CN116891479A - 一种靶向mor的响应性半花菁荧光探针、其合成方法及应用 - Google Patents
一种靶向mor的响应性半花菁荧光探针、其合成方法及应用 Download PDFInfo
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Abstract
本发明公开了一种靶向MOR的响应性半花菁荧光探针、其合成方法及应用，所述半花菁荧光探针的结构式如下式(I)所示。该响应性荧光探针通过把一种醛基修饰的半花菁染料和具有氨基延长链修饰的MOR拮抗剂纳曲酮连接而设计。本发明的荧光探针能够作为工具分子用于筛选MOR的激动剂或拮抗剂，可以快速、准确地确证小分子化合物与受体蛋白的结合情况。该探针对MOR具有高选择性的识别作用，在675‑850nm发射下，可对MOR受体蛋白细胞高效响应，发出荧光信号。作为一种靶向工具分子，在靶向识别领域以及分析药物相互作用，研究药物作用机制方面具有重要的应用价值和广阔的应用前景。
Description
技术领域
本发明涉及一种荧光分子探针及其合成方法和应用，具体涉及一种靶向MOR的响应性半花菁荧光探针、其合成方法及应用。
背景技术
荧光染料被广泛应用于生物标记和识别、体内成像、微环境监测、光声成像结合化学发光技术等多个领域当中，在DNA识别基因测序、生物特异性识别蛋白、靶向肿瘤标志物等应用中发挥重要作用。目前常见的商业化荧光染料主要为荧光素，香豆素，罗丹明，萘亚胺类，CY染料等。荧光染料的性能将直接影响到分析的准确度和灵敏度，然而这些染料都在一定程度上存在缺陷而影响它们的应用。例如：1.水溶性普遍较差；2.吸收波长和发射波长较短，容易在成像和分析过程中受到生物背景荧光的干扰；3.光稳定性差，增加了产品运输和储藏成本，而且无法重复检测；4.与生物大分子结合后，可能会受到生物大分子的影响而导致本身光物理性质发生改变，从而影响检测和分析的结果。因此，研究开发水溶性好、光稳定性好、特异性高、灵敏度好、组织深度穿透力高以及信噪比高，可有效防止假阳性信号以及波长可调控的，标记前后无明显光物理性质变化的荧光染料对荧光检测和生命健康领域具有重要的意义。
μ阿片受体(μopioid receptors，MOR)是一种典型的G蛋白偶联受体。MOR受体是与Gi蛋白偶联结合的7跨膜家族成员受体，是阿片类药物发挥作用的主要靶点。外源性阿片类物质(如吗啡)和内源性阿片配体(如内啡肽、脑啡肽以及dinorphins)均可使其激活。MOR广泛存在于中枢和外周神经系统，还在多种组织中表达。纳曲酮是阿片受体拮抗剂，药效学与纳洛酮的作用相似，能明显的减弱或完全阻断阿片受体，甚至反转由静脉注射阿片类药物所产生的作用，能解除其对阿片的身体依赖性，使已戒断阿片瘾者保持正常生活，作用维持时间较长，而且不产生躯体或精神依赖性。
发明内容
发明目的：本发明针对现有技术的不足，提供一种靶向MOR的响应性半花菁荧光探针、其合成方法及应用。
本发明提供的探针分子由MOR特异性药效团纳曲酮与近红外半花菁染料作为荧光基团组成，利用该探针扭曲分子内电荷转移(TICT)等光物理特性，将合理的荧光开关机制引入并构建出一种针对μ阿片受体的响应型荧光配体。当探针与μ阿片受体发生识别过程后，探针分子内的电荷转移与运动会受到影响，导致荧光发射增加，并以此荧光探针作为工具分子用于实现μ阿片受体的靶向成像与其配体的筛选。
技术方案：本发明所述的靶向MOR的响应性半花菁荧光探针，结构式如式(I)所示：
所述的靶向MOR的响应性半花菁荧光探针的合成方法，包括如下步骤：
(1)以2，3，3-三甲基吲哚和丙磺酸内酯为原料合成磺酸吲哚，再通过缩合反应得到全花菁染料，全花菁染料和2，4-二羟基苯甲醛发生retro-Knoevenagel反应生成半花菁染料，即中间体1-3；
(2)以纳曲酮作为原料还原为纳曲醇，通过Boc保护酚羟基、再通过酯化反应与丙氨酸连接、脱BOC保护，即可在特定位点连上伯氨基，得到中间体2-4；
(3)醛基修饰的半花菁染料中间体1-3和氨基连接链修饰的纳曲酮中间体2-4反应即得通式(I)。
所述的合成方法，步骤(1)具体包括：
所述的合成方法，步骤(2)具体包括：
所述的合成方法，步骤(3)具体包括：
所述的荧光探针在聚集诱导发光材料方面的应用。
所述的荧光探针在制备与μ阿片受体相关疾病的检测/诊断试剂方面的应用。
所述的应用，所述相关疾病为疼痛病或阿片类物质使用障碍。
所述的荧光探针在筛选μ阿片受体相关疾病药物中的应用，所述药物为μ阿片受体激动剂或拮抗剂。
所述的荧光探针在制备检测μ阿片受体的诊断试剂中的应用。
选用近红外区的半花菁荧光染料作为荧光基团，纳曲酮作为药效团，共价连接后成为荧光探针。相较于短波长荧光分子，近红外荧光分子的活体成像效果更加优越，细胞成像效果较稳定、不易淬灭。进行细胞层面的荧光成像，具有免洗、信噪比高等优点，并且可以定性表征细胞表面受体的表达量。
响应型的荧光探针可被用于受体结合的原位可视化，这类探针在与受体结合前的自由状态下表现出微弱的背景荧光，但在结合后将表现出明亮的荧光。因此，合成制备靶向MOR荧光探针可以广泛应用于靶向识别领域，在药物受体相互作用分析，药物作用机制方面具有重要的应用价值。
有益效果：与现有技术相比，本发明具有以下技术优势：(1)当探针与μ阿片受体结合时荧光会显著增强，能够实现对受体的靶向和原位成像，提高了信噪比，避免了繁琐的洗涤步骤。(2)本发明所述探针显示出与μ阿片受体较高的亲和力，同时对μ阿片受体特异性较高，可以在配体筛选实验中发挥有利作用。(3)本发明所选用的荧光发色团是处于近红外区的半花菁染料，且用磺酸基做修饰，其在水溶液中溶解性较好，结合到受体的疏水结构域中时可释放出明亮的荧光。由于其荧光背景干扰低，毒性小，可实现对活细胞受体结合状态的的实时监测，从而应用于μ阿片受体的功能学研究与其配体的筛选。(4)本发明的探针对MOR具有高选择性的识别作用，在675-850nm发射下，尤其是710-740nm，可对MOR受体蛋白细胞高效响应，发出荧光信号。
附图说明
图1为本发明所述的小分子荧光探针(I)的质谱图；
图2为荧光探针与MOR相互作用的荧光光谱图。
具体实施方式
为了对本发明的技术特征，目的和效果有更准确的理解，下面将通过参考附图并结合具体实施例对本发明做进一步的说明。但不应将此理解为本发明上述主体的范围仅限于以下的实施例。凡基于本发明上述内容所实现的技术和应用均属于本发明范畴。
实施例1：一种靶向MOR的响应性半花菁荧光探针，合成路线如下：
中间体化合物1-1的合成和结构表征：
将2，3，3-三甲基吲哚(3.185g，20.0mmol)和丙磺酸内酯(3.66g，30.0mmol)溶于乙腈(25mL)中，将混合物在110℃下加热回流反应18小时后冷却至室温，将其滴入乙醚(3×50mL)中沉淀，过滤得粗产物。经水溶解后以氯仿萃取3次得水层溶液，冻干得浅红色固体(3.420g，产率74％)，即中间体化合物1-1。MS(ESI，m/z，C14H20NO3S，[M+H]+)：calcd.，282.1；found 282.1.
中间体化合物1-2的合成和结构表征：
将中间体化合物1-1(0.562g，2.0mmol)和缩合剂2-氯-1-甲酰基-3-羟甲基环已烯(0.172g，1.0mmol)及乙酸钠(0.328g，2.0mmol)溶于乙酸酐(10mL)中，混合物在氮气条件下，80℃加热反应6小时。反应完成冷却至室温，反应液加入到剧烈搅拌的乙醚中，沉淀得绿色固体产物。用G6砂芯漏斗过滤，乙醚洗涤，所得固体用硅胶柱色谱(二氯甲烷/甲醇＝20∶1-5∶1)进行分离提纯，减压干燥，得绿色固体(0.428g，产率43％)，即中间体化合物1-2。MS(ESI，m/z，C36H44ClN2O6S2，[M+H]+)：calcd.，699.2；found 699.2.
中间体化合物1-3的合成
将2，4-二羟基苯甲醛(0.138g，1.0mmol)和碳酸钾(2.0mmol)溶于无水DMF(5.0mL)中，室温搅拌下20min后，将中间体化合物1-2(0.350g，0.5mmol)的DMF(3mL)溶液缓慢加入其中。混合液在氮气条件下，50℃加热反应5小时，减压蒸馏去除溶剂，粗产品用硅胶柱色谱(二氯甲烷/甲醇＝30∶1-10∶1)进行分离提纯，减压干燥，得蓝色固体(0.049g，产率25％)，即化合物1-3。MS(ESI，m/z，C29H29NO6S，[M+H]+)：calcd.，520.2；found520.2.
中间体化合物2-1的合成和结构表征：
在氮气保护下，将纳曲酮(0.300g，0.88mmol)溶于0.533M的氢氧化钠水溶液(5mL)中，然后将甲脒亚磺酸(0.380g，3.51mmol)加入上述溶液中，在氮气条件下85℃反应1.5小时，冷却至室温。用氯仿(30mL×3)萃取，收集有机层溶液，减压干燥，得白色泡沫状固体，即中间体化合物2-1(0.272g，产率91％)。MS(ESI，m/z，C20H25NO4，[M+H]+)：calcd.，343.2；found 343.2.
中间体化合物2-2的合成和结构表征：
将中间体化合物2-1(0.253g，0.74mmol)、二碳酸二叔丁酯(0.193g，0.88mmol)、碳酸钾(0.511g，3.7mmol)溶入丙酮(15mL)，在氮气条件下回流反应1小时，冷却至室温。减压蒸馏去除溶剂，粗产品用硅胶柱色谱(二氯甲烷/甲醇＝20：1)进行分离提纯，减压干燥，得白色固体，即中间体化合物2-2(0.296g，产率91％)。MS(ESI，m/z，C25H33NO6，[M+H]+)：calcd.，443.2；found 443.2.
中间体化合物2-3的合成和结构表征：
将中间体化合物2-2(0.245g，0.55mmol)、β-丙氨酸(0.157g，0.83mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.159g，0.83mmol)溶于50mL无水二氯甲烷中，在0℃下加入4-二甲氨基吡啶(0.101g，0.83mmol)，逐渐恢复为室温，继续搅拌反应12小时。减压蒸馏去除溶剂，粗产品用硅胶柱色谱(乙酸乙酯/石油醚＝1∶1)进行分离提纯，减压干燥后得白色固体，即中间体化合物2-3(0.276g，产率82％)。MS(ESI，m/z，C33H46N2O9，[M+H]+)：calcd.，614.3；found 614.3.
中间体化合物2-4的合成和结构表征：
将中间体化合物2-3(0.219g，0.36mmol)溶于10mL二氯甲烷，加入1mL三氟乙酸，在氮气条件下室温反应1小时，减压蒸馏去除溶剂，粗产品用硅胶柱色谱(二氯甲烷/甲醇＝10∶1)进行分离提纯，减压干燥，得白色固体，即中间体化合物2-4(0.095g，产率65％)。
MS(ESI，m/z，C23H30N2O5，[M+H]+)：calcd.，414.2；found 414.2.
探针分子(I)的合成和结构表征：
将中间体化合物1-3(0.052g，0.1mmol)和2-4g(0.050g，0.12mmol)溶于5mL无水乙醇，在室温条件下搅拌2小时后，旋干溶剂，复溶于二氯乙烷(5mL)中，并加入三乙酰氧基硼氢化钠(0.030g，0.14mmol)，继续反应24小时，通过制备液相色谱系统(水/甲醇＝5∶1-0.1∶1)进行纯化，减压干燥，得蓝色固体，即探针分子(I)(0.030g，产率30％)。质谱图见图1，MS(ESI，m/z，C52H59N3O10S[M+H]2+)：calcd.，459.7；found 460.3.
1H NMR(300MHz，DMSO-d6)δ9.50(s，1H)，8.57(d，J＝14.6Hz，1H)，7.73(d，J＝6.60Hz，2H)，7.50(s，2H)，7.48-7.39(m，2H)，6.91(s，1H)，6.84(d，J＝8.1Hz，1H)，6.80(s，1H)，6.76(d，J＝14.6Hz，1H)，6.58(s，1H)，6.40(s，1H)，4.69(d，J＝6.7Hz，1H)，4.55(s，2H)，4.47(d，J＝12.0，1H)，3.80(brs，1H)，3.25(s，1H)，3.05(m，J＝7.1Hz，4H)，2.79(d，1H)，2.71(s，4H)，2.70(t，J＝7.1Hz，2H)，2.60(s，2H)，2.40(d，2H)，2.08(s，2H)，1.82(m，3H)，1.75(s，6H)，1.69(m，2H)，1.37(m，2H)，1.05(m，J＝7.0Hz，1H)，0.63(d，J＝23.0Hz，2H)，0.39(d，J＝22.2Hz，2H).
实施例2：探针分子对MOR响应
MOR的基因OPRM1从国家生物技术信息中心(NCBI)的基因表达综合系统下载，将含有人源的MOR的质粒(订购于常州基宇生物科技有限公司，G33835-1)克隆到pcDNA3.1载体中，将其转化为大肠杆菌BL21(DE3)菌株后对质粒进行提取和表达。
取100μL的探针分子(5μM in PBS)，加入100μL不同浓度的MOR，混合均匀，使得溶液中MOR终浓度为0μg/mL、25μg/mL、50μg/mL、100μg/mL、200μg/mL，分别加入96孔酶标板中，使用酶标仪进行扫描，记录在激发波长650nm下，发射波长为675-850nm时的荧光信号值，每个浓度重复测定3次。同时配制上述同等浓度的BSA作为对照。以波长为横坐标，荧光强度为纵坐标。使用不同浓度的MOR蛋白，测定了荧光探针的荧光发射光谱。如图2所示，随着BSA浓度的增加，探针分子的荧光强度变化不大，而随着MOR浓度的增加，探针分子的荧光强度也逐渐增加。试验表明，本发明的探针分子可特异性响应MOR并具有定量分析MOR配体结合事件的潜力。
Claims (10)
1.一种靶向MOR的响应性半花菁荧光探针，其特征在于，结构式如式(I)所示：
2.一种权利要求1所述的靶向MOR的响应性半花菁荧光探针的合成方法，其特征在于，包括如下步骤：
(1)以2，3，3-三甲基吲哚和丙磺酸内酯为原料合成磺酸吲哚，再通过缩合反应得到全花菁染料，全花菁染料和2，4-二羟基苯甲醛发生retro-Knoevenagel反应生成半花菁染料，即中间体1-3；
(2)以纳曲酮作为原料还原为纳曲醇，通过Boc保护酚羟基、再通过酯化反应与丙氨酸连接、脱BOC保护，即可在特定位点连上伯氨基，得到中间体2-4；
(3)醛基修饰的半花菁染料中间体1-3和氨基连接链修饰的纳曲酮中间体2-4反应即得通式(I)。
3.根据权利要求2所述的合成方法，其特征在于，步骤(1)具体包括：
4.根据权利要求2所述的合成方法，其特征在于，步骤(2)具体包括：
5.根据权利要求2所述的合成方法，其特征在于，步骤(3)具体包括：
6.根据权利要求1所述的荧光探针在聚集诱导发光材料方面的应用。
7.根据权利要求1所述的荧光探针在制备与μ阿片受体相关疾病的检测/诊断试剂方面的应用。
8.根据权利要求7所述的应用，其特征在于，所述相关疾病为疼痛病或阿片类物质使用障碍。
9.根据权利要求1所述的荧光探针在筛选μ阿片受体相关疾病药物中的应用，所述药物为μ阿片受体激动剂或拮抗剂。
10.根据权利要求1所述的荧光探针在制备检测μ阿片受体的诊断试剂中的应用。
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