CN111615509A - 具有信号转导与转录激活因子3抑制活性的化合物及其用途 - Google Patents
具有信号转导与转录激活因子3抑制活性的化合物及其用途 Download PDFInfo
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Images
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Abstract
本发明涉及具有信号转导与转录激活因子3抑制活性的化合物,或其药剂学上可接受的盐、溶剂化物或水合物以及它们的药剂学用途。本发明的化合物有效地抑制与各种疾病相关的信号转导与转录激活因子3的非正常活性,因此,可有用地用于预防及治疗与癌症、自身免疫性疾病、炎症性疾病等相关的各种信号转导与转录激活因子3相关疾病的目的。
Description
技术领域
本发明涉及具有信号转导与转录激活因子3抑制活性的化合物或其药剂学上可接受的盐、溶剂化物或水合物以及它们的药剂学用途。
背景技术
在以往的研究中,本发明人确认了如下的事实,即,信号转导与转录激活因子3(Signal Transducer and Activator of Transcription 3;STAT3)对低氧诱导因子-1α(Hypoxia Inducible Factor-1alpha;HIF-1alpha)蛋白的稳定性起到重要作用,与人肾癌细胞的低氧诱导因子-1α相互作用,来改善血管内皮生长因子(Vascular EndothelialGrowth Factor;VEGF)的低氧诱导因子-1-媒介表达(Jung JE,et al.FASEB J.19,1296-1298(2005))。并且,咖啡酸衍生物通过抑制信号转导与转录激活因子3的酪氨酸-705的活性来有效抑制血管内皮生长因子基因的表达(Jung JE,et al.Carcinogenesis.28,1780-1787(2007))。而且,以调节细胞分裂及细胞增殖而周知的细胞周期蛋白D1(cyclin D1)的转录活性依赖于信号转导与转录激活因子3酪氨酸-705的活性来调节(Won C,etal.Anticancer Res.30,481-488(2010))。在上述事实中,信号转导与转录激活因子3调节实体癌细胞中的低氧-媒介血管内皮生长因子表达,以证明为癌细胞的增殖所必须的血管生成的重要上调因子,通过调节癌细胞的细胞周期来参与癌细胞的分裂和增殖。
信号转导与转录激活因子s(STATs)为通过作为受体酪氨酸激酶(receptortyrosine kinase)的一种的酪氨酸蛋白激酶(JAK,Januse Kinase)、表皮生长因子受体(EGFR,Epidermal Growth Factor Receptor)及血小板衍生生长因子受体(PDGFR,Platelet-derived Growth Factor Receptor)等磷酸化来活性化的转录因子(Darnell JEJr.Science.277,1630-1635(1997))。通过磷酸化来活性化的信号转导与转录激活因子s形成二聚物(dimer),向核内部移动来与靶基因的启动子附近结合,以诱导与疾病相关的多种基因的转录(Darnell JE Jr.Science.277,1630-1635(1997);Bromberg JF,etal.Cell.98,295-303(1999))。作为信号转导与转录激活因子s蛋白种类的一种的信号转导与转录激活因子3在包括血液癌和实体癌的多种人肿瘤过多地活性化而周知(BrombergJF,et al.Cell.98,295-303(1999)),过多地活性化的信号转导与转录激活因子3通过促进与癌细胞的生存、增殖及生长相关的如Bcl-XL、原癌基因(c-myc)及细胞周期蛋白D1等的靶基因的表达来促进变异细胞的癌细胞化而周知(Vera J,et al.Prog Biophys MolBiol.106,426-434(2011);Turkson J.Expert Opin Ther Targets.8,409-422(2004))。并且,最近的报告教示信号转导与转录激活因子3抑制剂作为潜在抗癌剂的可能性(Duan H,et al.Oncogene.27,6720-6728(2008);Bai L,et al.Int J Cancer.130,2693-2702(2012);Kan CE,et al.Cancer Res.71,6930-6939(2011))。
在本说明书全文中,参照并引用大量的论文及专利文献。所引用的论文及专利文献的公开内容作为整体通过引用插入于本说明书,更明确地说明本发明所属技术领域的水平及本发明的内容。
发明内容
技术问题
本发明人为了预防及治疗与如癌症、自身免疫性疾病、炎症性疾病的信号转导与转录激活因子3的过多的表达或活性化相关的疾病,努力研发了具有与信号转导与转录激活因子3有关的选择性抑制活性的新化合物。结果,确认了具有3-苯氧甲基-1,2,4-恶二唑或3-苯氧甲基-1,2,4-噻二唑作为骨骼结构的衍生物通过抑制信号转导与转录激活因子3的活性化,即,抑制磷酸化来使半胱天冬酶-3(caspase-3)和聚腺苷二磷酸核糖聚合酶(PARP)活性化,抑制基质金属蛋白酶(MMPs)的活性并有效抑制Twist基因的表达,从而对于信号转导与转录激活因子3引起的疾病有效,因此完成了本发明。
因此,本发明的目的在于,提供下述化学式1至化学式60的化合物、或其药剂学上可接受的盐、溶剂化物或水合物。
本发明的再一目的在于,提供用于预防或治疗信号转导与转录激活因子3相关疾病的药剂学组合物。
本发明的另一目的在于,提供用于预防或改善信号转导与转录激活因子3相关疾病的食品组合物。
本发明的其他目的及优点通过下述发明的具体描述、权利要求书及附图变得更加明确。
技术方案
根据本发明的一实施方式,本发明提供选自由下述化学式1至化学式60所示的化合物组成的组中的化合物或其药剂学上可接受的盐、溶剂化物或水合物。
本发明人为了预防及治疗由于信号转导与转录激活因子3的过多的表达或活性化导致的包括癌症、自身免疫性疾病及炎症性疾病的各种疾病,努力研发了具有与信号转导与转录激活因子3有关的选择性抑制活性的新化合物。结果,确认了具有3-苯氧甲基-1,2,4-恶二唑或3-苯氧甲基-1,2,4-噻二唑作为骨骼结构的衍生物通过抑制信号转导与转录激活因子3的活性化,即,抑制磷酸化来使半胱天冬酶-3与聚腺苷二磷酸核糖聚合酶活性化,抑制基质金属蛋白酶的活性并有效抑制Twist基因的表达,从而对于信号转导与转录激活因子3相关疾病有效。因此,有效抑制信号转导与转录激活因子3的活性的本发明的物质可称为对于癌症、糖尿病视网膜病变、糖尿病、自身免疫性疾病及炎症性疾病等的多种信号转导与转录激活因子3相关疾病有效的预防剂及治疗剂。
本发明不仅包含选自由化学式1至化学式60所示的化合物组成的组中的化合物,还包含其药剂学上可接受的盐、溶剂化物及水合物。
本说明书中的术语“药剂学上可接受的盐”为不对给药化合物的有机体诱发严重的刺激且不损伤化合物的生物学活性和物性的化合物的剂型。上述药剂学盐可通过将本发明的化合物与如盐酸、溴酸、硫酸、硝酸、磷酸等的无机酸、如甲磺酸、乙磺酸、对甲苯磺酸等的磺酸、如酒石酸、甲酸、柠檬酸、醋酸、三氯乙酸、三氟乙酸、癸酸、异丁酸、丙二酸、琥珀酸、邻苯二甲酸、葡萄糖酸、苯甲酸、乳酸、富马酸、马来酸、水杨酸等的有机碳酸进行反应来获取。并且,还可通过将本发明的化合物与碱进行反应并形成铵盐、钠盐或钾盐等的碱金属盐、钙盐或镁盐等的碱土金属盐等的盐、二环己基胺、N-甲基-D-葡萄糖胺、三(羟甲基)甲胺等的有机碱盐及精氨酸、赖氨酸等的氨基酸盐来获取。
本说明书中的术语“水合物(hydrate)”为通过非共价分子间作用力(non-covalent intermolecular force)结合的包含化学计量(stoichiometric)或非化学计量(non-stoichiometric)的量的水的本发明的化合物或其盐,术语“溶剂化物(solvate)”为通过非共价分子间作用力结合的包含化学计量的或非化学计量的量的溶剂的本发明的化合物或其盐。作为与之相关的优选溶剂为挥发性溶剂、非毒性溶剂和/或适合向人给药的溶剂。
根据再一实施方式,本发明提供一种药剂学组合物,用于预防或治疗信号转导与转录激活因子3相关疾病,包含:(a)选自由上述化学式1至化学式60所示的化合物组成的组中的化合物或其药剂学上可接受的盐、溶剂化物或水合物的药剂学有效量;以及(b)药剂学上可接受的载体。
本说明书中的术语“预防”为通过给药本发明的组合物来抑制或延迟信号转导与转录激活因子3相关疾病的发展的所有行为,术语“治疗”为信号转导与转录激活因子3相关疾病的(i)发展的抑制、(ii)疾病的减轻及(iii)疾病的去除。
本说明书中的术语“信号转导与转录激活因子3相关疾病”为在其发病、发展、预后或治疗敏感性中信号转导与转录激活因子3的过度表达和/或过度活性化直接或间接影响的疾病。上述信号转导与转录激活因子3相关疾病包括癌症、糖尿病视网膜病变、糖尿病、血友病性关节病、动脉粥样硬化、瘢痕疙瘩、创面肉芽、血管粘连、自身免疫性疾病、再狭窄、肠粘连、猫抓病、溃疡、肝硬化、糖尿病性肾病、恶性肾硬化、血栓性微血管病、器官移植排斥、肾小球病变、神经变性疾病及炎症性疾病。
根据本发明的一实例,上述癌症选自由胃癌、大肠癌、肺癌、乳腺癌、卵巢癌、肝癌、支气管癌、鼻咽癌、喉癌、胰腺癌、膀胱癌、结肠癌、宫颈癌、脑癌、前列腺癌、骨癌、皮肤癌、甲状腺癌、白血病、淋巴瘤、肾上腺皮质癌、甲状旁腺癌、输尿管癌、神经胶质瘤、食道癌、小肠肿瘤、胶质母细胞瘤、脑肿瘤及肾癌组成的组中。
根据本发明的一实例,上述自身免疫性疾病选自由斑秃(alopecia greata)、强直性脊柱炎、抗磷脂综合征、自身免疫性艾迪生病、肾上腺自身免疫疾病、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性卵巢炎及睾丸炎、自身免疫性血小板减少症、白塞病、大疱性类天疱疮、心肌病、腹泻性皮炎(celiac sprue-dermatitis)、慢性疲劳免疫缺陷综合征、慢性炎症性脱髓鞘性多发性神经病、变应性肉芽肿性(Churg-strauss syndrome)、疤痕性类天疱疮、肢端硬皮综合征(CREST syndrome)、冷凝集素病、克罗恩氏病、盘状狼疮、原发性冷球蛋白血症、纤维肌痛-纤维肌炎、肾小球肾炎、格雷夫斯病、格林-巴利综合征、桥本氏甲状腺炎、特发性肺纤维化、特发性血小板减少性紫癜、免疫球蛋白A(IgA)神经炎、幼年型关节炎、扁平苔癣、红斑狼疮、梅尼耳氏症、混合性结蒂组织病、多发性硬化症、1型糖尿病或免疫介导型糖尿病、重症肌无力、寻常型天疱疮、恶性贫血、结节性多动脉炎、多发性软骨炎、自身免疫性多腺体综合征、类风湿性多发性肌痛、多发性肌炎和皮肌炎、原发性无丙种球蛋白血症、原发性血糖性肝硬化、银屑病、银屑病性关节炎、雷诺氏现象、赖特尔综合征、类风湿性关节炎、结节病、硬皮病、全身肌强直综合征、全身性红斑狼疮、红斑狼疮、大动脉炎(Takayasu's arteritis)、颞动脉炎、巨细胞动脉炎(giant cell arteritis)、溃疡性大肠炎、葡萄膜炎、白斑病及韦格纳肉芽肿病组成的组中。
根据本发明的一实例,上述炎症性疾病选自由哮喘、脑炎(encephalitis)、炎症性肠炎、类风湿性关节炎、慢性阻塞性肺疾病、过敏症、异位性皮肤炎、银屑病、败血性休克、肺纤维化、未分化型脊柱关节病、克罗恩氏病、胰腺炎、皮肤炎、未分化型关节病、关节炎、肾小球性肾炎、支气管炎、炎症性骨溶解及由病毒或细菌感染引起的慢性炎症组成的组中。
根据本发明的一实例,本发明的化学式1至化学式60所示的化合物选择性地抑制信号转导与转录激活因子3的活性,抑制癌细胞的转移。如在下述实施例中所确认,本发明的化合物抑制半胱天冬酶-3和聚腺苷二磷酸核糖聚合酶的活性化及基质金属蛋白酶的活性,并且,有效抑制Twist基因的表达,因此,有效抑制人类癌细胞的生长及转移。更详细地,本发明的化合物通过抑制信号转导与转录激活因子3的酪氨酸705残基与丝氨酸727残基的磷酸化来抑制向信号转导与转录激活因子3的信号传递路径、信号转导与转录激活因子3二聚物的核移动,抑制半胱天冬酶-3与聚腺苷二磷酸核糖聚合酶的活性抑制引起的癌细胞的增殖以及癌细胞死亡抑制机制和抑制基质金属蛋白酶的活性、Twist基因的表达引起的癌细胞移动及渗透和肿瘤的生长及转移。
本发明的组合物包含药剂学上可接受的载体。本发明的组合物所包含的药剂学上可接受的载体包括通常用于制剂的乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯树胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油等,但并不限定于此。除上述成分之外,本发明的药剂学组合物还可包括润滑剂、保湿剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等。在雷明登氏药学全书(Remington's Pharmaceutical Sciences)(19th ed.,1995)详细记载了适合的药剂学上可接受的载体及制剂。
本发明的药剂学组合物可口服给药或肠胃外给药,在肠胃外给药的情况下,可通过静脉注射、皮下注射、肌肉注射、腹腔注射、透皮给药等给药。
本发明的药剂学组合物的适合剂量可根据制剂化方法、给药方式、患者年龄、体重、性别、病态、饮食、给药时间、给药路径、排泄速度及反应灵敏度的因素处方的不同。例如,本发明药剂学组合物的1天剂量为0.0001~100mg/kg。
本发明的药剂学组合物可根据本发明所属技术领域的普通技术人员容易实施的方法,利用药剂学上可接受的载体和/或赋形剂来制剂化,从而以单位容量形态制备或向多容量容器内添加来制备。在此情况下,剂型可以为油介质或水介质中的溶液、悬浮液、糖浆剂或乳化液形态或提取剂、散剂、粉末剂、颗粒剂、片剂或胶囊剂形态,还可包括分散剂或稳定化剂。
根据另一实施方式,本发明提供一种用于预防或改善信号转导与转录激活因子3相关疾病的食品组合物,包含选自由上述化学式1至化学式60所示的化合物组成的组中的化合物或其盐作为有效成分。
上述食品组合物可以为保健功能性食品、营养辅助剂、营养剂、医药食品(pharmafood),保健食品、营养制剂(nutraceutical)、特制食品、食品添加剂等的所有形态的食品,但并不限定于此,例如,可以为肉类、香肠、面包、巧克力、糖果类、零嘴类、饼干类、披萨、泡面、其他面食类、口香糖类、包括冰淇淋类的奶制品、各种汤、饮料、茶、口服液、酒精饮料及维生素复合剂等。
本发明的食品组合物包含制造食品时通常添加的成分,例如,包含蛋白质、碳水化合物、脂肪、营养素、调味料及调味剂。上述碳水化合物的例为如下的常规糖及糖醇,即,如葡萄糖、果糖等的单糖、如麦芽糖、蔗糖、低聚糖等的二糖,如糊精、环糊精等的多糖,如木糖醇、山梨糖醇、赤藓糖醇等的糖醇。作为调味剂,可使用天然调味剂[非洲甜果素,甜叶菊提取物(例如,莱苞迪甙A、甘草甜素等)]及合成调味剂(糖精、阿斯巴甜等)。
除上述成分之外,本发明的食品组合物可包含各种营养剂、维生素类、矿物质(电解质)、膳食成分、合成调味剂及天然调味剂等的调味剂、着色剂、增强剂(奶酪、巧克力等)、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定化剂、防腐剂、甘油、酒精、用于碳酸饮料的碳化剂等。例如,在将本发明的食品组合物制备为口服液的情况下,除本发明的有效成分之外,还可包含柠檬酸、液态果糖、砂糖、葡萄糖、醋酸、苹果酸、果汁、各种植物提取物等。
作为还有一实施方式,本发明提供一种用于预防或改善信号转导与转录激活因子3相关疾病的化妆品组合物(功能性化妆品组合物),包含选自由上述化学式1至化学式60所示的化合物组成的组中的化合物或其盐作为有效成分。
上述化妆品组合物可制备为在本领域通常制备的任何剂型,除有效成分之外,包含通常用于制备化妆品的成分,例如,可包括如抗氧化剂、稳定化剂、溶解剂、维生素、颜料及香料的普通辅助剂。
作为又一实施方式,本发明提供一种信号转导与转录激活因子3相关疾病的预防或治疗方法,包括向对象给药药剂学上有效量的选自由上述化学式1至化学式60所示的化合物组成的组中的化合物或其盐的步骤。
作为又一实施方式,本发明提供一种化合物或其盐的用途,上述化合物选自由用作用于预防或治疗信号转导与转录激活因子3相关疾病的药学组合物的上述化学式1至化学式60所示的化合物组成的组中。
作为又一实施方式,本发明提供一种化合物或其盐的用途,上述化合物选自由用作用于预防或改善信号转导与转录激活因子3相关疾病的食品组合物的上述化学式1至化学式60所示的化合物的组中的组中。
作为又一实施方式,本发明提供一种化合物或其盐的用途,上述化合物选自由用作用于预防或改善信号转导与转录激活因子3相关疾病的化妆品组合物(功能性化妆品组合物)的上述化学式1至化学式60所示的化合物组成的组中。
发明的效果
本发明的特征及优点如下:
(i)本发明提供具有信号转导与转录激活因子3抑制活性的新化合物及其用途。
(ii)可将本发明的化合物作为有效成分来制备药剂学、功能性化妆品(cosmeceutical)、化妆品、功能性食品(neutraceutical)或食品组合物。
(iii)本发明的化合物有效抑制与各种疾病相关的信号转导与转录激活因子3的非正常活性,因此,可有用地用于预防及治疗与癌症、自身免疫性疾病、炎症性疾病等相关的各种信号转导与转录激活因子3相关疾病。
附图说明
图1a至图1g示出利用与果蝇与人源癌细胞和信号转导与转录激活因子3结合的SH2结构域有关的结合分子结构模型的模型,呈现出本发明的ODZ17690化合物具有对于信号转导与转录激活因子3的选择性活性。
图2a及图2b示出本发明的ODZ17690化合物在人源性霍奇金淋巴瘤细胞株(L540细胞)中选择性抑制信号转导与转录激活因子3的活性的作用优秀。
图3a至图3c示出将3-苯氧甲基-1,2,4-恶二唑或3-苯氧甲基-1,2,4-噻二唑作为骨骼结构的144种物质中的抑制信号转导与转录激活因子3的活性优秀的13种物质。
图4a至图4h示出与信号转导与转录激活因子3结合的与SH2结构域有关的ODZ10117化合物的结合分子结构模型和各种人源癌细胞中抑制信号转导与转录激活因子3的作用。
图5a至图5c示出ODZ10117化合物在人源胶质母细胞瘤(U87-MG)细胞和乳腺癌细胞(MDA-MB-231)中抑制信号转导与转录激活因子3的活性。
图6a及图6b示出ODZ10117化合物在果蝇细胞中抑制信号转导与转录激活因子92E(哺乳类的信号转导与转录激活因子)的活性。
图7a至图7d示出ODZ10117化合物在各种人类胶质母细胞瘤中抑制信号转导与转录激活因子3的活性。
图8a至图8c示出ODZ10117化合物在各种乳腺癌细胞中抑制信号转导与转录激活因子3的活性。
图9a至图9d示出ODZ10117化合物抑制信号转导与转录激活因子3二聚化反应(dimerization)、核移位(nuclear translocation)及转录活性(transcriptionalactivity)。
图10示出ODZ10117化合物在人类胶质母细胞瘤中抑制信号转导与转录激活因子3的依赖性细胞生存。
图11a至图11e示出ODZ10117化合物抑制U87-MG细胞与MDA-MB-231细胞的增殖,诱导细胞死亡。
图12a至图12d示出ODZ10117化合物抑制U87-MG细胞与MDA-MB-231细胞的移动和渗透。
图13a至图13d示出ODZ10117化合物在异种移植小鼠中抑制生长的肿瘤大小。
图14a至图14d示出在人源性霍奇金淋巴瘤细胞株中示出于本发明的表1的46种化合物的信号转导与转录激活因子3抑制活性。
图15a及图15b示出在人源性霍奇金淋巴瘤细胞株中示出于本发明的表1的46种化合物中的抑制信号转导与转录激活因子3的活性更优秀的33种化合物的信号转导与转录激活因子3抑制活性。
图16示出示出于本发明的表1的46种化合物中的抑制信号转导与转录激活因子3的活性最优秀的2种化合物的信号转导与转录激活因子3抑制活性。
具体实施方式
以下,通过实施例更详细地说明本发明。这些实施例仅用于具体说明本发明,根据本发明的主旨,本发明的范围并不局限于这些实施例,这对普通技术人员而言是显而易见的。
实施例
实验材料及实验方法
物质试样
通过下述方法制备将3-苯氧甲基-1,2,4-恶二唑作为骨骼结构的5-叔丁基-3-(3-硝基-苯氧甲基)-[1,2,4]恶二唑(ODZ17690)、3-(2,4-二氯-苯氧甲基)-5-三氯甲基-[1,2,4]恶二唑(ODZ10117)、5-仲丁氧基-3-(2,4-二氯-苯氧甲基)-[1,2,4]恶二唑(ODZ8292)、3-(2,4-二氯-苯氧甲基)-5-异丁氧基-[1,2,4]恶二唑(ODZ8293)、3-(2,4-二氯-苯氧甲基)-5-丙氧基-[1,2,4]恶二唑(ODZ10181)、3-(2,4-二氯-苯氧甲基)-5-丙-2-炔氧基-[1,2,4]恶二唑(ODZ8297)、5-烯丙氧基-3-(4-氯-2-甲基-苯氧甲基)-[1,2,4]恶二唑(ODZ8315)、3-(2,4-二氯-苯氧甲基)-[1,2,4]恶二唑-5-羧酸甲酰胺(ODZ10159)、3-(2,4-二氯-苯氧甲基)-5-乙氧基-[1,2,4]恶二唑(ODZ10177)、1-{4-氯-5-[5-(2,4-二氯-苯基)-[1,2,4]恶二唑-3-基甲氧基]-2-氟-苯基}-3,4-二甲基-吡咯-2,5-二酮(ODZ11296)、3,6-二氯-8-(3-间苯氧基甲基-[1,2,4]恶二唑-5-基)-喹啉(ODZ16717)、1-苯基-3-[2-(3-间苯氧基甲基-[1,2,4]恶二唑-5-基)-苯基]-尿素(ODZ16998)、3-氯-2-(3-间苯氧基甲基-[1,2,4]恶二唑-5-基)-苯胺(ODZ16999)及将3-苯氧甲基-1,2,4-噻二唑作为骨骼结构的2-{2-[3-(2-氯-4-氟-苯氧甲基)-[1,2,4]噻二唑-5-基氧甲基]-苯基}-2-甲氧基亚胺-N-甲基-乙酰胺(ODZ9562),在100%二甲基亚砜(DMSO)中悬浮,在-20℃的温度条件下保存并使用。
化合物的合成
制备例1:制备3-((2,4-二氯苯氧基)甲基-5-(三氯甲基)-1,2,4-恶二唑(3-((2,
4-dichlorophenoxy)methyl)-5-(trichloromethyl)-1,2,4-oxadiazole;ODZ 10117)
1-1:制备2-(2,4-二氯苯氧基)乙腈
将2,4-二氯苯酚(1g,6.10mmol)溶解于二甲基甲酰胺(8ml)后,在室温条件下添加碳酸钾(840mg,6.10mmol),将溴乙腈(0.44ml,6.10mmol)溶解于二甲基甲酰胺(3ml)并慢慢滴落。在室温条件下搅拌24小时之后,向反应混合物添加水,并利用乙酸乙酯提取。之后,利用硫酸钠饱和水溶液清洗有机层,利用硫酸镁干燥,之后,减压并去除溶剂,通过硅胶管色谱法(n-己烷:乙酸乙酯=3:1)获取目的化合物(1.18g,95%)。
1-2:制备2-(2,4-二氯苯氧基)-N'-羟乙酰胺酰亚胺
将三乙胺(2.70ml,19.52mmol)溶解于50%乙醇水溶液(21ml)后,在常温条件下添加盐酸羟胺(1.36g,19.52mmol)。将在常温条件下搅拌5分钟后获取的2-(2,4-二氯苯氧基)乙腈溶解于乙醇(83ml)并添加,之后,在100℃的温度条件下回流3小时。之后,利用水稀释并过滤反应混合物,再次利用水清洗,从而获取了目的化合物(2.71g,77%)。1H NMR(500MHz,CDCl3)δ4.58(s,2H),4.85(s,2H),6.53(s,1H),6.96(d,J=8.8Hz,1H),7.17(dd,J=2.3Hz,8.8Hz,1H),7.37(d,J=2.4Hz,1H)
1-3:制备3-((2,4-二氯苯氧基)甲基-5-(三氯甲基)-1,2,4-恶二唑(ODZ10117)
将所获取的2-(2,4-二氯苯氧基)-N'-羟乙酰胺酰亚胺(100mg,0.43mmol)和三氯乙腈(0.040ml,0.43mmol)溶解于二甲基甲酰胺(1ml)后,添加对甲苯磺酸(41mg,0.22mmol)和氯化锌(30mg,0.22mmol)。之后,对于在80℃的温度条件下回流16小时后获取的反应化合物,利用碳酸氢钠清洗有机层及利用硫酸镁干燥,在减压条件下去除溶剂。之后,通过硅胶管色谱法(n-己烷:乙酸乙酯=10:1)从剩余残留物获取目的化合物(81mg,53%)。1H NMR(300MHz,CDCl3)δ5.27(s,2H),7.01(d,J=8.8Hz,1H),7.20(dd,J=2.5Hz,8.7Hz,1H),7.40(d,J=2.6Hz,1H)
制备例2:制备3-((2,4-二氯苯氧基)甲基)-5-丙氧基-1,2,4-恶二唑(3-((2,4-
dichlorophenoxy)methyl)-5-propoxy-1,2,4-oxadiazole;ODZ10181)
在室温条件下添加将丙酸钠(119mg,1.45mmol)溶解于二甲基甲酰胺(10ml)后获取的3-((2,4-二氯苯氧基)甲基-5-(三氯甲基)-1,2,4-恶二唑(350mg,0.97mmol)后,在常温条件下搅拌10分钟。利用硫酸钠饱和水溶液和生理盐水清洗反应混合物后,利用硫酸镁干燥有机层。之后,在减压条件下去除溶剂,通过硅胶管色谱法(n-己烷:乙酸乙酯=10:1)从残留物获取目的化合物(64mg,22%)。1H NMR(400MHz,CDCl3)δ1.02(t,J=7.4Hz,3H),1.85(qd,J=7.0Hz,14.1Hz,2H),4.47(t,J=6.6Hz,2H),5.05(s,2H),7.00(d,J=8.8Hz,1H),7.17(dd,J=2.0Hz,8.8Hz,1H),7.37(d,J=1.9Hz,1H)
制备例3:制备5-(仲丁氧基)-3-((2,4-二氯苯氧基)甲基)-1,2,4-恶二唑(5-
(sec-butoxy)-3-((2,4-dichlorophenoxy)methyl)-1,2,4-oxadiazole;ODZ8292)
在室温条件下添加将仲丁醇钠(613mg,6.37mmol)溶解于二甲基甲酰胺(20ml)后获取的3-((2,4-二氯苯氧基)甲基-5-(三氯甲基)-1,2,4-恶二唑(462mg,1.27mmol),并在常温条件下搅拌10分钟。之后,利用硫酸钠饱和水溶液和生理盐水清洗所获取的反应混合物后,利用硫酸镁干燥借助乙酸乙酯提取的有机层。之后,在减压条件下去除溶剂,通过硅胶管色谱法(n-己烷:乙酸乙酯=15:1)从残留物获取目的化合物(78mg,19%)。1H NMR(400MHz,CDCl3)δ0.97(t,J=7.4Hz,3H),1.42(d,J=6.2Hz,3H),1.67-1.87(m,2H),5.05(s,2H),7.00(d,J=8.8Hz,1H),7.17(dd,J=2.0Hz,8.8Hz,1H),7.37(d,J=2.0Hz,1H)
基于结构的虚拟筛选
为了筛选抑制信号转导与转录激活因子3活性的化合物,利用了AutoDockversion 4.2软件,利用ChemBridg(https://www.hit2lead.com/)的化合物文库执行虚拟筛选。在信号转导与转录激活因子3的X射线结晶结构(PDB ID:1BG1)中,利用相当于SH2结构域的部分的三维结构(Becker S,et al.Nature.394,145-151(1998)),利用AMBERpackage(ver.11)计算了最小能量(Case DA,et al.J Comput Chem.26,1668-1688(2005))。并且,与AMBER程序一同,对ChgemBridge的筛选化合物生成结构,并进行分子动力学模拟(molecular dynamics simulation)。所有构象异构体(conformer)通过具有默认参数(default parameter)的AutoDock package(ver 4.2)向SH结构域对接。为了使通过GB/SA模型的蛋白质-配体相互作用再评分化,通过利用AMBER力场(force field)的分子动力学模拟生成所有对接的结构。以结构相似性为基础,聚集结果结构,并选择属于表示最低函数的群的结构。对于结合能量,考虑熵效应来选择代表性的群的核心构象异构体(centralconformer)结构和能量值。所有过程通过自动集群使用的基于迭代结构的对接(ALIS-DOCK,Automatic cLuster-used Iterative Structure-based DOCKing)脚本自动执行。所有计算通过使用基于Mac mini群系统来执行。
果蝇细胞培养及发光酶分析
通过在上述内容记载的方法培养了用于实验的果蝇细胞(S2-NP,24×3)(Kim BH,et al.Mol Cancer Ther.7,2672-2680(2008))。S2-NP(施奈德果蝇细胞(DrosophilaSchneider cell))细胞为果蝇源巨噬细胞相似细胞,在施耐德培养基(Schneider'smedium)培养,24×3细胞为将10×信号转导与转录激活因子92E-荧光素酶和标记有脊髓灰质炎(PolIII-Renilla)荧光素酶的质粒载体脱氧核糖核酸(DNA)作为报告基因向S2-NP细胞插入而稳定地表达的细胞株,向如S2-NP的培养基添加500mmg/ml的遗传霉素(geneticin)来培养。作为配体以规定比例混合未配对(unpaired,upd)或表达HOPTTum-l的S2-NP细胞与构建报告基因的24×3细胞并在化合物的存在下培养24小时,利用发光测定仪测定信号转导与转录激活因子92E的表达程度,与处理二甲基亚砜的组进行比较来比较抑制效果。并且,对阳性对照组和AG490、硝呋酚酰肼(nifuroxazide)、NSC628869(STA-21或STA)或NSC74859(S31-001)处理组进行比较来比较抑制效果。
培养人类癌细胞
用于实验的人类癌细胞株为U87-MG(人类胶质母细胞瘤,human malignantglioblastoma)细胞株和MDA-MB-231(人类乳腺癌,human malignant breast cancer)细胞株,与此同时,通过在上述内容记载的方法培养各种人源血液癌细胞及实体癌细胞(JungJE,et al.FASEB J.19,1296-1298(2005))。用于实验的人源性霍奇金淋巴瘤细胞株L540及HLDM-2从德国微生物菌种保藏中心(German Collection of Microorganism and CellCultures)(DSMZ,德国(Germany))获取,利用包含20%胎牛血清(FBS)的RPMI 1640培养基以37℃的温度条件在5%CO2培养基培养。
设计结合分子模型
在信号转导与转录激活因子3的X射线结晶结构(PDB ID:1BG1)利用了相当于SH2结构域的部分的三维结构(Becker S,et al.Nature.394,145-151(1998)),利用AMBERpackage(ver.11)计算了最小能量(Case DA,et al.J Comput Chem.26,1668-1688(2005))。并且,与AMBER程序一同对于包括ODZ10117在内的所有化合物生成500个结构,并进行分子动力学模拟。
分析细胞增殖
通过以往记载的方式分析细胞增殖(Won C,et al.Anticancer Res.30,481-488(2010))。为了分析细胞的增殖率,向6孔培养盘分注U87-MG细胞株和MDA-MB-231细胞株,第二天,处理二甲基亚砜和ODZ10117,在0小时、24小时、48小时及72小时之后,利用结晶紫染色,并利用血细胞计(hemocytometer)计算活着的细胞(live cells)数。
分析转化及发光酶
通过以往记载的方式分析发光酶的表达(Jung JE,et al.FASEB J.19,1296-1298(2005))。作为报告基因,利用脂质体2000将具有信号转导与转录激活因子3-TA-荧光素酶的质粒载体脱氧核糖核酸在HEK293T细胞暂时表达并处理ODZ10117,利用发光测定仪测定了信号转导与转录激活因子3的表达程度,通过与二甲基亚砜处理组进行比较来比较抑制效果。并且,通过对阳性对照组与AG490、硝呋酚酰肼(nifuroxazide)、NSC628869(STA-21或STA)或NSC74859(S31-001)处理组进行比较来比较抑制效果。
实时聚合酶链式反应(qRT-PCR)
通过以往的记载方式分离核糖核酸(RNA)并执行实时聚合酶链式反应(Jung JE,et al.FASEB J.19,1296-1298(2005))。向人源Bcl-XL、Bcl-2、Twist及磷酸苷油酸脱氢酶(GADPH)基因混合特异性引物和定量SYBR绿色聚合酶链式反应主混合物(QuantiFast SYBRGreen PCR master mix),利用Applied Biosystems 7300实时聚合酶链式反应系统来扩增各个基因,并比较确认表达程度。
免疫印迹分析
实施免疫印迹分析(Jung JE,et al.FASEB J.19,1296-1298(2005))。利用磷酸盐缓冲液(PBS)清洗2次细胞,在溶解液(50mM的三(羟甲基)氨基甲烷(Tris-HCl),pH7.4,350mM的氯化钠(NaCl),1%聚乙二醇辛基苯基醚(Triton X-100),0.5%乙基苯基聚乙二醇(Nonidet P-40),10%甘油,0.1%十二烷基硫酸钠(SDS),1mM的乙二胺四乙酸(EDTA),1mM的乙二醇二乙醚二胺四乙酸(EGTA),1mM的Na3VO4,1mM的苯甲基磺酰氟(PMSF),蛋白质分解酶及磷酸化抑制剂)悬浮细胞来破碎细胞膜和核膜。从而溶解细胞。进行离心分离来去除不溶性蛋白质组分,将上清液与十二烷基硫酸钠电泳缓冲液混合来进行电泳(SDS-PAGE),以利用所要的抗体进行检测来确认蛋白质的表达程度。
伤口治疗分析(Wound healing assay)
通过以往记载的方式实施伤口治疗分析(Jung JE,et al.FASEB J.19,1296-1298(2005))。向12孔板(U87-MG:5×105细胞/ml;MDA-MB-231:3×105细胞/ml)分注各个细胞,到细胞增殖至90%以上为止进行培养。通过移液管的尖端并利用磷酸盐缓冲液清洗2次挂落的细胞。并且,24小时之后,在去除细胞的部分通过显微镜观察细胞的增殖(渗透)并拍摄图像。
基质胶渗透分析
在不包含血清的培养液以1:3的比例稀释去除生长因子的基质胶(growth factorreduced matrigel),移动至24孔板并在37℃的温度条件下固体化5小时。将细胞放入添加1%血清的培养液并添加固体化的基质胶,之后,添加600ul的包含10%血清的培养液并培养24小时,上述培养液添加有5ul/ml浓度的纤维粘连蛋白。并且,通过添加迪夫快速染色液(Diffquick)来固定细胞并染色,之后,通过徕卡应用套件(Leica Application Suite)显微镜观察并拍摄图像。
流细胞分析(Flow-cytometry)
为了分析细胞的死亡程度,利用FACS缓冲液清洗各个细胞,在2000rpm的条件下进行2分钟的离心分离。利用碘化丙啶(propidium iodide)对清洗的细胞进行15分钟的染色,之后,利用FACS流逝细胞仪(Canto flow cytometry)进行分析来利用Flow-Jo软件分析。
人类癌细胞的异种移植
从查尔斯河日本公司(Charles River Japan Inc.)(Shin-Yokohama,日本)购买了雄性裸鼠(BALB/cAnNCrj-nu/nu)。在温度和湿度恒定的无菌室饲养小鼠,根据在首尔大学实验动物维持指南记载的方法实施饲养过程。在磷酸盐缓冲液稀释U87-MG细胞或MDA-MB-231细胞,在100ul的25%浓度基质胶悬浮,向小鼠背部侧注入并饲养6周至10周。从注入细胞2周之后开始利用游标尺(vernier caliper)每2天测定人肿瘤的生长。针对人类癌细胞形成的抑制程度,在注入肿瘤细胞4周开始的第0天、第3天及第5天向人肿瘤直接注入40μM的ODZ10117,在第7天牺牲小鼠来分离肿瘤,与处理1%二甲基亚砜的对照组进行比较来测定药物的肿瘤细胞抑制功效。
肿瘤组织学及磷酸化信号转导与转录激活因子3(p-STAT3)、裂解半胱天冬酶-3(cleaved caspase-3)、Bcl-XL、Ki67及MMP2的免疫染色
利用福尔马林固定从小鼠分离的肿瘤,利用石蜡进行包埋并从各个石蜡块剪切切片。分别利用苏木精-伊红、磷酸化信号转导与转录激活因子3(phospho-STAT3)、裂解半胱天冬酶-3、Bcl-XL、Ki67及pro/active MMP-2对各个切片进行染色,从而进行组织学评价。在去除切片的石蜡并利用酒精去除水分之后,在10mM的柠檬酸钠缓冲液(pH6.0)利用微波加热5分钟。利用包含2.5%牛血清白蛋白及2%正常血清氯的磷酸盐缓冲液反应1小时来去除非特异性结合,在4℃的温度条件下和与以1:100稀释的磷酸化信号转导与转录激活因子3、裂解半胱天冬酶-3、Bcl-XL、Ki67及pro/active MMP-2有关的抗体反应一夜。作为阴性对照组,与没有一次抗体的稀释溶液进行反应。之后,清洗切片并与利用适当的生物素标记的二次抗体进行反应,利用亲和素-生物素-辣根(avidin-biotin-horseradish)复合物确认了结合的抗体的位置和表达。在100倍和400倍的倍率通过显微镜确认了各个染色切片,利用索尼XC-77CCD摄像机及微机成像器件4型图像分析系统进行分析,从而进行组织学评价。
统计分析
利用Microsoft Excel 2000软件分析所有数据。以平均值和平均误差表达数据,未配对双尾t检验(unpaired two-tailed Student's t-test)(p<0.05)计算统计学重要度。
实验结果
利用选择性信号转导与转录激活因子3抑制前体物质鉴定ODZ17690
利用果蝇细胞、人源性霍奇金淋巴瘤细胞株(L540)及分子模型坚定了作为具有3-苯氧甲基-1,2,4-恶二唑作为骨骼结构的化合物的ODZ17690(5-tert-Butyl-3-(3-nitro-phenoxymethyl)-[1,2,4]oxadiazole)(图1a)。首先,在利用果蝇细胞的发光酶分析(luciferase assay)中,ODZ17690有效抑制了通过作为配体的未配对或信号转导与转录激活因子92E(相当于哺乳动物的信号转导与转录激活因子)的高等级的Hop(相当于哺乳动物的酪氨酸蛋白激酶)的活性活性化的信号转导与转录激活因子92E的表达(图1b及图1b)。在作为人类癌细胞的L540细胞中,ODZ17690也有效抑制了信号转导与转录激活因子3的705号酪氨酸残基的磷酸化和作为低级调节物质的细胞因子信号传导抑制蛋白3(SOCS3)的表达(图1d)。在作为人类癌细胞的人源性霍奇金淋巴瘤细胞(HDLM-2)细胞中,ODZ17690也选择性抑制了信号转导与转录激活因子3的705号酪氨酸残基的磷酸化(图1e)。在作为信号转导与转录激活因子3的结合部位的与SH2结构域有关的结合-分子模型中,确认了以标准物质而周知的作为信号转导与转录激活因子3选择性抑制剂的NSC-628869和NSC-74859的pTyr-Leu基质在SH2结构域选择性抑制,从而确认了结合分子模型的正确性(图1f),ODZ17690也很好地与SH2结构域结合并结合能量最低,与对照物质相似(图1g)。
在人类癌细胞株确认ODZ17690的选择性信号转导与转录激活因子3的抑制作用
在作为人源性霍奇金淋巴瘤细胞株的L540确认了ODZ17690的人类癌细胞株中的选择性信号转导与转录激活因子3的活性抑制作用。相比于信号转导与转录激活因子1或信号转导与转录激活因子5,ODZ17690对于信号转导与转录激活因子3呈现出强抑制作用(图2a)。并且,对于上层信号传递过程的酪氨酸蛋白激酶3呈现出弱抑制作用,在作为Src家族激酶的Lyn或细胞外信号调节激酶(ERK)信号传递过程中,未呈现抑制作用(图2b)。通过以上结果确认了在结合-分子模型和果蝇细胞中确认的ODZ17690的选择性信号转导与转录激活因子3抑制作用也作用于人类癌细胞。
确认功效比ODZ17690优秀的衍生物
为了确认选择性信号转导与转录激活因子3抑制功效比ODZ17690优秀的化合物,在具有3-苯氧甲基-1,2,4-恶二唑或3-苯氧甲基-1,2,4-噻二唑作为骨骼结构的144种化合物中构建果蝇细胞和信号转导与转录激活因子3-荧光素酶结构,来在选择性表达信号转导与转录激活因子3的人类乳腺癌细胞源MDA-MB-231细胞中实施发光酶分析。结果,将判断为具有优秀的功效的13种化合物选定为最终候选物质(图3a及图3b)。同时,利用13种化合物实施免疫印迹分析来再次确认了判断为具有优秀的信号转导与转录激活因子3抑制作用的化合物,其中,判断为ODZ10117最优秀(图3c)。
在结构-结合分子模型和人类癌细胞中确认了ODZ10117的信号转导与转录激活因子3活性抑制作用
利用结构-结合分子模型确认了化合物ODZ10117的选择性信号转导与转录激活因子3抑制功效。当通过模型示出与SH2结构域有关的磷酸化的酪氨酸残基的结合时,确认了ODZ10117适当地结合(青绿色)。与SH2结构域有关的结合与选择性信号转导与转录激活因子3抑制物质而周知的NSC628869(黄色)和NSC74859(粉色)相似,在自由结合能量中,ODZ10117、NSC628869及NSC74859分别以-11.14kcal/mol、-10.89kcal/mol及-10.01kcal/mol呈现出更低的结合能量,确认了结合能力比对照物质优秀(图4a及图4c为ODZ10117)。在X射线复合(X-ray complex)结构复合物中,以绿色标记与Pro-pTyr-Leu的SH2结构域有关的结合(图4a及图4b)。
在信号转导与转录激活因子3过于活性化的各种人类癌细胞株中,确认了ODZ10117的信号转导与转录激活因子3活性抑制作用。结果,ODZ10117在用于实验的所有种类的细胞种中抑制了信号转导与转录激活因子3的活性(图4d及图4e)。并且,还有效抑制了利用白细胞介素6(IL-6)诱导的信号转导与转录激活因子3的活性(图4f及图4g)。并且,相比于以选择性信号转导与转录激活因子3抑制物质而周知的NSC628869及NSC74859,ODZ10117更有效地抑制了利用白细胞介素6诱导的信号转导与转录激活因子3的活性(图4h)。通过以上结果,可确认ODZ10117具有能够优异地抑制在人类癌细胞株中活性化的信号转导与转录激活因子3的作用。
在人类癌细胞株中确认ODZ10117的选择性信号转导与转录激活因子3活性抑制作用
在人类胶质母细胞瘤和作为乳腺癌细胞株的U87-MG细胞和MDA-MB-231细胞中,确认了化合物ODZ10117的与信号转导与转录激活因子3有关的选择性活性抑制作用。化合物ODZ10117为具有3-(2,4-二氯-苯氧甲基)-5-三氯甲基-[1,2,4]恶二唑(3-(2,4-Dichloro-phenoxymethyl)-5-trichloromethyl-[1,2,4]oxadiazole)的结构的化合物(图5a)。首先,为了确认信号转导与转录激活因子3的启动子活性,将磷酸化信号转导与转录激活因子3-TA-荧光素酶脱氧核糖核酸结构在HEK293T细胞株转化,并确认了ODZ10117的功效。结果,相比于二甲基亚砜处理组,ODZ10117显著减少信号转导与转录激活因子3的启动子活性(图5b)。
接着,为了分析与信号转导与转录激活因子3蛋白的酪氨酸和丝氨酸残基有关的活性程度,实施了免疫印迹。结果,ODZ10117在U87-MG和MDA-MB-231细胞中显著抑制信号转导与转录激活因子3的酪氨酸705和丝氨酸727残基的磷酸化(图5c)。
在果蝇细胞株中确认ODZ10117的选择性信号转导与转录激活因子92E活性抑制作用
在果蝇细胞中确认了与化合物ODZ10117的信号转导与转录激活因子92E(相当于哺乳类的信号转导与转录激活因子)有关的选择性活性抑制作用。结果,相比于二甲基亚砜处理组,ODZ10117以浓度依赖性显著减少信号转导与转录激活因子92E的启动子活性(图6a及图6b)。
在人类胶质母细胞瘤中确认ODZ10117的选择性信号转导与转录激活因子92E活性抑制作用
在人类胶质母细胞瘤中确认了化合物ODZ10117的与信号转导与转录激活因子3有关的选择性活性抑制作用。首先,利用在市场销售的人类胶质母细胞瘤和人类胶质母细胞瘤原代培养细胞株实施免疫印迹分析,以筛选将信号转导与转录激活因子3磷酸化的人类胶质母细胞瘤(图7a)。之后,为了分析信号转导与转录激活因子3在磷酸化的人类胶质母细胞瘤中的与信号转导与转录激活因子3蛋白的酪氨酸有关的活性程度,实施免疫印迹。结果,ODZ10117在将信号转导与转录激活因子3磷酸化的人类胶质母细胞瘤中浓度依赖性地抑制信号转导与转录激活因子3的酪氨酸705的磷酸化(图7b),在处理ODZ10117之后的2小时内完全抑制信号转导与转录激活因子3的磷酸化(图7c)。并且,相比于以选择性信号转导与转录激活因子3抑制物质而周知的NSC628869及NSC74859,ODZ10117呈现优秀的信号转导与转录激活因子3抑制功效(图7d)。
在人类乳腺癌细胞株中确认ODZ10117的选择性信号转导与转录激活因子92E活性抑制作用
在人类乳腺癌细胞株中确认了化合物ODZ10117的与信号转导与转录激活因子3有关的选择性活性抑制作用。为了在人类乳腺癌细胞株中分析与信号转导与转录激活因子3蛋白的酪氨酸有关的活性程度,实施了免疫印迹。结果,ODZ10117在人类乳腺癌细胞株中浓度依赖性地抑制信号转导与转录激活因子3的酪氨酸705的磷酸化(图8a),在处理ODZ10117之后的2小时内完全抑制了信号转导与转录激活因子3的磷酸化(图8b)。并且,相比于以选择性信号转导与转录激活因子3抑制物质而周知的NSC628869及NSC74859,ODZ10117呈现出优秀的信号转导与转录激活因子3抑制功效(图8c)。之后,在人类乳腺癌细胞株中对化合物ODZ10117与以抗癌物质而周知的2-乙酰基呋喃并-1,4-萘醌(napabucasin)的与信号转导与转录激活因子3有关的选择性活性抑制作用进行比较。为了在人类乳腺癌细胞株中分析与信号转导与转录激活因子3蛋白的酪氨酸有关的活性程度,实施了免疫印迹。结果,ODZ10117在高浓度中呈现与2-乙酰基呋喃并-1,4-萘醌相似的信号转导与转录激活因子3抑制功效(图8d)。
确认ODZ10117的信号转导与转录激活因子3的二聚化反应、核移位及转录活性抑制作用
确认了化合物ODZ10117的信号转导与转录激活因子3的二聚化反应(dimerization)、核移位(nuclear translocation)及转录活性(transcriptionalactivity)抑制作用。首先,为了确认信号转导与转录激活因子3的二聚化反应,将信号转导与转录激活因子3-Flag脱氧核糖核酸结构或信号转导与转录激活因子3-HA脱氧核糖核酸结构在HEK293T细胞株转化,并实施免疫沉淀及免疫印迹分析。结果,ODZ10117抑制信号转导与转录激活因子3的二聚化反应(图8a)。并且,相比于2-乙酰基呋喃并-1,4-萘醌,ODZ10117具有优秀的信号转导与转录激活因子3的二聚化反应抑制功效(图9b)。接着,为了去人信号转导与转录激活因子3的核移位,利用上述细胞株通过荧光显微镜观察了信号转导与转录激活因子3的核移位。结果,相比于对照组,ODZ10117抑制了信号转导与转录激活因子3的核移位(图9c)。之后,为了确认信号转导与转录激活因子3的转录活性,利用报告基因将具有信号转导与转录激活因子3-TA-荧光素酶的质粒载体脱氧核糖核酸在HEK293T细胞株转化,按浓度处理ODZ10117后,执行发光酶分析。结果,ODZ10117浓度依赖性地抑制信号转导与转录激活因子3的转录活性(图9d)。
确认将信号转导与转录激活因子3活性化的人类癌细胞株中的ODZ10117的细胞生存抑制作用
在癌细胞中活性化的信号转导与转录激活因子3增加与细胞生存相关的蛋白质的表达来增加细胞的增殖和生长。因此,在利用白细胞介素6处理24小时或48小时或者未处理的人类胶质母细胞瘤中按浓度处理ODZ10117后,当确认细胞存活率时,相比于ODZ10117未处理组,ODZ10117处理组浓度依赖性地抑制细胞生存(图10)。
确认ODZ10117的癌细胞死亡诱导作用
在癌细胞中活性化的信号转导与转录激活因子3通过增加与细胞生存及细胞周期相关的蛋白质的表达来增加细胞的增殖和生长。因此,当按照时间段确认根据U87-MG和MDA-MB-231细胞株的细胞增殖的ODZ10117的效果时,相比于作为对照组的处理二甲基亚砜的组,ODZ10117有效抑制了2个细胞的增殖(图11a)。之后,为了分析与2个细胞株有关的ODZ10117的细胞死亡效果,处理化合物48小时,并利用碘化丙锭(PI,propidium iodide)和膜联蛋白(Annexin V)染色来执行流细胞分析。结果,ODZ10117对于U87-MG细胞株和MDA-MB-231细胞株分别诱导约15.3~26.7%和40.2~43.0%的细胞死亡(图11b及11c)。多种基因的表达参与细胞死亡,因此,通过分析免疫印迹来分析了作为参与细胞死亡的代表性促凋亡(pro-apoptosis)基因的半胱天冬酶-3和聚腺苷二磷酸核糖聚合酶的活性程度。经确认,ODZ10117显著增加片段半胱天冬酶-3和聚腺苷二磷酸核糖聚合酶蛋白的量来增加这些蛋白质的活性。通过上述结果,可确认ODZ10117通过增加半胱天冬酶-3和聚腺苷二磷酸核糖聚合酶的活性来诱导细胞死亡(图11d)。之后,通过实时聚合酶链式反应来分析作为抗凋亡基因的Bcl-2和Bcl-XL的表达程度。结果,ODZ10117有效抑制这些基因的表达(图11e)。通过以上结果,经确认,ODZ10117增加促凋亡基因的活性,减少抗凋亡基因的表达,从而增加癌细胞的细胞死亡。
确认ODZ10117的细胞移动和渗透抑制作用
确认了对于与人类癌细胞的转移相关的细胞移动性及渗透性的ODZ10117的功效。首先,为了确认与细胞移动性有关的效果,执行了伤口治疗分析法。在U87-MG细胞和MDA-MB-231细胞处理24小时的化合物,当通过显微镜观察细胞移动时,在处理二甲基亚砜的对照组中,细胞移动活跃,ODZ10117显著抑制这些细胞的移动(图12a)。
为了验证与癌细胞的细胞渗透性有关的效果,执行了细胞渗透分析法(invasionassay)。向基质胶分注U87-MG细胞和MDA-MB-231细胞,在下端腔室填充添加有纤维粘连蛋白的培养液,处理ODZ10117并培养24小时之后,通过显微镜观察细胞向下方腔室的渗透程度。结果,相比于处理二甲基亚砜的对照组,ODZ10117在2个细胞均显著减少细胞的渗透(图12b)。
多种因子参与癌细胞的移动和渗透。由此,确认了与作为参与细胞的移动和渗透的代表性因子的一种的Twist的表达和MMP-2的活性有关的ODZ10117的功效。结果,当进行24小时的ODZ10117处理时,在U87-MG细胞和MDA-MB-231细胞中,显著减少Twist的表达和MMP-2的活性(图12c及图12d)。
确认人类癌细胞异种移植中的ODZ10117的肿瘤生长抑制效果
为了在动物实验确认与信号转导与转录激活因子3的活性抑制有关的ODZ10117的功效,将作为人类癌细胞株的U87-MG细胞和MDA-MB-231细胞分别与25%基质胶混合并向免疫缺乏小鼠(BALB/c nude mice)的背后侧注入,4周后筛选肿瘤生长至适当大小的小鼠。在第0天、第3天、第5天、第7天、第9天、第11天及第13天,向这些小鼠的肿瘤块周期性地直接注入二甲基亚砜或空白试剂(vehicle)和ODZ10117,并测定肿瘤的生长。结果,相比于注入二甲基亚砜的对照组,ODZ10117显著抑制肿瘤生长(图13a及图13b)。
在药物给药之后的第7天,麻醉小鼠并牺牲其来摘除肿瘤块。利用福尔马林固定肿瘤组织,利用石蜡进行包埋并从剪切的组织切片分析了信号转导与转录激活因子3的酪氨酸705残基的磷酸化、Ki67的表达、半胱天冬酶-3的活性及Bcl-XL和pro/activated MMP2的表达。结果,相比于注入二甲基亚砜的对照组,在注入ODZ10117的肿瘤组织中,信号转导与转录激活因子3的磷酸化显著减少。并且,显著减少作为细胞生长因子中的一种的Ki67、与抗细胞死亡相关的Bcl-XL及与细胞渗透相关的pro/active MMP2的表达。并且,增加了与细胞死亡相关的半胱天冬酶-3的活性(图13c)。
并且,向注入作为上述人类癌细胞株的U87-MG细胞的小鼠直接注入二甲基亚砜或ODZ10117,并确认存活率。结果,相比于注入二甲基亚砜的对照组,ODZ10117的生存时间增加(图13d)。
这种结果示出ODZ10117选择性抑制信号转导与转录激活因子3的活性,来抑制肿瘤细胞的生长和增殖、渗透及转移,诱导癌细胞的死亡来抑制肿瘤的生长。
通过基于结构的虚拟筛选来筛选选择性信号转导与转录激活因子3的抑制化合物
通过基于结构的筛选获取了预计选择性抑制信号转导与转录激活因子3的46种化合物。在下述表1示出上述46种化合物信息。
表1
在人类癌细胞株确认通过基于结构的虚拟筛选筛选的化合物的选择性信号转导与转录激活因子3的活性抑制作用
为了了解上述表1的46种化合物是否呈现选择性信号转导与转录激活因子3抑制功效,在作为人源性霍奇金淋巴瘤细胞株的L540及HDLM-2中利用46种化合物实施免疫印迹分析。结果,初筛46种化合物中的判断为信号转导与转录激活因子3抑制功效更优秀的33种化合物(上述表1的No.1、4、5、6、8、9、11、14、16、18、19、20、21、22、23、24、27、28、29、30、31、32、33、34、35、36、37、38、41、42、43、44、45、46的化合物)(图14a至图14d)。
之后,在作为人源性霍奇金淋巴瘤细胞株的L540及HDLM-2中处理初筛的33种化合物中的50uM的21种化合物(上述表1的No.5、6、9、11、14、16、19、20、23、24、30、32、34、36、37、38、42、43、44、45、46的化合物)或100uM的12种化合物(上述表1的No.1、4、8、18、21、22、27、28、29、31、33、35、41),并实施免疫印迹分析。结果,复筛了初筛的33种化合物中判断为信号转导与转录激活因子3抑制功效更优秀的2种化合物(上述表1的No.37及46的化合物)(图15a及图15b)。接着,在作为人源性霍奇金淋巴瘤细胞株的L540及HDLM-2按浓度处理复筛的2种化合物(上述表1的No.37及46的化合物),实施免疫印迹分析。结果,复筛的2种化合物均浓度依赖性地显著抑制信号转导与转录激活因子dml酪氨酸705的磷酸化(图16)。
以上,详细记述了本发明的特定部分,对于本技术领域的普通技术人员而言,这种具体记述仅为优选实例,可以明确的是,本发明的范围并不局限于此。因此,通过发明要求保护范围和其等同技术方案定义本发明的实质性范围。
产业上的可利用性
本发明涉及具有信号转导与转录激活因子3抑制活性的化合物或其药剂学上可接受的盐、溶剂化物或水合物以及它们的药剂学用途,本发明的具有信号转导与转录激活因子3抑制活性的化合物或其药剂学上可接受的盐、溶剂化物或水合物可有用地用于预防及治疗与癌症、自身免疫性疾病、炎症性疾病等相关的多种信号转导与转录激活因子3相关疾病。
Claims (11)
1.一种化合物或其药剂学上可接受的盐、溶剂化物或水合物,其特征在于,选自由下述化学式1至化学式60所示的化合物组成的组中:
2.一种药剂学组合物,用于预防或治疗信号转导与转录激活因子3相关疾病,其特征在于,
包含:
(a)权利要求1所述的化合物或其药剂学上可接受的盐、溶剂化物或水合物的药剂学有效量;以及
(b)药剂学上可接受的载体,
上述信号转导与转录激活因子3相关疾病选自由癌症、糖尿病视网膜病变、糖尿病、血友病性关节病、动脉粥样硬化、瘢痕疙瘩、创面肉芽、血管粘连、自身免疫性疾病、再狭窄、肠粘连、猫抓病、溃疡、肝硬化、糖尿病性肾病、恶性肾硬化、血栓性微血管病、器官移植排斥、肾小球病变、神经变性疾病及炎症性疾病组成的组中。
3.根据权利要求2所述的组合物,其特征在于,上述化合物选择性地抑制信号转导与转录激活因子3的活性。
4.根据权利要求2所述的组合物,其特征在于,上述组合物抑制癌细胞的转移。
5.根据权利要求2所述的组合物,其特征在于,上述信号转导与转录激活因子3相关疾病为选自由胃癌、大肠癌、肺癌、乳腺癌、卵巢癌、肝癌、支气管癌、鼻咽癌、喉癌、胰腺癌、膀胱癌、结肠癌,宫颈癌、脑癌、前列腺癌、骨癌、皮肤癌、甲状腺癌、白血病、淋巴瘤、肾上腺皮质癌、甲状旁腺癌、输尿管癌、神经胶质瘤、食道癌、小肠肿瘤、胶质母细胞瘤、脑肿瘤及肾癌组成的组中的癌症。
6.根据权利要求2所述的组合物,其特征在于,上述信号转导与转录激活因子3相关疾病为选自由斑秃、强直性脊柱炎、抗磷脂综合征、自身免疫性艾迪生病、肾上腺自身免疫疾病、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性卵巢炎及睾丸炎、自身免疫性血小板减少症、白塞病、大疱性类天疱疮、心肌病、腹泻性皮炎、慢性疲劳免疫缺陷综合征、慢性炎症性脱髓鞘性多发性神经病、变应性肉芽肿性、疤痕性类天疱疮、肢端硬皮综合征、冷凝集素病、克罗恩氏病、盘状狼疮、原发性冷球蛋白血症、纤维肌痛-纤维肌炎、肾小球肾炎、格雷夫斯病、格林-巴利综合征、桥本氏甲状腺炎、特发性肺纤维化、特发性血小板减少性紫癜、免疫球蛋白A神经炎、幼年型关节炎、扁平苔癣、红斑狼疮、梅尼耳氏症、混合性结蒂组织病、多发性硬化症、1型糖尿病或免疫介导型糖尿病、重症肌无力、寻常型天疱疮、恶性贫血、结节性多动脉炎、多发性软骨炎、自身免疫性多腺体综合征、类风湿性多发性肌痛、多发性肌炎和皮肌炎、原发性无丙种球蛋白血症、原发性血糖性肝硬化、银屑病、银屑病性关节炎、雷诺氏现象、赖特尔综合征、类风湿性关节炎、结节病、硬皮病、全身肌强直综合征、全身性红斑狼疮、红斑狼疮、大动脉炎、颞动脉炎、巨细胞动脉炎、溃疡性大肠炎、葡萄膜炎、白斑病及韦格纳肉芽肿病组成的组中的自身免疫性疾病。
7.根据权利要求2所述的组合物,其特征在于,上述信号转导与转录激活因子3相关疾病为选自由哮喘、脑炎、炎症性肠炎、类风湿性关节炎、慢性阻塞性肺疾病、过敏症、异位性皮肤炎、银屑病、败血性休克、肺纤维化、未分化型脊柱关节病、克罗恩氏病、胰腺炎、皮肤炎、未分化型关节病、关节炎、肾小球性肾炎、支气管炎、炎症性骨溶解及由病毒或细菌感染引起的慢性炎症组成的组中的炎症性疾病。
8.一种用于预防或改善信号转导与转录激活因子3相关疾病的食品组合物,其特征在于,包含权利要求1所述的化合物或其盐作为有效成分,上述信号转导与转录激活因子3相关疾病选自由癌症、糖尿病视网膜病变、糖尿病、血友病性关节病、动脉粥样硬化、瘢痕疙瘩、创面肉芽、血管粘连、自身免疫性疾病、再狭窄、肠粘连、猫抓病、溃疡、肝硬化、糖尿病性肾病、恶性肾硬化、血栓性微血管病、器官移植排斥、肾小球病变、神经变性疾病及炎症性疾病组成的组中。
9.一种信号转导与转录激活因子3相关疾病的预防或治疗方法,其特征在于,
包括向对象给药(a)权利要求1所述的化合物或其药剂学上可接受的盐、溶剂化物或水合物的药剂学有效量;以及(b)药剂学上可接受的载体的步骤,
上述信号转导与转录激活因子3相关疾病选自由癌症、糖尿病视网膜病变、糖尿病、血友病性关节病、动脉粥样硬化、瘢痕疙瘩、创面肉芽、血管粘连、自身免疫性疾病、再狭窄、肠粘连、猫抓病、溃疡、肝硬化、糖尿病性肾病、恶性肾硬化、血栓性微血管病、器官移植排斥、肾小球病变、神经变性疾病及炎症性疾病组成的组中。
10.一种权利要求1所述的化合物或其药剂学上可接受的盐、溶剂化物或水合物的用途,其特征在于,用作用于预防或治疗选自由癌症、糖尿病视网膜病变、糖尿病、血友病性关节病、动脉粥样硬化、瘢痕疙瘩、创面肉芽、血管粘连、自身免疫性疾病、再狭窄、肠粘连、猫抓病、溃疡、肝硬化、糖尿病性肾病、恶性肾硬化、血栓性微血管病、器官移植排斥、肾小球病变、神经变性疾病及炎症性疾病组成的组中的信号转导与转录激活因子3相关疾病的药学组合物。
11.一种权利要求1所述的化合物或其药剂学上可接受的盐、溶剂化物或水合物的用途,其特征在于,用作用于预防或改善选自由癌症、糖尿病视网膜病变、糖尿病、血友病性关节病、动脉粥样硬化、瘢痕疙瘩、创面肉芽、血管粘连、自身免疫性疾病、再狭窄、肠粘连、猫抓病、溃疡、肝硬化、糖尿病性肾病、恶性肾硬化、血栓性微血管病、器官移植排斥、肾小球病变、神经变性疾病及炎症性疾病组成的组中的信号转导与转录激活因子3相关疾病的食品组合物。
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