CN116041225B - 一种前列腺特异性膜抗原靶向的aie荧光化合物及制备方法 - Google Patents
一种前列腺特异性膜抗原靶向的aie荧光化合物及制备方法 Download PDFInfo
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Abstract
本发明公开了前列腺特异性膜抗原靶向的AIE荧光化合物及其制备方法与应用,属于前列腺特异性膜抗原探针制备技术领域。本发明通过在不破坏靶向结构和功能的前提下,实现了前列腺特异性膜抗原的AIE荧光探针的构建。相比现有的荧光分子和靶向肽连接的策略,本发明将AIE分子嵌合于前列腺特异性膜抗原靶向肽GUL的结构中,可以在前列腺特异性膜抗原高表达的肿瘤细胞表面发生聚集,分子内旋转受限(RIR)产生AIE发光,具有发光强度高,背景低和灵敏度高的特性。
Description
技术领域
本发明属于前列腺特异性膜抗原制备技术领域,具体涉及一种前列腺特异性膜抗原(PSMA)靶向的AIE荧光化合物,及其制备方法与应用。
背景技术
一直以来肿瘤细胞的标记和成像被应用于癌症的诊断和临床治疗,这促进了癌细胞标记探针的开发。而标记的效果取决于靶向分子对癌细胞表达标志物的亲和力,以及荧光分子的生物相容性和荧光特性。
前列腺特异性膜抗原(PSMA)是一种表达在细胞膜上的跨膜糖蛋白,是一种独特的分子靶点。相比于正常前列腺组织和身体的其他部位,PSMA在前列腺癌(PCa)中呈现出特异性高表达模式,并且其表达水平与PCa的侵袭性高度相关。因此,PSMA成为了PCa的经典分子靶标,并在过去的二十年中吸引了大量研究者的瞩目。谷氨酸的主链氨基与赖氨酸的主链氨基通过形成脲的结构序列(GUL)可以与PSMA特异性的相结合。因此,基于该GUL结构的很多荧光标记探针被开发出来,包括与荧光素、罗丹明、BODIPY、花菁等传统染料的结合。但是这些探针都存在着荧光染料在生物溶液中带来的高背景问题,很难将非特异性的探针荧光发射和目标靶区的荧光发射区分开来,给探针精确度带来了不好的影响。另外传统荧光分子在生物靶向聚集的过程中会产生荧光猝灭现象(ACQ),使探针灵敏度降低。聚集诱导发光(AIE)分子则很好的解决了这种困扰,其发光机制依靠聚集体中分子内旋转(RIR)被限制,荧光强度随这分子聚集被开启和增强,在稀溶液中几乎不发光,这种低背景和高灵敏度的优势使它普遍应用于癌症识别、细胞器成像和生物大分子成像。
发明内容
本发明通过将AIE荧光分子嵌合在多肽中,构建了一种具有AIE荧光性质的靶向肽Ac-f-TPE-GUL,目的是提供一种新的PSMA靶向的AIE荧光探针,及其制备方法与应用。
本发明采用的技术方案是:
一种PSMA靶向的具有AIE荧光性质的化合物,其结构如式(VII)所示:
所述Ac-f-TPE-GUL(VII)具有AIE发光特性,在溶解性强的溶剂中无荧光;在溶解性较差的溶液中,随着浓度的增高,分子内旋转(RIR)被限制而产生荧光,最大发射波长为460nm。进一步具有特异性靶向前列性特异性膜抗原高表达的癌细胞的能力。
本发明还涉及制备所述的荧光化合物的方法,所述方法包括:
第一步,化合物(II)与联硼酸频那醇脂在DMF溶剂中,70~80℃和氮气保护条件下,以PdCl2(dppf)为催化剂,在KOAc存在下进行suzuki反应,反应结束后分离纯化得到化合物(III);
第二步,化合物(III)与三苯基溴乙烯在THF和H2O混合溶剂中,70~80℃和氮气保护条件下,以Pd(pph3)4为催化剂,在K2CO3存在下进行suzuki反应,反应结束后分离纯化得到化合物(IV);
第三步,化合物(IV)使用HCl-1,4二氧六环溶液脱去Boc保护基得到化合物(I);
第四步,式(I)所示的具有AIE特性的苯丙氨酸衍生物在50℃条件,DIEA存在下,在DMF溶剂中用Fmoc-OSU保护氨基得到化合物(V)。
第五步,采用常规的多肽树脂固相合成(VI)所示三肽链。式(V)所示作为特殊氨基酸,置于直链肽末端。氨基酸C端到N端延伸顺序为:H-Glu(OtBu)-OtBu、Fmoc-Lys(Dde)-OH、化合物(V)。
第六步,化合物(VI)使用95%TFA脱去氨基酸所有保护基,得到所述荧光化合物(VII);
第二步中,化合物(II)、联硼酸频那醇脂、PdCl2(dppf)和KOAc的物质的量之比优选为1:1.5:0.06:2.8。具体的,步骤(2)中分离纯化方法为柱层析,以二氯甲烷:甲体积比30:1混合液为洗脱剂,收集目标组分,干燥,获得所述式(III)化合物。
第三步中,化合物(III)、三苯基溴乙烯、Pd(pph3)4、K2CO3的物质的量之优选为1:1.2:0.05:3;溶剂中THF:H2O体积比为10:1。具体的,步骤(3)中分离纯化方法为柱层析,以二氯甲烷:甲体积比15:1混合液为洗脱剂,收集目标组分,干燥,获得所述式(IV)化合物。
第四步中,化合物(I):Fmoc-OSU:DIEA物质的量之比为1:1.5:3。
第五步中,氨基酸缩合条件为:树脂:氨基酸:HBTU:DIEA=1:3:3:3。Fmoc保护基以20%哌碇DMF的溶液脱除。
本发明还涉及所述荧光化合物作为荧光探针在细胞荧光共聚焦成像中的应用,具体的,所述荧光探针靶向PSMA高表达的癌细胞。
本发明的有益效果主要体现在:本发明合成了一种新的具有AIE发光功能的靶向肽Ac-f-TPE-GUL,实现了在不破坏靶向结构和功能的前提下,前列腺特异性膜抗原(PSMA)的AIE荧光探针的构建。相比现有将传统荧光分子和靶向肽GUL相连的策略,本发明将AIE分子嵌合于PSMA靶向肽GUL的结构中,可以在PSMA高表达的肿瘤细胞表面发生聚集,分子内旋转受限(RIR)而产生AIE发光,具有发光强度高,背景低和灵敏度高的特性。
附图说明
图1为化合物(III)的核磁氢谱图。
图2为化合物(IV)的核磁氢谱图。
图3为化合物(I)的核磁氢谱图。
图4为化合物(I)的核磁碳谱图。
图5为化合物(V)的核磁氢谱图。
图6为化合物(VII)的核磁氢谱图。
图7为化合物(VII)浓度为40μM时,在二甲亚砜和PBS溶液中的荧光光谱图。
图8为在PBS溶液中(1%DMSO),不同浓度化合物(VII)的荧光光谱图。
图9为化合物(VII)在PC-3细胞中孵育30min后的荧光共聚焦成像图。
图10为化合物(VII)在A549细胞中孵育30min后的荧光共聚焦成像图。
具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此:
实施例1:化合物(VII)的合成
(1)化合物II 2.0g(5.12mmol)溶于3mL无水DMF中,加入联硼酸频那醇脂1.9g(7.67mmol),PdCl2(dppf)224.3mg(0.306mmol),醋酸钾1.4g(14.3mmol),在氮气保护,80℃条件下反应12小时。TLC点板反应完全(TFA熏后茚三酮显色),分别加入50mL的二氯甲烷和水,萃取2遍收集有机相。饱和氯化钠溶液洗涤,无水硫酸钠干燥后,减压旋蒸去除溶剂,取浓缩物进行硅胶柱分离(二氯甲烷:甲醇=30:1,v/v),得到无色油状物化合物III 1.82g,产率91%。化合物III核磁氢谱图见图1,(1H NMR(500MHz,CDCl3)δ7.77(d,J=7.8Hz,2H),7.21(d,J=7.5Hz,2H),4.94(d,J=7.0Hz,1H),4.61(d,J=5.5Hz,1H),4.14(q,J=7.1Hz,1H),3.18(ddd,J=51.3,13.9,5.6Hz,2H),1.35(s,12H),1.32–1.20(m,9H).
(2)化合物(III)准确称取939mg(2.4mmol),加入三苯基溴乙烯670.4mg(2mmol),Pd(PPh3)4 115.55mg(0.1mmol),碳酸钾828mg(6mmol),溶于3mL四氢呋喃溶液中,并加入300μL ddH2O。在80℃氮气保护条件下反应8小时。TLC监测反应完全后,加入等体积的乙酸乙酯和水,萃取收集有机相层,饱和氯化钠水洗并用无水硫酸钠干燥。减压旋蒸去除溶剂,取浓缩物进行硅胶柱分离(二氯甲烷:甲醇=15:1,v/v),收集得到1.18g黄色油状物,即为化合物IV,产率95%。化合物IV核磁氢谱图见图2,(1H NMR(500MHz,CDCl3)δ7.11–7.06(m,3H),7.06–6.94(m,12H),6.88(s,4H),4.17(s,1H),2.87(d,J=210.4Hz,2H),1.30–1.24(m,9H)。
(3)1.18g化合物IV加入20mL HCl-二氧六环溶液,常温搅拌1h,减压浓缩后加入乙醚,抽滤得到白色固体化合物(I)。化合物(I)核磁氢谱图见图3,1H NMR(500MHz,DMSO)δ8.48(s,2H),7.17–7.07(m,9H),7.06(d,J=8.1Hz,2H),7.01–6.94(m,6H),6.92(d,J=8.2Hz,2H),4.06(t,J=6.4Hz,1H),3.09–2.98(m,2H)。化合物(I)核磁碳谱见图4。
(4)准确称取化合物(I)1.0g(2.39mmol),Fmoc-OSU 1.2g(3.58mmol)溶解在30mLDMF溶液中,加入1.2mL DIEA,40℃下反应4小时。TLC监测反应完全后,加入二氯甲烷和水,萃取收集有机相层。减压旋蒸去除溶剂,取浓缩物进行硅胶柱分离(二氯甲烷:甲醇=20:1,v/v),收集得到白色固体化合物1.58g,即为化合物V。化合物V核磁氢谱图见图5,1H NMR(500MHz,DMSO)δ7.93–7.82(m,2H),7.62(dd,J=6.7,3.3Hz,2H),7.44–7.33(m,2H),7.30–7.21(m,2H),7.12–7.00(m,9H),6.92(dd,J=19.3,7.3Hz,8H),6.77(d,J=7.8Hz,2H),4.26(dd,J=9.6,7.0Hz,1H),4.10(dt,J=17.6,7.4Hz,2H),3.94(s,1H),3.02(d,J=11.3Hz,1H),2.82–2.71(m,1H).
(5)化合物(VI)的合成使用多肽的固相合成方法:在固相合成装置中加入1gFmoc-Lys(Dde)-Wang树脂(0.5mmol),1.53g N,N'-二琥珀酰亚胺基碳酸酯(3mmol)和61mg(0.5mmol)的DMAP,DMF做溶剂,最后加入1.57mL DIEA(6mmol)反应3个小时,茚三酮检测确定反应终点。抽去反应液,DMF洗涤3次。洗净后,直接投料,根据比例加入0.9g(3mmol)H-Glu(OtBu)-OtBu.HCl,61mg(0.5mmol)的DMAP,DMF做溶剂,最后加入1.57mL DIEA(6mmol)反应过夜,抽去反应液,DMF洗涤3次。加入3%水合肼的DMF溶液脱去Dde保护,30分钟后抽去反应液。化合物(V)940mg(1.5mmol),HBTU 570mg(1.5mmol),DIEA250μL(1.5mmol)反应30分钟茚三酮检测试剂检测反应完全后抽去反应液。加入20%哌啶的DMF溶液脱保护20min,DMF洗涤4次。再用醋酸酐封端液10mL(10%醋酸酐:6%N-甲基吗啉:84%DMF)封端1个小时,茚三酮检测试剂检测反应完全后抽去反应液。DMF洗涤3次,甲醇洗涤3次,抽干得树脂化合物(VI)。
(6)所得化合物(VI)加入95%TFA和5%H2O的溶液20mL,反应2小时脱去所有保护基团,倒入100mL冰乙醚中析出白色固体(VII)。进一步反向制备得到150mg纯品化合物(VII),核磁图谱见图6,H NMR(400MHz,DMSO)δ8.04(d,J=8.5Hz,1H),7.93(t,J=5.6Hz,1H),7.17–7.05(m,9H),7.01–6.90(m,8H),6.84(d,J=8.1Hz,2H),6.31(dd,J=14.2,8.2Hz,2H),4.36(td,J=9.0,5.5Hz,1H),4.06(dtd,J=23.8,8.1,5.4Hz,2H),2.96(dd,J=12.5,6.4Hz,2H),2.83(dd,J=13.7,5.1Hz,1H),2.62(dd,J=13.6,9.8Hz,1H),2.24(dd,J=15.6,7.2Hz,2H),1.98–1.83(m,1H),1.72(s,3H),1.64–1.78(m,3H),1.39–1.20(m,4H).
实施例2:化合物(VII)的荧光性能检测
(1)不同溶剂中荧光性能检测:
移液枪吸取10μL的化合物(VII)DMSO母液(4mM)分别加入到990μL PBS溶液(pH7.2,50mmol/L)和990μL DMSO溶液中,探针浓度均为40μM。使用酶标仪,37℃下分别测定其荧光值,激发波长为340nm,发射波长为460nm,荧光谱图见图7。
实验证明,化合物(VII)(40μM)在溶解性好的DMSO溶液中荧光强度大大低于在溶解性较差的PBS溶液,由溶解性导致的AIE荧光特征明显。
(2)不同浓度下荧光性能检测:
移液枪吸取10μL的化合物(VII)DMSO溶液(8mM)加入到990μL PBS溶液(pH 7.2,50mmol/L)中,化合物(VII)浓度为80μM,依次稀释为不同浓度(2μM、20μM、40μM、80μM),37℃、340nm激发下测定其荧光值。发射波长为460nm,荧光谱图见图8。
实验证明,在PBS溶液中,发射波长为460nm的条件下,随着荧光化合物(VII)随着浓度逐渐升高,荧光差异变化明显,80μM浓度的荧光强度超过了2μM荧光强度的150倍,表现出AIE灵敏的荧光响应以及低荧光背景值。
实施例3:化合物(VII)的靶向功能研究
PC-3和A549细胞以接近3×105个细胞分别接种培养在2个共聚焦盘中,由DMEM培养液在37℃、5%CO2条件下进行恒温培养,培养24小时后,移除DMEM培养液,PBS 7.2缓冲液洗涤3次。分别加入配好的5μM浓度化合物(VII)的DMEM培养基(1%DMSO),37℃下孵育30分钟。移除DMEM培养液,PBS 7.2缓冲液洗涤2次,用荧光共聚焦显微镜进行荧光成像,发射波长为460nm。图9为PC-3细胞荧光成像图,图10为A549细胞荧光成像图。
实验证明,在前列腺特异性膜抗原(PSMA)相对高表达的PC-3细胞中,细胞膜被成功的标记,出现明显的荧光,而细胞内部和细胞外溶液中基本没有荧光显示,说明了化合物(VII)良好的膜靶向。在PSMA低表A549细胞中,没有明显的荧光出现,进一步证明了化合物(VII)的特异性靶向功能。
Claims (8)
1.一种前列腺特异性膜蛋白靶向的AIE荧光化合物,其特征在于:所述AIE荧光化合物得结构如下式所示:
2.一种前列腺特异性膜蛋白靶向的AIE荧光化合物的制备方法,其特征在于:所述方法包括:
第一步,化合物(II)与联硼酸频那醇脂在DMF溶剂中,在反应条件为70~80℃和氮气保护条件下,以PdCl2(dppf)为催化剂,在KOAc存在下进行suzuki反应,反应结束后分离纯化得到化合物(III);
第二步,化合物(III)与三苯基溴乙烯在THF和H2O混合溶剂中,在反应条件为70~80℃和氮气保护条件下,以Pd(pph3)4为催化剂,在K2CO3存在下进行suzuki反应,反应结束后分离纯化得到化合物(IV);
第三步:化合物(IV)脱去Boc保护基得到化合物(I);
第四步,式(I)所示的苯丙氨酸衍生物在DIEA存在下,DMF溶剂中用Fmoc-OSU保护氨基得到化合物(V);
第五步,采用Wang树脂固相合成式(VI)所示三肽链,氨基酸C端到N端延伸顺序为H-Glu(OtBu)-OtBu、Fmoc-Lys(dde)-OH、化合物(V);
第六步,化合物(VI)脱去氨基酸所有保护基,得到所述荧光化合物(VII);
3.根据权利要求2所述的一种前列腺特异性膜蛋白靶向的AIE荧光化合物的制备方法,其特征在于:第一步中,所述的化合物(II)、联硼酸频那醇脂、PdCl2(dppf)和KOAc的物质的量之比为1:1.5:0.06:2.8。
4.根据权利要求3所述的一种前列腺特异性膜蛋白靶向的AIE荧光化合物的制备方法,其特征在于:第三步中,所述的化合物(III)、三苯基溴乙烯、Pd(pph3)4、K2CO3的物质的量之比为1:1.2:0.05:3;溶剂中THF:H2O体积比为10:1。
5.根据权利要求2所述的一种前列腺特异性膜蛋白靶向的AIE荧光化合物的制备方法,其特征在于:第四步中所述的化合物(I):Fmoc-OSU与DIEA物质的量之比为1:1.5:3。
6.根据权利要求2所述的一种前列腺特异性膜蛋白靶向的AIE荧光化合物的制备方法,其特征在于:所述荧光化合物在制备用于荧光共聚焦细胞成像的荧光探针中。
7.根据权利要求6所述的一种前列腺特异性膜蛋白靶向的AIE荧光化合物的制备方法,其特征在于:所述荧光探针靶向前列腺特异膜抗原高表达的癌细胞。
8.根据权利要求7所述的一种前列腺特异性膜蛋白靶向的AIE荧光化合物的制备方法,其特征在于:所述癌细胞为前列腺癌(PCa)细胞。
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