会使得Z1的发射增强。
实施例3
Z1分别对碳酸酐酶I,II和IX抑制常数的测定
抑制常数的测定我们使用Stopped-flow方法来获得,原理是利用碳酸酐酶催化CO2的水合,从而改变测试体系的pH值,再利用检测酚红指示剂在不同pH下557nm处的吸收来计算得到探针与酶的抑制常数,具体见表2(Z1、AZA(对照物,购自Sigma公司)和EZA(对照物,购自Sigma公司)对碳酸酐酶I,II和IX的抑制常数)。
表2
实施例4
Z1在活体细胞中的分析:
将SiHa细胞株均匀的接种到24孔板中,分别在有氧培养箱(5%CO2)和乏氧培养箱(5%CO2+95%N2)培养48h。然后将探针分子溶解在DMSO中,并用PBS稀释到10-3mol/L,备用。取出培养48h后的24孔板,分别用PBS和无血清的培养基洗涤三次,然后再加入500μL的无血清培养基,加入一定量的探针分子,使探针分子在培养基中的最终浓度为10-5mol/L,随后在1min-20min内,间隔固定时间用倒置荧光显微镜拍摄细胞的明场图片和荧光图片,结果见图5和6。
图5所表述的内容为:SiHa细胞分别在有氧条件下和乏氧条件下培养48h,PBS处理后加入一定量的探针分子,并且培养一段时间后,用倒置荧光显微镜拍摄的有氧条件和乏氧条件下细胞的明场图片和荧光图片。
图6所表述的内容为:SiHa细胞分别在有氧条件下和乏氧条件下培养48h,PBS处理后加入一定量的探针分子,使探针分子在培养基中的最终浓度为10-5mol/L,随后在1min-20min内,间隔固定时间用倒置荧光显微镜拍摄的有氧条件和乏氧条件下细胞的明场图片和荧光图片。
Claims (3)
1.一种二卤荧光素衍生物:为式I所示化合物或其在药理上能接受的盐:
式I中,R1和R2分别独立选自Cl或Br中一种,X为NH。
2.如权利要求1所述的二卤荧光素衍生物,其特征在于,其中R1和R2均为Cl。
3.如权利要求1或2所述的二卤荧光素衍生物在制备非标记型碳酸酐酶IX荧光探针中的应用。
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