CN116854689A - 一种咪唑[4,5f][1,10]邻菲啰啉类化合物及其制备方法和应用 - Google Patents
一种咪唑[4,5f][1,10]邻菲啰啉类化合物及其制备方法和应用 Download PDFInfo
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- CN116854689A CN116854689A CN202311127783.5A CN202311127783A CN116854689A CN 116854689 A CN116854689 A CN 116854689A CN 202311127783 A CN202311127783 A CN 202311127783A CN 116854689 A CN116854689 A CN 116854689A
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- acid
- compound
- pharmaceutically acceptable
- phenanthroline
- acceptable salt
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Abstract
本发明公开了一种咪唑[4,5f][1,10]邻菲啰啉类化合物及其制备方法和应用，该化合物选自结构式如式A‑2或式A‑4所示的化合物，本发明还公开了上述化合物对RNA编辑酶ADAR1的翻译有明显的抑制作用,该类化合物可抑制多种肿瘤细胞的增殖，包括胰腺癌、肺癌、胃癌、前列腺癌、卵巢癌、睾丸癌、结肠癌、白血病、乳腺癌、多发性骨髓瘤、肝癌、黑色素瘤、神经胶质瘤、脑胶质瘤、脑垂体瘤等多种实体瘤和血液瘤。本发明为肿瘤治疗提供一项选择。
Description
技术领域
本发明涉及一种化合物及其制备方法和应用，具体地，涉及一种咪唑[4,5f][1,10]邻菲啰啉类化合物及其制备方法和应用。
背景技术
RNA编辑是最常见的转录后修饰之一，它增加了转录物的多样性和基因调控机制，在肿瘤的发生和发展中发挥着重要作用。作用于RNA的腺苷脱氨酶（ADARs）是RNA编辑酶家族的成员。ADARs催化腺苷在双链RNA（dsRNA）中转录后转化为肌苷，导致其序列、编码潜力和二级结构发生变化。ADAR1是ADARs家族的成员，是研究最广泛的RNA编辑酶，具有两种异构体，干扰素（IFN）诱导的全长ADAR1-p150和较短的ADAR1-p110。ADAR1的表达和活性升高与多种癌症和病毒感染的进展密切相关，包括严重急性呼吸系统综合征冠状病毒的感染和进化。肿瘤中ADAR1的缺失不仅导致许多肿瘤细胞系的增殖减少和细胞凋亡增加，而且克服了对免疫检查点阻断的抵抗。因此，抑制ADAR1功能是许多癌症的可行治疗策略。
G-quadruplex (G-四联体)是由堆叠鸟嘌呤(G)通过Hoogsteen氢键组成的DNA或RNA二级结构。特定的离子强度下能够折叠形成G-四链体结构。由于 G-四联体平面的堆积，在中轴方向形成了一个极性的中央空腔，这个空腔可以螯合适当体积的阳离子，从而增强G-四链体结构的稳定性。5’非翻译区(5’UTR)中的RNA G-四链体(rG4)结构在基本细胞过程中发挥着至关重要的作用。ADAR1是一种与双链RNA结合的重要酶，负责在RNA编辑中将腺苷转化为肌苷，rG4在控制ADAR1翻译中发挥着关键作用。稳定rG4可以抑制ADAR1的翻译，从而达到抗肿瘤或抗病毒的功能。
胰腺癌是一种高度致命的恶性肿瘤，被誉为“癌中之王”，其5年生存率仅约10%。研究表明，高表达的ADAR1与胰腺癌的不良预后相关。目前，关于ADAR1的特异性抑制剂的研究很少，并无靶向ADAR1的小分子公认药物在临床研究报道，并且尚无ADAR1的G四联体稳定剂报道。因此，开发ADAR1 rG4稳定剂用于胰腺癌和其他癌症的治疗是必要的。
发明内容
发明目的：本发明的目的是提供一种咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐，针对并稳定G四联体发挥强效抗肿瘤活性，可以有效克服因ADAR1抑制剂开发难的问题，为针对ADAR1的药物开发提供新的化合物；本发明的另一目的是提供一种咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐的制备方法；本发明的另一目的是提供一种药物组合物；本发明的另一目的是提供一种咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐在制备用于预防和/或治疗癌症或肿瘤以及病毒感染相关疾病的药物中的应用。
技术方案：本发明的一种咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐，该化合物为如式A-2或式A-4所示的化合物：。
进一步地，所述药学上可接受的盐为如式A-2或式A-4所示的化合物的酸加成盐，其中用于成盐的酸包括无机酸及有机酸。
更进一步地，所述无机酸为盐酸、硫酸、磷酸或有机酸；有机酸为乙酸、三氯乙酸、三氟乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、甲磺酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸或酒石酸。
另一方面，本发明提供一种咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐的制备方法，如式A-2所示的化合物由以下步骤制备：
将1,10-邻二氮杂菲-5,6-二酮和3-甲基噻吩醛溶于冰醋酸中，加入醋酸铵，反应一段时间，反应完毕后，倒入冰水中，氨水调pH值至中性，析出固体为目标产物。
优选地，上述制备中，反应温度为120℃，反应时间为6小时。
进一步地，如式A-4所示的化合物由以下步骤制备：
将1,10-邻二氮杂菲-5,6-二酮和2,6-二氯-3-吡啶甲醛溶于冰醋酸中，加入醋酸铵，反应一段时间，反应完毕后，倒入冰水中，氨水调pH值至中性，析出固体为目标产物。
优选地，上述制备中，反应温度为120℃，反应时间为6小时。
另一方面，本发明提供一种药物组合物，所述药物组合物包含上述的咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐，以及药学上可接受的载体。
药学上可接受的载体指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的赋形剂或稀释剂。所述赋形剂包括矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、黏合剂、防腐剂、抗氧剂、渗透压调节剂、着色剂填充剂、崩解剂、润滑剂等，所述稀释剂包括淀粉、生理盐水、蔗糖、乳糖、糊精等。
另一方面，本发明提供一种咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐在制备用于预防和/或治疗癌症或肿瘤以及病毒感染相关疾病的药物中的应用。
优选地，所述癌症或肿瘤相关疾病包括胰腺癌、肺癌、胃癌、前列腺癌、卵巢癌、睾丸癌、结肠癌、白血病、乳腺癌、多发性骨髓瘤、肝癌、黑色素瘤、神经胶质瘤、脑胶质瘤、脑垂体瘤多种实体瘤和血液瘤。
进一步地，咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐发挥抗肿瘤活性的靶点为G四联体。
在其中一些实施例中，所述G四联体来源于RNA编辑酶ADAR1、肝细胞生长因子受体(c-Met)以及原癌基因c-Myc。
本发明所述的通式（I）化合物或其药学上可接受的盐，对于RNA编辑酶ADAR1的翻译具有抑制活性，对相关恶性肿瘤具有治疗效果。
本发明中的术语除特别说明外，一般具有如下的含义：
术语“烷基”表示具有所述数目碳原子的直链或支链饱和烃基。
术语“C1-C4烷基”是指具有1-4个碳原子的直链或支链饱和烃基；C1-C4烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基等。卤代C1-C4烷基是指烷基链有一个及以上卤素取代的C1-C4烷基。
术语“环烷基”表示具有环状结构的烷基，包括但不限于环丙基，环丁基，环戊基、环己基等。
术语“烷氧基”表示末端含有一个氧原子的烷基，包括但不限于甲氧基，乙氧基，正丙氧基，异丙氧基。
术语“卤素”为氟、氯、溴或碘；优选为氟、氯、溴。
术语“杂环”包括饱和和不饱和的多元含氮杂环，包括但不限于环乙胺，环丙胺，吗啉，哌嗪，吡嗪，吡咯，四氢吡咯，咪唑，N-甲基哌嗪，N-乙基哌嗪，N-乙磺酰基哌嗪等。
有益效果：与现有技术相比，本发明具有如下显著优点：高表达的ADAR1与胰腺癌的不良预后相关。目前，关于ADAR1的特异性抑制剂的研究很少，并且尚无ADAR1 G四联体（ADAR1-G4s）化合物报道。因此，本发明制备的咪唑[4,5f][1,10]邻菲啰啉类化合物可以稳定ADAR1 rG4，抑制ADAR1的翻译，对胰腺癌和其他癌症治疗具有显著抗增殖活性。此外，针对ADAR1的G四联体来抑制ADAR1的表达从而发挥抗肿瘤的生物学功能，可以克服ADAR1小分子抑制剂开发难度大的问题。
附图说明
图1为化合物A-4调控ADAR1的蛋白水平结果图；
图2为化合物A-4调控mRNA水平结果图；
图3为MST测定化合物A-4与ADAR-G4s的结合能力图。
实施方式
下面对本发明作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。
本发明实施例提供一种具有如通式（I）所示的化合物，或其药学上可接受的盐：
R选自取代的五元芳杂环、取代的六元芳环或六元芳杂环、取代的并环。
其中，所述药学上可接受的盐为通式（I）化合物的酸加成盐，其中用于成盐的酸包括无机酸及有机酸，所述无机酸包括盐酸、硫酸、磷酸，有机酸包括乙酸、三氯乙酸、三氟乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、甲磺酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸和酒石酸。
本发明实施例提供一种上述化合物的制备方法，包括以下步骤：
将1,10-邻二氮杂菲-5,6-二酮和相应的醛溶于冰醋酸中，加入醋酸铵，反应一段时间，反应完毕后，倒入冰水中，氨水调pH值至中性，析出固体为目标产物。
本发明实施例涉及的具体化合物如下：
下面结合具体实施例对本申请做出详细说明。
一、化合物A-1—A-4的合成
实施例1
2-（喹啉-6-基）-1H-咪唑并[4,5-f][1,10]菲咯啉（A-1）的合成：
将1,10-邻二氮杂菲-5,6-二酮(1eq, 1 mmol)和喹啉-6-甲醛(1eq, 1 mmol)溶于冰醋酸中，加入醋酸铵，于120 ℃反应6小时，反应完毕后，倒入冰水中，氨水调pH值至中性，析出固体为A-1,收率80%。1H NMR (300 MHz, DMSO-d 6) δ 9.06 (dd,J= 4.3, 1.8 Hz,2H), 9.03 – 8.93 (m, 3H), 8.89 (d,J= 2.0 Hz, 1H), 8.70 (dd,J= 8.8, 2.0 Hz,1H), 8.57 (dd,J= 8.5, 1.8 Hz, 1H), 8.24 (d,J= 8.9 Hz, 1H), 7.87 (dd,J= 8.1,4.3 Hz, 2H), 7.65 (dd,J= 8.3, 4.2 Hz, 1H)。
实施例2
2-（3-甲基噻吩-2-基）-1H-咪唑并[4,5-f][1,10]菲咯啉（A-2）的合成：
参照A-1的合成方法，浅黄色固体，产率83%。1H NMR (300 MHz, DMSO-d 6) δ 13.56(s, 1H), 9.09 – 8.81 (m, 4H), 7.84 (s, 2H), 7.70 (d,J= 5.0 Hz, 1H), 7.14 (d,J= 5.0 Hz, 1H), 2.70 (s, 3H)。
实施例3
2-（1H-吲哚-3-基）-1H模拟物[4,5-f][1,10]菲咯啉（A-3）的合成：
参照A-1的合成方法，浅黄色固体，产率60%。1H NMR (400 MHz, DMSO-d 6) δ 13.40(s, 1H), 11.70 (d,J= 2.7 Hz, 1H), 9.03 (td,J= 5.8, 5.2, 3.3 Hz, 3H), 8.85(dd,J= 8.2, 1.8 Hz, 1H), 8.72 – 8.65 (m, 1H), 8.23 (d,J= 2.7 Hz, 1H), 7.85(ddd,J= 10.2, 8.1, 4.3 Hz, 2H), 7.58 – 7.52 (m, 1H), 7.30 – 7.23 (m, 2H)。
实施例4
2-（2,6-二氯吡啶-3-基）-1H-咪唑并[4,5-f][1,10]菲咯啉（A-4）的合成：
参照A-1的合成方法，浅黄色固体，产率75%。1H NMR (400 MHz, DMSO-d 6) δ 9.06(dd,J= 4.4, 1.7 Hz, 2H), 8.89 (dd,J= 8.1, 1.8 Hz, 2H), 8.50 (d,J= 8.1 Hz,1H), 7.92 – 7.76 (m, 3H)。
二、生物学评价实验：
（1）、ADAR1蛋白水平检测：
将对数生长期细胞以4×105- 5×105cells/孔接种于6孔板，置于37°C，5% CO2条件下培养12-24小时；向培养板加入梯度稀释的不同浓度的待测化合物溶液100 μL，将培养板在37 °C，5% CO2培养箱条件下孵育24小时；孵育结束后收集细胞，1200 rpm离心3分钟，PBS洗涤两次，1 mL PBS重悬细胞，转移至1.5 mL离心管2500 rcf离心5分钟；小心弃去上清，加入细胞裂解液和蛋白酶抑制剂及磷酸酶抑制剂，摇匀15分钟，4 °C 1400 rcf离心15分钟收集上清测定蛋白浓度用于后续Western-Blotting检测。
从图1可以看出，本发明实施例化合物A-4可以显著抑制ADAR1蛋白的表达。
（2）、ADAR1 mRNA水平检测：
将对数生长期细胞以4×105- 5×105cells/孔接种于6孔板，置于37°C，5% CO2条件下培养12-24小时；向培养板加入梯度稀释的不同浓度的待测化合物溶液100 μL，将培养板在37 °C，5% CO2培养箱条件下孵育24小时；孵育结束后收集细胞，1200 rpm离心3分钟，PBS洗涤两次，1 mL PBS重悬细胞，转移至1.5 mL离心管2500 rcf离心5分钟；小心弃去上清，加入RNA-easy试剂500 μL吹打至细胞充分裂解，加入200 μL RNA-free双蒸水混匀，静置5分钟；取上清650 μL加入等体积异丙醇颠倒混匀，-20 °C静置30分钟；12000 rcf离心，弃去上清，加入500 μL 75%乙醇洗涤两次，8000 rcf离心3分钟，吸走上清，风干；加入30 μLRNA-free双蒸水充分溶解，-80 °C保存；所得RNA样品在测完浓度后用于后续的PCR实验。
从图2可以看出，本发明实施例化合物A-4并不影响ADAR1 mRNA的水平，结合之前WB结果，表明本发明实施例化合物A-4只影响翻译水平而不影响转录水平。
（3）、微量热泳动法（Microscale thermophoresis，MST）测试化合物与ADAR1 rG4的结合能力：
实验材料：
毛细管：MO-K022 MonolithNT.115 Capillaries Lot:899917；
缓冲液：Folding Buffer：pH 7.5,50mM HEPES，100mM KCl，10mM MgCl2，0.005%Tween-20；
RNA：
用缓冲液配制浓度为2 μM的RNA溶液，于95oC加热3分钟，并缓慢冷却至室温。用缓冲液配制25 μM的化合物，并从25μM开始向下倍比稀释15个浓度梯度。在室温条件下，将化合物与G4-RNA 1:1混合混匀，并避光孵育20分钟。孵育完成后，用MO-K022玻璃毛细管按顺序吸取混合物于样品架，用MO.Affinity软件检测。采用MO.Affinity Analysisv 2.2.4软件（Nano TemperTechnologies）进行数据处理。
从图3可以看出，本发明实施例化合物A-4对ADAR1 rG4的结合能力较强，其Kd值为0.287 ± 0.093 μM。
（4）、体外细胞活性测定：
按照CCK-8法进行测定化合物对多种癌细胞增殖的抑制作用，并得出化合物抑制细胞增殖活性的半数抑制浓度IC50值。将对数生长期细胞以3000-5000 cells/孔接种于96孔板，置于37°C，5% CO2条件下培养12-24小时；向培养板加入梯度稀释的不同浓度的待测化合物溶液100 μL，将培养板在37 °C，5% CO2培养箱条件下孵育72小时；孵育结束前4 h，每孔加入10 μL CCK-8溶液（5 mg/mL）。孵育结束后，用酶标仪测定OD450，抑制率=（对照组OD值－实验组OD值）/对照组OD值×100%；得出数据后，GraphPad Prism 拟合得出IC50。其中个化合物的IC50:
表1、本发明化合物对胰腺癌细胞系PANC-1的抗增殖活性
| A-1 | A-2 | A-3 | A-4 | |
| IC50(μM) | 3.64 | 0.32 | 6.68 | 0.22 |
根据实验结果可以得出，本发明实施例的化合物对胰腺癌细胞系有着强效的抗增殖活性。
Claims (6)
1.一种咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐，其特征在于，该化合物为结构式如式A-2或式A-4所示的化合物：。
2.根据权利要求1所述的咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐，其特征在于，所述药学上可接受的盐为如式A-2或式A-4所示的化合物的酸加成盐，其中用于成盐的酸包括无机酸及有机酸。
3.根据权利要求2所述的咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐，其特征在于，所述无机酸为盐酸、硫酸或磷酸；有机酸为乙酸、三氯乙酸、三氟乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、甲磺酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸或酒石酸。
4.一种根据权利要求1-3中任一项所述的咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐的制备方法，其特征在于，如式A-2所示的化合物由以下步骤制备：
将1,10-邻二氮杂菲-5,6-二酮和3-甲基噻吩醛溶于冰醋酸中，加入醋酸铵，反应一段时间，反应完毕后，倒入冰水中，氨水调pH值至中性，析出固体为目标产物；
如式A-4所示的化合物由以下步骤制备：
将1,10-邻二氮杂菲-5,6-二酮和2,6-二氯-3-吡啶甲醛溶于冰醋酸中，加入醋酸铵，反应一段时间，反应完毕后，倒入冰水中，氨水调pH值至中性，析出固体为目标产物。
5.一种药物组合物，其特征在于，所述药物组合物包含根据权利要求1-3中任一项所述的咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐，以及药学上可接受的载体。
6.一种根据权利要求1-3中任一项所述的咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐在制备用于预防和/或治疗癌症或肿瘤以及病毒感染相关疾病的药物中的应用；咪唑[4,5f][1,10]邻菲啰啉类化合物或其药学上可接受的盐发挥抗肿瘤活性的靶点为G四联体；所述G四联体来源于RNA编辑酶ADAR1的mRNA。
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