CN111892668B - 一种化合物及其制备方法、荧光探针和抗肿瘤药物 - Google Patents

一种化合物及其制备方法、荧光探针和抗肿瘤药物 Download PDF

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CN111892668B
CN111892668B CN202010630922.6A CN202010630922A CN111892668B CN 111892668 B CN111892668 B CN 111892668B CN 202010630922 A CN202010630922 A CN 202010630922A CN 111892668 B CN111892668 B CN 111892668B
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hyaluronic acid
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卞旺青
何燕
卢宇靖
龙威
张焜
张智
陈泽丰
王亚坤
陈霓平
黄艺斌
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Guangdong University of Technology
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Abstract

本发明涉及化学合成技术领域，尤其涉及一种化合物及其制备方法、荧光探针和抗肿瘤药物。本发明公开了一种化合物如式(I)所示该化合物通过透明质酸配体‑受体介导作用准确地靶向识别并到达肿瘤区域时，肿瘤细胞中过表达的酯酶通过破坏TP‑PPh3与透明质酸之间的酯键，从而释放出TP‑PPh3，其因聚集而猝灭的荧光就会得到恢复。由于线粒体呼吸期间，膜内的质子泵将质子转运到线粒体膜内空间，形成高度负性的线粒体跨膜电位，导致三苯基膦阳离子具有靶向线粒体的能力，所以在近红外光的照射下，肿瘤的线粒体区域就会发出红色的荧光，从而实现肿瘤部位的荧光成像。当用650‑980nm的激光器照射肿瘤组织时，TP‑PPh3会将吸收的光能转化为热能，从而消融肿瘤，实现光热治疗。

Description

一种化合物及其制备方法、荧光探针和抗肿瘤药物
技术领域
本发明涉及有机合成技术领域，尤其涉及一种化合物及其制备方法、荧光探针和抗肿瘤药物。
背景技术
恶性肿瘤一直是一项让人们很头疼的问题，因为它们威胁着人类的健康，并将成为现代社会的头号杀手。传统的肿瘤治疗方案包括手术、化疗和放疗，但由于其严重的副作用和预后的低效率而陷入瓶颈。而目前新兴的光热疗法(PTT)，使得这一局面有所扭转，它通过使用近红外灯来激发光热剂，并将光能转化为热能来杀死癌细胞，提供了一种新的工具来改善肿瘤的治疗结果，并且光热疗法有着许多的优点，如效率高、侵袭性小等。然而，大多数已开发的光热剂由于其不稳定或在体内的不可生物降解性，并伴有长期毒性而被进一步的临床应用所抑制。因此，开发出一种具有优良的生物相容性和高的光热转化效率的光热治疗物质是急不可待的。
发明内容
有鉴于此，本发明提供了一种化合物及其制备方法、荧光探针和抗肿瘤药物，该化合物能够与肿瘤物异性结合，实现肿瘤的双模态成像和光热治疗。
其具体技术方案如下：
本发明提供了一种化合物，如式(I)所示结构；
Figure GDA0003638911900000011
n为4000～7000。
本发明还提供了上述化合物的制备方法，包括以下步骤：
步骤1：将式(II)所示的化合物与式(III)所示的化合物进行反应，得到式(IV)所示的化合物；
步骤2：将所述式(IV)所示的化合物与三苯基磷在催化剂的条件下进行反应，得到(V)所示化合物；
步骤3：将所述式(V)所示的化合物与透明质酸进行酯化反应，得到式(I)所示的化合物；
Figure GDA0003638911900000021
其中，R1为甲基，R2选自脂肪羧酸或芳香羧酸，优选为C3～C8的直链羧酸或苯环数量为1～3的芳香羧酸R3为卤代C2～C10的直链烷基，优选为卤代C4～C8的直链烷基，R4为三苯基磷直链脂肪烷基，优选为三苯基磷C2～C6的直链烷基；
n为4000～7000。
本发明步骤1中，所述式(II)所示的化合物与所述式(III)所示的化合物的摩尔比为1：(1～1.5)，优选为1：1；所述反应的温度为室温，所述反应的时间为18～36h，优选为24h；所述反应的溶剂优选为三乙胺。
本发明步骤1中式(II)所示的化合物的制备方法优选为：将4-甲基喹啉与4-溴甲基苯甲酸进行反应，得到式(II)所示的化合物；所述反应的溶剂优选为无水乙腈，所述反应优选在70℃下反应24h；
所述式(III)所示的化合物的制备方法优选为：将2-甲基硫苯并噻唑与1，4-二溴丁烷在催化剂下进行反应，得到式(III)所示的化合物；所述催化剂优选为三乙胺，所述反应的溶剂优选为DMF，所述反应优选在室温下反应12h；
本发明步骤2中，所述式(IV)所示的化合物与所述三苯基磷的摩尔比为1：(1～1.5)，优选为1：1；所述反应的温度为110℃～130℃，所述反应的时间为10h～18h，优选120℃下反应12h；所述反应的溶剂优选为无水乙腈，所述反应的催化剂优选为碳酸钠。
本发明步骤3中，所述式(V)所示的化合物与所述透明质酸的摩尔比为1:(1～1.5)，优选为1:1；所述酯化反应的温度为室温，时间为10h～16h，优选为14h；
所述式(I)所示的化合物的制备方法优选为：将式(V)所示的化合物与N,N'-羰基二咪唑(CDI)溶解在DMF中并搅拌，通入氮气后，向反应得到的溶液加入到溶解在DMF中的透明质酸，在催化剂的作用下，得到式(I)所示的化合物；所述式(V)所示的化合物与CDI、DMAP的质量比为26.67：75.84：57.12，所述搅拌的速率优选为500rmp，时间优选为0.5h；所述催化剂优选为4-二甲氨基吡啶(DMAP)。
透明质酸(HA)是一种天然带负电荷的亲水性强的多糖，与式(V)所示的化合物，一种的疏水有机小分子(TP-PPh3)以化学键的形成结合形成两亲性前药，使得前药纳米粒子保持着更可靠的稳定性，因此可将其设计为一种按需给药的系统，从而最大限度地减少药物的泄漏。并且由于透明质酸与在肿瘤细胞膜表面过度表达的CD44受体有着天然的亲和力，这就使得透明质酸不仅成为载体，而且成为肿瘤特异性药物传递的靶向配体。另外，透明质酸作为一种多糖，具有良好的生物相容性，用其递送TP-PPh3，可防止过敏反应，而且由于肿瘤的繁殖会消耗大量的葡萄糖，这也就使得透明质酸表现出更强的靶向性。
透明质酸配体-受体介导作用准确地靶向识别并到达肿瘤区域时，肿瘤细胞中过表达的酯酶通过破坏肿瘤细胞中过表达的酯酶通过破坏TP-PPh3与透明质酸之间的酯键，从而释放出TP-PPh3，当TP-PPh3被释放之后，其因聚集而猝灭的荧光就会得到恢复，且由于线粒体呼吸期间，膜内的质子泵将质子转运到线粒体膜内空间，形成高度负性的线粒体跨膜电位，导致三苯基磷阳离子具有靶向线粒体的能力，所以在近红外光的照射下，肿瘤的线粒体区域就会发出红色的荧光，从而实现肿瘤部位的荧光成像。当采用650-980nm波长，优选采用808nm波长的激光器照射肿瘤组织时，TP-PPh3会将吸收的光能转化为热能，从而消融肿瘤，实现光热治疗。
本发明还提供了式(I)所示化合物或上述制备方法制备得式(I)所示化合物在荧光探针中的应用。
本发明还提供了一种荧光探针，包括式(I)所示化合物或上述制备方法制备得式(I)所示化合物。
本发明还提供了另一种化合物，如式(VI)所示结构；
Figure GDA0003638911900000041
所述式(VI)所示化合物由式(I)所示化合物与紫杉醇(PTX)反应制得。
本发明提供的式(VI)所示的化合物为一种纳米胶束。
本发明中，所述式(I)化合物与所述紫杉醇的摩尔比为1：(1～1.5)，优选为1：1；所述反应的温度为室温，所述反应的时间优选为24h。
所述式(VI)所示化合物的制备方法优选为：将式(I)所示化合物与CDI混合，将其溶解在DMF中并搅拌，向反应得到的溶液加入到溶解在DMF中的紫杉醇和DMAP中反应、透析、冻干后，得到式(VI)所示化合物；所述式(I)所示化合物与CDI、DMAP的质量比为31.32：79.87：60，所述搅拌的速率优选为500rmp，时间优选为1h。
本发明中，所述室温为25±5℃。
透明质酸(HA)配体-受体介导作用准确地靶向识别并到达肿瘤区域时，肿瘤细胞中过表达的酯酶还会破坏通过破坏紫杉醇与透明质酸之间的酯键，释放出紫杉醇。由于TP-PPh3对肿瘤的光热治疗本身通常不能破坏亚致死的肿瘤细胞，所以不能彻底的消除肿瘤，而此时释放出来的紫杉醇所展示出来的化学疗法就可以和TP-PPh3的光热治疗一起协同实现对肿瘤的双治疗效果。
本发明还提供了式(VI)所示的化合物在制备抗肿瘤药物中的应用。
本发明还提供了一种抗肿瘤药物，包括式(VI)所示的化合物。
从以上技术方案可以看出，本发明具有以下优点：
本发明提供了一种如式(I)所示的化合物。该化合物中透明质酸作为肿瘤的的靶向载体和肿瘤细胞表面过度表达的CD44配体。该化合物通过透明质酸配体-受体介导作用准确地靶向识别并到达肿瘤区域时，肿瘤细胞中过表达的酯酶通过破坏TP-PPh3与透明质酸之间的酯键，从而释放出TP-PPh3，当TP-PPh3被释放之后，其因聚集而猝灭的荧光就会得到恢复，且由于线粒体呼吸期间，膜内的质子泵将质子转运到线粒体膜内空间，形成高度负性的线粒体跨膜电位，导致三苯基膦阳离子具有靶向线粒体的能力，所以在近红外光的照射下，肿瘤的线粒体区域就会发出红色的荧光，从而实现肿瘤部位的荧光成像。当采用650-980nm波长的激光器照射肿瘤组织时，TP-PPh3会将吸收的光能转化为热能，从而消融肿瘤，实现光热治疗。
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简单地介绍，显而易见地，下面描述中的附图仅仅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它的附图。
图1为本发明实施例1中化合物3的氢谱图；
图2为本发明实施例1中化合物6的氢谱图；
图3为本发明实施例1中化合物6的质谱图；
图4为本发明实施例2中的TP-PPh3的光热检测图，其中，(a)在同浓度，不同功率下TP-PPh3的升温情况(浓度为2.0mM)，(b)在同功率，不同浓度下TP-PPh3的升温情况(P＝2.3W/cm2)；
图5为本发明实施例4中的MTT法检测细胞毒性结果图；
图6为本发明实施例5中的倒置荧光成像图，其中，(a)为DAPI在U87细胞中的成像图，(b)为TP-PPh3在U87细胞中的成像图；
图7为本发明实施例6中的U87细胞的激光共聚焦成像，其中，(a)为DAPI在U87细胞中的亚细胞定位图，(b)和(c)为TP-pph3在U87细胞中的亚细胞定位图；(d)TP-PPh3在U87细胞中的的明场图；(e)Merge；
具体实施方式
为使得本发明的发明目的、特征、优点能够更加的明显和易懂，下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，下面所描述的实施例仅仅是本发明一部分实施例，而非全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
本发明实施例中神经胶质瘤细胞U87细胞和鼠源的脑微血管内皮细胞bEnd.3细胞均由广东工业大学生物医药学院提供。
本发明实施例中所用的试剂和原料均为市售。
实施例1
本实施例为式(VI)所示化合物(TPHP)的合成
Figure GDA0003638911900000071
Figure GDA0003638911900000081
(1)准确称量0.143g的化合物1与0.214g的化合物2混合，加入10ml的无水乙腈作溶剂，在70℃下反应24h得到化合物3(式II化合物)。
(2)称量0.181g化合物4和0.214g 1，4-二溴丁烷,混合后加入10ml的无水DMF做反应溶剂，200ul的三乙胺做催化剂，在室温下反应12h得到化合物5(式III化合物)。
(3)称取0.397g的化合物5和0.358g的化合物3混合，加入200μl的三乙胺做溶剂，在室温下以300rmp搅拌24小时得到化合物6(式IV化合物)。
(4)称取0.626g的化合物6与0.262g的三苯基膦混合，加入10ml的无水乙腈做溶剂，称取100mg的碳酸钠做催化剂，在120℃下反应12h得到化合物7(式V化合物)。
(5)取26.67mg的化合物7与75.84mg的N,N'-羰基二咪唑(CDI)溶解在DMF中并以500rmp搅拌0.5h，通N2，反应得到的溶液逐滴加入到溶解在DMF中的6mg的化合物8(透明质酸)和57.12mg的4-二甲氨基吡啶(DMAP)中，室温下反应14h得到化合物9(式I化合物)。
(6)称取31.32mg的化合物9和79.87mg的CDI混合，将其溶解在DMF中，以500rmp搅拌1h后，加入到溶解在DMF中的27.35mg的化合物10(紫杉醇)和60mg的DMAP中，以500rmp搅拌24h后，透析，冻干，得到化合物11(式VI化合物)。
本实施例制得的化合物3、5、6、7、9和11经核磁共振分析，确认成功制得各化合物，部分化合物氢谱和质谱结果如图1～3所示。
实施例2
本实施例为TPHP的光学性质和光稳定性测定
为了探讨光热性能，将不同浓度的TP-PPh3(式V化合物)和TPHP纳米胶束分别暴露在808nm(1.0w/cm2)激光器中5min。在预定的时间点，使用红外热成像摄像机对溶液的区域最高温度进行了监测，以磷酸盐缓冲液为阴性对照。
TP-PPh3(如图4所示)和TPHP的光热性能良好，并且随着激光密度的增大与TP-PPh3和TPHP浓度的提高，溶液温度不断的上升，说明TP-PPh3和TPHP光稳定性良好，因而TP-PPh3和TPHP将吸收的光能转化为热能，从而消融肿瘤，实现光热治疗。
实施例3
本实施例为荷U87小鼠的皮下模型建立
准备6-8周大的Balb/c裸鼠，取对数生长期的U87细胞进行消化，重悬，计数。对于皮下瘤小鼠的接瘤，每只小鼠准备5×106个细胞(100μl)，在小鼠背部右下方进行皮下注射。待观察小鼠皮下肿瘤大小长到60mm3左右时，将小鼠分为TP-PPh3组和TPHP组，每组均为5只小鼠，进行后续成像实验。
实施例4
本实施例为TPHP毒性检测
选择对数生长期的U87细胞，消化、离心，弃上清后重悬细胞，收集单细胞悬液，进行细胞计数，计算后用完全培养基稀释成合适浓度，接种在96孔板中，在37℃，5％CO2和95％相对湿度的条件下培养24h后，弃掉培养基，PBS洗涤三次，加入含不同浓度TP-PPh3和TPHP纳米胶束进行细胞培养，孵育4h后，弃掉培养基，加入含CCK-8试剂的新鲜培养基孵育4h，用多功能酶标仪检测样品在450nm处的吸收，计算细胞存活率。
TP-PPh3(如图5所示)和TPHP在激光照射下均可杀伤肿瘤细胞，而且在与化疗药物紫杉醇共同作用后对肿瘤细胞的杀伤效果更加显著。
实施例5
本实施例为TPHP的倒置荧光显微镜成像研究
选择对数生长期的人源的神经胶质瘤细胞U87细胞和鼠源的脑微血管内皮细胞bEnd.3细胞，消化、离心、计数、稀释、接种。培养箱中培养24h后，弃掉培养基，PBS洗涤三次；分别加入TP-PPh3和TPHP纳米颗粒的新鲜培养基孵育细胞4h，弃掉培养基，PBS洗涤三次；4％多聚甲醛，37℃固定细胞10min，PBS洗涤三次；DAPI染色10min，PBS洗涤三次，用倒置荧光显微镜，在激发波长330nm激发下，分别观察TP-PPh3和TPHP在细胞内的成像情况。
TP-PPh3(如图6所示)和TPHP纳米胶束均发出红色荧光，且荧光成像效果较好，适用于胶质瘤的检测。
实施例6
本实施例为TPHP的体外靶向研究
选择对数生长期的人源的神经胶质瘤细胞U87细胞和鼠源的脑微血管内皮细胞bEnd.3细胞，消化、离心、计数、稀释、接种。培养箱中培养24h后，弃掉培养基，PBS洗涤三次；分别加入TP-PPh3和TPHP纳米颗粒的新鲜培养基孵育细胞4h，弃掉培养基，PBS洗涤三次；4％多聚甲醛，37℃固定细胞10min，PBS洗涤三次；DAPI染色10min，PBS洗涤三次，激光共聚焦显微镜，在激发波长330nm激发下，分别观察TP-PPh3和TPHP进入细胞的情况。
TP-PPh3(如图7所示)和TPHP释放的TP-PPh3可以靶向到线粒体，发出红色荧光，在细胞内的成像效果较好。
以上所述，以上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精神和范围。

Claims (10)

1.一种化合物，如式(I)所示结构；
Figure FDA0003659083590000011
其中，n为4000～7000。
2.一种化合物的制备方法，其特征在于，包括以下步骤：
步骤1：将式(II)所示的化合物与式(III)所示的化合物进行反应，得到式(IV)所示的化合物；
步骤2：将所述式(IV)所示的化合物与三苯基磷在催化剂的条件下进行反应，得到(V)所示化合物；
步骤3：将所述式(V)所示的化合物与透明质酸进行酯化反应，得到式(I)所示的化合物；
Figure FDA0003659083590000012
Figure FDA0003659083590000021
其中，R1为甲基，R2选自羧基，R3为卤代C2～C10的直链烷基，R4为三苯基磷直链脂肪烷基，n为4000～7000。
3.根据权利要求2所述的制备方法，其特征在于，R3为卤代C2～C10的直链烷基，R4为三苯基磷C2～C6的直链烷基。
4.根据权利要求2所述的制备方法，其特征在于，所述式(II)所示的化合物与所述式(III)所示的化合物的摩尔比为1：(1～1.5)；
所述式(IV)所示的化合物与所述三苯基磷的摩尔比为1：(1～1.5)；
所述式(V)所示的化合物与所述透明质酸的摩尔比为1：(1～1.5)。
5.根据权利要求2所述的制备方法，其特征在于，步骤1所述反应的温度为室温，所述反应的时间为18～36hh；
步骤2所述反应的温度为110℃～130℃，所述反应的时间为10h～18h；
步骤3所述酯化反应的温度为室温，时间为10～14h。
6.权利要求1所述的化合物或权利要求2至5任意一项所述的制备方法制得的化合物在荧光探针中的应用。
7.一种荧光探针，其特征在于，包括权利要求1所述的化合物或权利要求2至5任意一项所述的制备方法制得的化合物。
8.一种化合物，如式(VI)所示结构；
Figure FDA0003659083590000031
所述式(VI)所示的化合物由权利要求1所述的式(I)化合物与紫杉醇反应制得。
9.根据权利要求8所述的化合物，其特征在于，所述式(I)化合物与所述紫杉醇的摩尔比为1：(1～1.5)。
10.权利要求8或9所述的化合物在制备抗肿瘤药物中的应用。
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