CN116284059A - 一种靶向线粒体功能药物鱼藤醇-叶酸偶联物及制法 - Google Patents
一种靶向线粒体功能药物鱼藤醇-叶酸偶联物及制法 Download PDFInfo
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Abstract
本发明公开了一种靶向线粒体功能药物鱼藤醇‑叶酸偶联物，作为一种靶向线粒体的药物，结构式如（I）所示；本发明的新型药物鱼藤醇‑叶酸偶联物具有较好的细胞毒活性。通过细胞活性实验检测，表明鱼藤醇‑叶酸偶联物有较好的细胞通透性；
（I）。
Description
技术领域
本发明涉及药物化学领域，特别涉及鱼藤酮衍生物的设计合成及在抗癌方面的用途。
背景技术
恶性肿瘤是一类威胁人类健康和生命的疾病，目前对恶性肿瘤的治疗常采用手术，放疗，化疗相结合的综合措施。化疗是一种全身性治疗，并可消灭远距离转移的癌细胞，因此在综合治疗中占有重要的地位。但在临床上化疗药物发挥抗肿瘤作用的同时，其副作用以及耐药问题也非常突出。因此，从不同角度寻找高效低毒的抗肿瘤药物仍是当务之急。
研究表明，线粒体通过其内膜中存在的氧化磷酸化复合物生成ATP，这些复合物被称为NADH泛醌氧化还原酶(复合物I)、琥珀酸脱氢酶(复合物II)、泛醌细胞色素c氧化还原酶(复合物III)、细胞色素c氧化酶(复合物IV)和ATP合酶(复合物V)。氧化磷酸化过程由复合物I酶氧化NADH开始。目前已知鱼藤酮可通过抑制复合物I，导致细胞线粒体通过氧化磷酸化复合物生成ATP显著下降，同时在复合物I处泄漏的电子可将在复合物IV处未还原的氧还原为活性氧物种(ROS)，导致ROS增高，进而诱导细胞凋亡。
从天然产物(NPs)开发生物活性分子已成为化学药物的重要来源。其中，鱼藤酮为黄酮类化合物，主要从热带和亚热带的鱼藤属、尖荚豆属和灰叶属植物中提取，是一种天然的植物质杀虫剂和杀螨剂。鱼藤酮具有触杀、胃毒、拒食和熏蒸作用，杀虫效果显著，杀虫谱广，作用方式多样。并且通过诱导细胞凋亡表现出对多种人类癌细胞系的细胞毒性。为降低鱼藤酮对正常细胞的毒副作用，将癌细胞靶向分子与鱼藤酮结合，将有效增加对肿瘤组织的靶向性，并促使其在肿瘤部位的富集。
因此，利用叶酸受体FRα在肿瘤中高表达、正常细胞低表达的特性，设计合成鱼藤酮-叶酸偶联物，可以为新型抗肿瘤靶向药物的开发提供新思路。
发明内容
本发明所要解决的技术问题是提供一种具有癌细胞靶向性并以线粒体为靶点的新型抗癌分子。
本发明目的的技术方案是：一种靶向线粒体功能药物鱼藤醇-叶酸偶联物，作为一种靶向线粒体的药物，结构式如下所示：
（I）
所述通式（I）的偶联物在制备抗癌药物中的用途。
本发明鱼藤醇-叶酸偶联物的合成方法，包括如下步骤：
步骤（1）：将鱼藤酮溶解于甲醇中，加入硼氢化钠作为还原剂得到鱼藤醇；
步骤（2）：将所得鱼藤醇与叶酸一同溶解在DMSO中，并加入EDCI和DMAP作为催化剂，反应过夜，得到靶向线粒体功能药物鱼藤醇-叶酸偶联物。
反应式如下：
优选方案，步骤（2）中，鱼藤醇与叶酸的摩尔比为1:1.2。
本发明的有益效果为：本发明的新型药物鱼藤醇-叶酸偶联物具有较好的细胞毒活性。通过细胞活性实验检测，表明鱼藤醇-叶酸偶联物有较好的细胞通透性。
说明书附图
图1为实施例1制备的鱼藤醇的氢谱表征图；
图2为实施例1制备的鱼藤醇的碳谱表征图；
图3为实施例1制备的鱼藤醇-叶酸偶联物的氢谱表征图；
图4为实施例1制备的鱼藤醇-叶酸偶联物的碳谱表征图；
图5为实施例1制备的鱼藤醇的质谱表征图；
图6为实施例1制备的鱼藤醇-叶酸偶联物的质谱表征图；
图7是实施例1制备的鱼藤醇-叶酸偶联物对人肺癌细胞（A549, A）、宫颈癌细胞（HeLa, B）、肝癌细胞（HepG2, C）、人正常肝细胞（L02, D）及小鼠乳腺癌细胞（4T1, E）的细胞毒性分析图。
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
鱼藤醇-叶酸偶联物线粒体功能药物的制备方法具体如下：
（1）将300毫克鱼藤酮溶解于10毫升甲醇中，然后加入127毫克的硼氢化钠，然后在室温下搅拌4h，反应溶液逐渐变澄清，之后向反应溶液中一边搅拌一边逐滴滴加10毫升的二次水；得到白色粉末状固体，得到化合物1；
1H NMR (500 MHz, DMSO-d 6) δ 7.26 (s, 1H), 7.05 (s,1H), 6.37 (s, 2H),5.64 (s, 1H), 5.18 (s, 1H), 5.01 (s, 2H), 4.86 (s, 2H), 4.46 (s, 1H), 4.17(s, 1H), 3.64 (d,J= 28.0 Hz, 6H), 3.39 (d,J= 4.7 Hz, 1H), 3.22 – 3.09 (m,1H), 2.80 (dd,J= 15.6, 7.8 Hz, 1H), 1.69 (s, 3H).
13C NMR (126 MHz, DMSO) δ 160.59, 149.88, 149.06, 148.92, 144.50,143.04, 128.18, 117.94, 114.06, 111.87, 111.47, 101.54, 100.77,85.85, 70.54,66.53, 66.22, 56.61, 55.83, 49.07, 40.50, 40.34, 40.17, 40.00, 39.84, 39.67,39.50, 36.97, 31.90, 17.52.
HR-MS: 820.3701 (M+Na+).
（2）将137毫克叶酸和93毫克EDCI溶解在10毫升DMSO中，然后室温搅拌10分钟至全部溶解，然后加入49毫克DMAP，活化4小时。之后加入119毫克的化合物1（鱼藤醇），反应过夜。然后将反应完的黄棕色澄清液体中滴加10毫升的二次水，产生大量黄色沉淀，之后用二次水和乙醇交替洗涤三次，真空干燥，得到粉末状固体，即为目标产物鱼藤醇-叶酸偶联物（化合物2）。
1H NMR (500 MHz, DMSO-d 6)：δ 11.45 (s, 1H), 8.65 (s, 1H), 8.33 – 8.02(m, 1H), 7.66 (d,J= 8.6 Hz, 2H), 7.15 – 6.73 (m, 2H), 6.65 (d,J= 8.7 Hz, 2H),4.49 (d,J= 6.0 Hz, 2H), 4.36 (m,J= 14.6, 9.8, 7.5, 5.0 Hz, 1H), 4.23 – 3.88(m, 1H), 3.18 (s, 1H), 2.91 – 2.72 (m, 1H), 2.60 (s,1H), 2.31 (s, 1H), 2.05(m,J= 15.3, 10.1, 6.5 Hz, 1H), 1.92 (m,J= 13.8, 9.9, 7.0 Hz, 1H), 1.17 (dt,J=11.4, 7.1 Hz, 1H).
13C NMR (126 MHz, DMSO)：δ 176.78, 174.89, 174.45, 169.85, 169.43,165.98, 161.76, 154.75, 154.60, 152.55, 152.21, 149.03, 148.69, 148.57,132.60, 132.51, 130.88, 129.55, 128.48, 121.89, 120.24, 118.84, 111.72,110.98, 56.67, 46.21, 44.85, 44.60, 40.47, 40.30, 40.13, 39.97, 39.80, 39.63,39.47, 35.50, 33.01, 32.43, 31.72, 29.71, 29.07, 26.53, 15.02.
HR-MS: 820.3701 (M+H+).
实施例2
鱼藤醇-叶酸偶联物的细胞毒性测试。
鱼藤醇-叶酸偶联物对多种癌细胞均有较强的细胞毒性，如图7中采用人肺癌细胞（A549, A）、宫颈癌细胞（HeLa, B）、肝癌细胞（HepG2, C）、人正常肝细胞（L02, D）及小鼠乳腺癌细胞（4T1, E）所做的毒性分析，尤其对人肝癌细胞的细胞毒性最强，而对人正常肝细胞的细胞毒性则相对较低。
Claims (4)
1.一种靶向线粒体功能药物鱼藤醇-叶酸偶联物：结构式如下
（I）。
2.根据权利要求1所述的通式（I）的偶联物在制备抗癌药物中的用途。
3.根据权利要求1所述的靶向线粒体功能药物鱼藤醇-叶酸偶联物的制备方法，其特征在于，包括如下步骤：
步骤（1）：将鱼藤酮溶解于甲醇中，加入硼氢化钠作为还原剂得到鱼藤醇；
步骤（2）：将所得鱼藤醇与叶酸一同溶解在DMSO中，并加入EDCI和DMAP作为催化剂，反应过夜，得到靶向线粒体功能药物鱼藤醇-叶酸偶联物。
4.根据权利要求3所述的制备方法，其特征在于，步骤（2）中，鱼藤醇与叶酸的摩尔比为1:1.2。
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| CN101904837A (zh) * | 2010-07-31 | 2010-12-08 | 南京大学 | 鱼藤酮作为非小细胞肺癌细胞增敏剂的应用 |
| CN107098907A (zh) * | 2017-06-13 | 2017-08-29 | 佛山科学技术学院 | 一种双环醇‑叶酸偶联物及其制备方法和用途 |
| CN110101866A (zh) * | 2019-06-13 | 2019-08-09 | 湖南大学 | 一种具有肿瘤靶向性的前体药物及其制备方法和用途 |
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| CN101904837A (zh) * | 2010-07-31 | 2010-12-08 | 南京大学 | 鱼藤酮作为非小细胞肺癌细胞增敏剂的应用 |
| CN107098907A (zh) * | 2017-06-13 | 2017-08-29 | 佛山科学技术学院 | 一种双环醇‑叶酸偶联物及其制备方法和用途 |
| CN110101866A (zh) * | 2019-06-13 | 2019-08-09 | 湖南大学 | 一种具有肿瘤靶向性的前体药物及其制备方法和用途 |
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