CN109071437B - 新型吲哚衍生物和包含其的抗癌组合物 - Google Patents
新型吲哚衍生物和包含其的抗癌组合物 Download PDFInfo
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- CN109071437B CN109071437B CN201780024510.4A CN201780024510A CN109071437B CN 109071437 B CN109071437 B CN 109071437B CN 201780024510 A CN201780024510 A CN 201780024510A CN 109071437 B CN109071437 B CN 109071437B
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Abstract
本发明涉及：吲哚衍生物，该吲哚衍生物是一种新型细胞有丝分裂抑制剂；其立体异构体或其药学上可接受的盐；其作为治疗剂的用途；包含其的组合物和使用该组合物的处理方法；及其制备方法。根据本发明，吲哚衍生物、其立体异构体或其药学上可接受的盐在有丝分裂期间抑制微管蛋白聚合以诱导凋亡，并且在具有多重耐药性的癌细胞中也具有优异的抗癌作用。
Description
技术领域
本发明涉及新型吲哚衍生物化合物和包含该新型吲哚衍生物化合物的抗癌组合物。具体而言，本发明涉及显示出优异的抗癌作用、低毒性和优异的溶解度的新型吲哚衍生物化合物和包含该新型吲哚衍生物化合物的抗癌组合物。
背景技术
微管执行许多细胞功能，包括细胞迁移、细胞分裂、细胞骨架保持和细胞内运输。微管的主要蛋白质成分是微管蛋白。癌细胞的快速生长显著依赖于微管蛋白聚合/解聚，使得微管蛋白成为开发抗癌剂的优异靶标。通过抑制微管蛋白聚合或抑制微管降解来干预微管装配，这增加了收集的中期细胞数并最终导致凋亡。使用微管蛋白靶向药物来抑制微管功能是化疗中公认的方法。
靶向微管的药物可根据其作用机制分为两组：微管稳定剂和微管去稳定剂。微管稳定剂包括紫杉烷、紫杉醇、多西紫杉醇等，其起到抑制微管解聚和增强微管聚合的作用。大多数微管稳定剂与紫杉烷结合位点或β-微管蛋白的重叠位点结合。第二组即微管去稳定剂，包括秋水仙碱、长春花生物碱等，其抑制微管的聚合，并且主要结合至秋水仙碱结合位点或长春花结合位点。此外，靶向微管的两组药物的工作浓度低于影响微管聚合物的药物的工作浓度。
然而，大多数微管蛋白抑制剂具有耐药性问题，这是增强癌症患者的长期反应或存活率的主要障碍。此外，神经毒性问题以及耐药性问题是源自复杂天然产物的微管蛋白抑制剂的主要副作用之一，这影响癌症患者的生活质量。此外，口服生物利用度低造成对舒适的口服给药的限制。因此，最近迫切需要开发显示出低副作用，但口服生物利用度优异，并且不会轻易导致耐药性的新微管蛋白抑制剂。
发明内容
技术问题
本发明的目的是提供一种显示出抗癌作用的新型微管蛋白抑制剂和包含该微管蛋白抑制剂的抗癌组合物。
本发明的另一个目的是提供一种新型微管蛋白抑制剂和包含该微管蛋白抑制剂的抗癌组合物，该微管蛋白抑制剂显示优异的抗癌作用、低毒性和优异的溶解度。
问题的解决方案
为了实现本发明的目的，本发明提供具有微管蛋白抑制活性的新型吲哚衍生物化合物、其立体异构体或其药学上可接受的盐。本发明还提供一种抗癌组合物，其包含作为活性成分的本发明的吲哚衍生物化合物、其立体异构体或其药学上可接受的盐。在下文中，将详细描述本发明。
新型吲哚衍生物化合物
本发明提供由下式I表示的吲哚衍生物化合物、其立体异构体或其药学上可接受的盐：
[式I]
在本发明中，药学上可接受的盐是指通常用于制药业的盐。药学上可接受的盐的实例包括：与钙、钾、钠、镁等形成的无机离子盐；与盐酸、硝酸、磷酸、溴酸、碘酸、高氯酸、硫酸等形成的无机酸盐；与乙酸、三氟乙酸、柠檬酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡萄糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸、氢碘酸等形成的有机酸盐；与甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、萘磺酸等形成的硫酸盐；与甘氨酸、精氨酸、赖氨酸等形成的氨基酸盐；以及与三甲胺、三乙胺、氨、吡啶、甲基吡啶等形成的胺盐。但是，本发明的盐的种类不限于上述盐。
由式I表示的化合物可以包含一个或多个不对称碳原子，因此可以以外消旋体、外消旋混合物、单一对映体、非对映体混合物和单独的非对映体的形式存在。通过本领域已知的方法例如柱色谱或HPLC，可以将式I的化合物分离为这样的异构体。可供选择地，可以使用光学纯起始物料和/或已知构型的试剂通过立体定向合成来合成式I的化合物的立体异构体。
根据本发明的由式I表示的吲哚衍生物、其立体异构体或其药学上可接受的盐通过在细胞有丝分裂期间抑制微管蛋白聚合来诱导细胞凋亡，并且在具有多重耐药性的癌细胞中也具有优异的抗癌作用，因此，它可以有效地用作抗癌剂。
此外，根据本发明的式I表示的吲哚衍生物、其立体异构体或其药学上可接受的盐显示出优异的体内稳定性和优异的溶解度，因此表现出优异的生物利用度。
包含新型吲哚衍生物化合物的抗癌组合物、其用途和使用其的治疗方法
本发明还提供一种抗癌组合物，其包含作为活性成分的由式I表示的吲哚衍生物化合物、其立体异构体或其药学上可接受的盐。
由式I表示的吲哚衍生物化合物、其立体异构体或其药学上可接受的盐在各种癌细胞系中显示出抗增殖活性，甚至在显示出多重耐药性的癌细胞系中也显示出抗增殖活性。因此，包含作为活性成分的由式I表示的吲哚衍生物化合物、其立体异构体或其药学上可接受的盐的组合物可用作预防和治疗癌症的药物组合物。
在本发明中，所述癌症可选自由直肠癌、乳腺癌、肺癌、胃癌、肝癌、白血病、神经胶质瘤、皮肤癌和宫颈癌组成的组。然而，本发明不限于此。
本发明的药物组合物还可包含至少一种具有抗癌活性的活性成分。
本发明的药物组合物可进一步包含药学上可接受的添加剂，例如淀粉、糊化淀粉、微晶纤维素、乳糖、聚维酮、胶体二氧化硅、磷酸氢钙、乳糖、甘露醇、糖稀、阿拉伯橡胶、预糊化淀粉、玉米淀粉、纤维素粉末、羟丙基纤维素、欧巴代、羧甲基淀粉钠、巴西棕榈蜡(carunauba wax)、合成硅酸铝、硬脂酸、硬脂酸镁、硬脂酸铝、硬脂酸钙、白糖、右旋葡萄糖、山梨糖醇、滑石等。本发明的药学上可接受的添加剂优选以0.1至90重量份的量添加到组合物中，但不限于此。
根据本发明的药物组合物可以配制成用于实际临床给药的口服或肠胃外制剂，在这种情况下，可以使用通常使用的填充剂、增量剂、粘合剂、润湿剂、崩解剂、稀释剂如表面活性剂、或赋形剂。用于口服给药的固体剂型可包括片剂、丸剂、粉剂、颗粒剂、胶囊等，并且可通过与至少一种赋形剂如淀粉、碳酸钙、蔗糖、乳糖或明胶混合来制备。此外，除了简单的赋形剂之外，还可以使用润滑剂(例如硬脂酸镁和滑石)。用于口服给药的液体剂型的实例包括悬液剂、内服液体、乳剂、糖浆等。除了通常使用的稀释剂如水和液体石蜡外，可以包括各种赋形剂，例如润湿剂、甜味剂、调味剂、防腐剂等。肠胃外给药的制剂的实例可包括灭菌溶液、非水溶剂、悬液剂、乳剂、冻干制剂和栓剂。作为非水溶剂和悬浮溶剂，可以使用丙二醇、聚乙二醇、植物油(如橄榄油)、可注射性酯(如油酸乙酯)。可以使用witepsol、聚乙二醇、吐温61、可可油、月桂酯(laurinum)、甘草明胶等作为栓剂的底物。
本发明的组合物可以根据所需方法口服给药或肠胃外给药。对于肠胃外给药，优选使用局部皮肤给药、腹膜内注射、直肠内注射、皮下注射、静脉内注射、肌内注射或胸腔内注射方法。剂量可以根据患者的重量、年龄、性别、健康状况以及饮食、给药时间、给药方法、排泄率和疾病的严重程度而变化。
根据本发明的组合物以药学有效量给药。在本发明中，“药学有效量”是指足够以对施加药物治疗有效的合理利益/风险比率来治疗疾病的量。有效剂量的水平可以根据包括以下的因素来确定：患者的疾病类型、严重程度、药物的活性、对药物的敏感性、给药时间、给药途径、排泄率、治疗时间和同时使用的药物以及医药领域众所周知的其他因素。本发明的组合物可以作为单独的治疗剂给药或与其他治疗剂组合给药。而且，本发明的组合物可以与常规治疗剂依次或同时添加，并且该组合物可以用于单次或多次给药。考虑到上述所有因素，以可以在没有副作用的情况下产生最大作用的最小剂量给药是重要的，并且本领域技术人员可以轻易地确定该剂量。
具体地，根据本发明的化合物的有效量可以根据患者的年龄、性别和重量而变化。通常，可以每天或每隔一天或每天给药1至3次，每1kg体重给药0.1mg至100mg，优选0.5mg至10mg。然而，可以根据给药途径、肥胖的严重程度、性别、重量、年龄等而增加或减少剂量，因此上述剂量不以任何方式限制本发明的范围。
本发明还提供由式I表示的吲哚衍生物化合物、其立体异构体或其药学上可接受的盐在用于预防或治疗癌症中的用途。
本发明还提供由式I表示的吲哚衍生物化合物、其立体异构体或其药学上可接受的盐在用于制备用于预防或治疗癌症的药物中的用途。
本发明还提供预防或治疗癌症的方法，所述方法包括将治疗有效量的式I的吲哚衍生物化合物、其立体异构体或其药学上可接受的盐给药至需要预防或治疗癌症的对象。在本发明中，“对象”包括哺乳动物，特别是人。
此外，根据本发明的由式I表示的吲哚衍生物、其立体异构体或其药学上可接受的盐显示出优异的抗增殖活性，因此包含作为活性成分的根据本发明的由式I表示的吲哚衍生物、其立体异构体或其药学上可接受的盐的组合物可以有效地用作用于预防或改善癌症的食品组合物。
本发明的食品组合物可以进一步含有用于其他食品组合物、功能性保健食品或饮料的常规添加剂。
例如，本发明的食品组合物可含有甜味剂(例如蔗糖、颗粒状果糖、葡萄糖、D-山梨糖醇、甘露醇、异麦芽低聚糖、甜菊苷、阿斯巴甜、乙酰磺胺酸钾、三氯蔗糖等)、酸化剂(例如无水柠檬酸、DL-苹果酸、琥珀酸及其盐等)、防腐剂(例如苯甲酸及其衍生物等)、各种营养补充剂、维生素、矿物质(电解质)、调味剂(例如合成调味剂和天然调味剂)、着色剂、增味剂(奶酪、胆酸盐等)、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、稳定剂、防腐剂、甘油、醇、用于碳酸饮料的碳酸化剂等。而且，本发明的食品组合物可包含用于制备天然果汁和蔬菜饮料的果肉。基于100重量份的本发明的食品组合物，可以确定这些添加剂的比率在约20重量份或以下的范围内。
当本发明的食品组合物是饮料时，所述食品组合物还可包含通常包含在饮料中的调味剂或天然碳水化合物。天然碳水化合物可以是单糖(例如葡萄糖和果糖)、二糖(例如麦芽糖和蔗糖)、多糖(例如糊精和环糊精)、或糖醇(例如木糖醇、山梨糖醇和赤藓糖醇)。此外，调味剂可以是天然调味剂，例如索马甜、甜菊提取物(莱鲍迪甙A、甘草甜素等)，或者可以是合成调味剂，例如糖精、阿斯巴甜等。当将食品组合物制备成饮料时，基于100mL组合物，通常可以包含量为约1至20g，优选约5至12g的天然碳水化合物。
本发明的食品组合物可以以粉剂、颗粒剂、片剂、胶囊或饮料的形式制备，并可用作食品、饮料、口香糖、茶、维生素复合物和保健辅食。
此外，根据本发明的式I表示的吲哚衍生物、其立体异构体或其药学上可接受的盐在人源皮肤癌细胞系(A432)植入小鼠模型中显示出优异的抗癌活性，含有作为活性成分的根据本发明的式I表示的吲哚衍生物、其立体异构体或其药学上可接受的盐的组合物可以有效地用作预防或改善皮肤癌的化妆品组合物。
本发明的组合物可以配制成本领域通常配制的任何制剂，例如溶液、悬液剂、乳剂、糊剂、凝胶、霜剂、洗剂、粉剂、肥皂、含表面活性剂的清洁剂、油、粉状粉底、乳化粉底、蜡粉底、喷雾剂等，但不限于此。更具体地，本发明的组合物可以配制成柔软洗液、营养洗液、营养霜、按摩霜、精华素、眼霜、清洁霜、清洁泡沫、洁肤水、面膜、喷雾剂或粉剂。
当将根据本发明的化妆品组合物配制成糊剂、霜剂或凝胶时，可以使用动物油、植物油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅树脂、膨润土、二氧化硅、滑石、氧化锌等作为载体成分。
当将根据本发明的化妆品组合物配制成粉剂或喷雾剂时，可以使用乳糖、滑石、二氧化硅、氢氧化铝、硅酸钙或聚酰胺粉末。特别地，喷雾剂可进一步含有推进剂，例如氯氟烃、丙烷/丁烷或二甲醚。
当将根据本发明的化妆品组合物配制成溶液或乳剂时，可以使用溶剂、增溶剂或乳化剂作为载体成分。例如，可以使用水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、脂肪族甘油酯、聚乙二醇或脱水山梨糖醇的脂肪酸酯。
当根据本发明的化妆品组合物配制成悬液剂时，可以使用液体稀释剂(例如水、乙醇或丙二醇)、悬浮剂(例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇酯和聚氧乙烯脱水山梨糖醇酯)、微晶纤维素、偏氢氧化铝、膨润土、琼脂、黄蓍胶等作为载体成分。
当将根据本发明的化妆品组合物配制成含表面活性剂的清洁剂时，可以使用脂族醇硫酸盐、脂族醇醚硫酸盐、磺基琥珀酸单酯、羟乙基磺酸盐、咪唑啉衍生物、牛磺酸甲酯、肌氨酸盐、脂肪酸酰胺醚硫酸盐、烷基酰基甜菜碱、脂肪族醇、脂肪酸甘油酯、脂肪酸二乙醇酰胺、植物油、羊毛脂衍生物、乙氧基化甘油脂肪酸酯等作为载体成分。
本发明的有益效果
根据本发明的吲哚衍生物、其立体异构体或其药学上可接受的盐通过在细胞有丝分裂期间使微管解聚来诱导细胞凋亡，并且在具有多重耐药性的癌细胞中也具有优异的抗癌作用。此外，本发明的吲哚衍生物、其立体异构体或其药学上可接受的盐表现出优异的体内稳定性和优异的溶解度。
附图说明
图1示出了根据由免疫荧光染色检验的实施例1的化合物(WCI-1031)的浓度，该化合物对有丝分裂细胞的纺锤丝和染色体的作用。
图2是示出在人源皮肤癌细胞系(A431)植入裸小鼠模型中用化合物处理后重量变化的图。
图3是示出在人源皮肤癌细胞系(A431)植入裸小鼠模型中用化合物处理后肿瘤大小变化的图。
图4提供示出在人源皮肤癌细胞系(A431)植入裸小鼠模型中用化合物处理后最后一天(第23天)小鼠的肿瘤大小的照片。
图5是示出在人源皮肤癌细胞系(A431)植入裸小鼠植入模型中用化合物处理后肿瘤重量的图。
图6提供示出在人源皮肤癌细胞系(A431)植入裸小鼠模型中用化合物处理后最后一天(第23天)从小鼠分离的肿瘤的照片。
图7是显示以实施例1的化合物(WCI-1031)静脉内给药后血浆浓度随时间的变化的图。
图8是实施例1的化合物(WCI-1031)在pH 6.5下的溶解度曲线。
图9是实施例1的化合物(WCI-1031)在pH 7.4下的溶解度曲线。
具体实施方式
本发明的方式
在下文中，通过实施例详细说明本发明。以下实施例旨在进一步说明本发明而不限制其范围。
<实施例1>(E)-2-(2-甲基-3-((2-(萘并[2,1-b]呋喃-2-羰基)亚肼基)甲基)-1H-吲哚-1-基)乙酸酯(WCI-1031)
将萘并[2,1-b]呋喃-2-碳酰肼(100mg，0.44mmol)和2-(3-甲酰基-2-甲基-1H-吲哚-1-基)乙酸甲酯(102mg，0.44mmol)和催化量的乙酸(0.1ml)的乙醇溶液(5ml)在90℃下搅拌2小时。在通过TLC确认起始物质耗尽后，将反应混合物冷却至室温并添加到冰水中。将分离的固体物质过滤，用水洗涤，然后干燥。使用混合比率为1:1的己烷和乙酸乙酯的混合物，通过硅胶快速柱色谱法来纯化由此产生的残余物，得到所需化合物，即(E)-2-(2-甲基-3-((2-(萘并[2,1-b]呋喃-2-羰基)亚肼基)甲基)-1H-吲哚-1-基)乙酸甲酯(174mg，90％)，为淡黄色固体。
ESIMS发现：m/z 440.36[M+H]+,879.16[2M+H]+。
<实验实施例1>检验本发明的吲哚衍生物的抗增殖活性
<1-1>在HeLa细胞系中检验抗增殖活性
进行以下实验以检验本发明的吲哚衍生物的抗增殖活性。
将作为人宫颈癌细胞系的HeLa细胞(ATCC，USA)以2×103个细胞/孔分配到96孔板中，并用DMSO或本发明的吲哚衍生物处理细胞，然后使细胞生长4天。然后，将MTT(溴化3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑)试剂以10μl/孔添加到孔中。2小时后，在“OD450”下测量吸光度，并使用plizm6程序获得统计值。数据代表两次重复测定结果的平均值(表1)。
[表1]
如表1所示，发现本发明的吲哚衍生物在HeLa细胞系(宫颈癌细胞系)中具有优异的抗增殖活性。
<1-2>在其他癌细胞系中检验抗增殖活性
进行以下实验以确定本发明的吲哚衍生物是否在其他癌细胞以及HeLa细胞系(宫颈癌细胞系)中显示出抗增殖活性。
具体地，在微量滴定板上培养各种癌细胞系(1-3×103个细胞/孔)，并用本发明的吲哚衍生物处理细胞并培养4天。通过与实验实施例1-1中相同的方法通过MTT测定检测细胞毒性，并通过对数-剂量反应曲线获得IC50。数据代表三次重复测定的结果的平均值(表2)。
[表2]
如表2所示，发现本发明的吲哚衍生物在各种癌细胞系中也具有优异的抗增殖活性。
<1-3>在显示多重耐药性的癌细胞中检验抗增殖活性
进行以下实验以检验本发明的吲哚衍生物在显示多重耐药性的癌细胞中是否有效。
具体地，分别以1-3×103个细胞/孔在微量滴定板上培养K562和MCF7(韩国生命工学研究院生物评估中心，韩国)以及上述细胞系中的多重耐药细胞系K562/ADR和MCF7/ADR(韩国生命工学研究院生物评估中心，韩国)。然后，用本发明的吲哚衍生物WCI-1031(实施例1的化合物)、Taxol、多柔比星、长春碱或秋水仙碱处理细胞，并培养4天。以与实验实施例1-1中相同的方法通过MTT测定来检验细胞毒性，通过对数-剂量反应曲线获得IC50(单位：nM)。数据代表三次重复测定的结果的平均值(表3和4)。
表现出多重耐药性的细胞系的耐药因子是多重耐药细胞系的IC50与非耐药亲本细胞系的IC50的比率。
[表3]
| WCI-1031 | Taxol | 多柔比星 | 长春碱 | 秋水仙碱 | |
| K562 | 532 | 1.347 | 2.848 | 17.13 | 15.86 |
| K562/ADR | 317.8 | 699.9 | 2187 | 267.8 | 363.4 |
| 耐药因子 | 0.60 | 519.6 | 767.91 | 15.63 | 22.91 |
[表4]
| WCI-1031 | Taxol | 多柔比星 | 长春碱 | 秋水仙碱 | |
| MCF7 | 1321 | 2.345 | 15.38 | 5.275 | 2.71 |
| MCF7/ADR | 481.1 | 1028 | 2608 | 95.87 | 92.54 |
| 耐药因子 | 0.36 | 438.38 | 169.57 | 18.17 | 34.15 |
如表3和4中所示，多重耐药细胞系表现出对常规抗癌剂的强耐药性，其耐药因子范围为数十至数百。然而，对实施例1的化合物(本发明的吲哚衍生物)的耐药因子范围为0.36至0.60，表明与常规抗癌剂相比，本发明的吲哚衍生物对显示出多重耐药性的癌细胞具有更强的细胞毒性作用。
<实验实施例2>检验本发明的吲哚衍生物对细胞周期进展的作用
在12孔板(3×104个细胞/孔)上培养若干种癌细胞系，并用DMSO或WCI-1031(本发明的吲哚衍生物)处理17小时，然后加入碘化丙锭染料将细胞DNA染色，并使用FACS进行测量。示出了聚集的G2/M期的细胞的浓度和以百分比表示的细胞数(表5)。
[表5]
| 细胞系 | 作用μM(G2/M％) |
| HeLa | 0.5(82.36) |
| Hep3B | 0.5(68.13) |
| A172 | 1.0(70.10) |
| A431 | 0.5(66.32) |
| MCF7 | 0.5(59.08) |
| MCF7ADR | 0.5(52.37) |
| PC3 | 0.5(65.35) |
| NCIH-125 | 1.0(48.10) |
| EL4 | 0.5(50.84) |
| K562 | 0.5(76.72) |
关于本发明的吲哚衍生物WCI-1031，聚集的G2/M期的细胞的浓度为0.5-1.0μM，细胞数为50％或更高，如表5所示。因此，发现本发明的吲哚衍生物抑制G2和M期的细胞周期。
<实验实施例3>检验本发明的吲哚衍生物对微管蛋白聚合的作用
为了检验本发明的吲哚衍生物对细胞内微管的作用，用DMSO或WCI-1031(0.1μM，0.5μM和1.0μM)处理HeLa细胞16小时。将细胞固定，用抗微管蛋白抗体和Alexa Fluor 488染色，并用抗中心体抗体和德克萨斯红(Texas Red)染色，然后使用Hoechst 33342对细胞核进行免疫染色以检验α-微管蛋白、中心体和DNA(图1)。
如图1所示，当用本发明的吲哚衍生物处理细胞时，与DMSO对照相比，随着衍生物的浓度变高，微管蛋白的形状变得松散且更短。并且偏离中心排列的DNA模式越来越多见。
因此，发现本发明的吲哚衍生物是使微管解聚的剂型。
<实验实施例4>检验在人源皮肤癌细胞(A431)植入模型中的抗癌作用
<4-1>癌细胞的培养和癌细胞的植入
将在液氮中保持冷冻的人癌细胞系A431解冻并进行细胞培养。在CO2培养箱(Forma，USA)中在37℃和5％CO2下将细胞培养适当的一段时间。
在培养的最后一天，收集所有癌细胞并计数，并使用无血清培养基将细胞浓度调节至1×107个细胞/ml。将如此制备的培养液以每只BALB/C雌性裸小鼠(5周龄，NaraBiotech)0.3ml的量(3×106个细胞/小鼠)皮下注射到肩胛骨和胸壁之间的腋窝区域。
<4-2>样品的制备和给药方法
使用本发明的吲哚衍生物化合物WCI-1031(实施例1)作为测试物质，使用5-FU和秋水仙碱作为阳性对照物质。
在即将给药之前，溶解于DMAC(二甲基乙酰胺)20％+吐温80 5％+20％HPbCD(2-羟丙基-β-环糊精)75％中至适当浓度之后使用该化合物。分别使用生理盐水和PBS制备用作阳性对照物质的5-FU和秋水仙碱，以2mg/ml和0.007mg/ml的浓度使用。
根据下面的剂量表，以所制备的物质按每20g小鼠0.2ml(10ml/kg)腹膜内和口服重复给药。
-载体，WCI-1031(10,20mg/kg)，秋水仙碱(0.07mg/kg)：第0至23天
-5-FU：第0至2天、第5至9天、第12至16天、第19-23天
<4-3>一般症状和重量变化验证
为了检验WCI-1031重复腹膜内给药对A431癌细胞植入裸小鼠的毒性水平，在给药期间观察动物的一般症状和重量变化。
结果，在测试期间，与溶剂对照组相比，在所有药物处理组中没有观察到统计学上显著的重量减轻，并且没有观察到显著的一般症状(图2)。
<4-4>检验肿瘤大小的变化
在植入癌细胞后，从平均肿瘤大小达到57.0mm3时的时间点至第23天，使用游标卡尺在三个方向上测量每只动物的肿瘤大小，总共11次，其由等式长×宽×高/2表示。
在最后一天(第23天)，与溶剂给药对照组相比，在分别以10mg/kg和20mg/kg的WCI-1031给药的组中观察到9.3％和37.2％(p<0.001)的肿瘤生长抑制。在5-FU和秋水仙碱给药组(阳性对照组)中的肿瘤生长抑制分别为20.7％(p<0.01)和17.6％(p<0.05)(图3和4)。
<4-5>检查肿瘤重量变化
在给药开始后第23天，在最后一次给药后2小时经眼静脉对小鼠进行采血，并使用CO2气体处死小鼠。然后对小鼠进行拍照，分离肿瘤并在化学天平中称重。拍照后，将每个肿瘤分成两半，并将所得肿瘤分别在液氮和福尔马林中固定。
在开始给药后第16天，切除A431肿瘤并称重。在分别以10mg/kg和20mg/kg WCI-1031给药的组中观察到肿瘤重量减少10.7％和38.0％(p<0.001)。5-FU和秋水仙碱给药组(阳性对照组)中的肿瘤重量减少分别为20.8％(p<0.05)和17.6％(p<0.05)(图5和6)。
<实验实施例5>检验本发明的吲哚衍生物在血浆中的稳定性
为了检验本发明的吲哚衍生物的体内稳定性，静脉注射实施例1的化合物(WCI-1031)，随时间观察血浆浓度(图7)。
如图7所示，发现WCI-1031在血浆中的稳定性是优异的。
<实验实施例6>检验本发明的吲哚衍生物的溶解度
为了检验本发明的吲哚衍生物的溶解度，在pH 6.5或pH 7.4下检验实施例1的化合物(WCI-1031)的溶解度。
具体地，将测试物质的固体样品(约1mg)放置在Whatman无注射器过滤器(PVDF膜，0.45μm孔径)上，并与0.5ml磷酸盐缓冲液(pH6.5或7.4)混合。将混合物超声处理15分钟并在室温下涡旋1小时。将平衡的混合物过滤，用多波长UV读板机分析滤液(图8和9)。
WCI-1031的溶解度等数据如下表6所示。
[表6]
(Ka：肠道吸收速率常数
SIWV：小肠水体积(约250ml)
SITT：小肠通过时间(约270分钟)
MAD：人最大可吸收剂量)
Claims (7)
1.一种由下式I表示的吲哚衍生物化合物或其药学上可接受的盐：
[式I]
2.一种用于预防或治疗癌症的药物组合物，所述药物组合物包含作为活性成分的由下式I表示的吲哚衍生物化合物或其药学上可接受的盐：
[式I]
3.根据权利要求2所述的药物组合物，其特征在于，所述癌症选自直肠癌、乳腺癌、肺癌、胃癌、肝癌、白血病、神经胶质瘤、皮肤癌和宫颈癌。
4.一种用于预防或改善癌症的食品组合物，所述食品组合物包含作为活性成分的由下式I表示的吲哚衍生物化合物或其药学上可接受的盐：
[式I]
5.一种用于预防或改善皮肤癌的化妆品组合物，所述化妆品组合物包含由下式I表示的吲哚衍生物化合物或其药学上可接受的盐：
[式I]
6.由下式I表示的吲哚衍生物化合物或其药学上可接受的盐在制备用于预防或治疗癌症的药物中的用途，
[式I]
7.根据权利要求6所述的用途，其特征在于，所述癌症选自直肠癌、乳腺癌、肺癌、胃癌、肝癌、白血病、神经胶质瘤、皮肤癌和宫颈癌。
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| WO2013076275A1 (en) * | 2011-11-23 | 2013-05-30 | The Provost, Fellows, Foundation Scholars, & The Other Members Of Board, Of The College Of The Holy & Undiv.Trinity Of Queen Elizabeth Near Dublin | Androgen receptor ligands |
| WO2014038894A1 (ko) * | 2012-09-07 | 2014-03-13 | 한국생명공학연구원 | 에틸(2-메틸-3{(E)-[(나프타[2,1-b]퓨란-2-일카보닐)하이드라조노]메틸}-1H-인돌-1-일)아세테이트, 이의 유사체를 유효성분으로 포함하는 암 예방 및 치료용 조성물 |
| WO2014175623A1 (ko) * | 2013-04-26 | 2014-10-30 | 한국생명공학연구원 | 신규 튜불린 중합 저해제 및 그 합성방법 |
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| KR101565430B1 (ko) * | 2012-09-07 | 2015-11-03 | 한국생명공학연구원 | N-메틸렌나프토[2,1-b]퓨란-2-카보하이드라지드 유도체를 유효성분으로 포함하는 암 예방 또는 치료용 조성물 |
| KR101584731B1 (ko) * | 2013-04-26 | 2016-01-12 | 한국생명공학연구원 | 신규 튜불린 중합 저해제 및 그 합성방법 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1842272A (zh) * | 2003-05-27 | 2006-10-04 | 巴斯福股份公司 | 用于防治有害昆虫和蜘蛛的腙衍生物 |
| WO2013076275A1 (en) * | 2011-11-23 | 2013-05-30 | The Provost, Fellows, Foundation Scholars, & The Other Members Of Board, Of The College Of The Holy & Undiv.Trinity Of Queen Elizabeth Near Dublin | Androgen receptor ligands |
| WO2014038894A1 (ko) * | 2012-09-07 | 2014-03-13 | 한국생명공학연구원 | 에틸(2-메틸-3{(E)-[(나프타[2,1-b]퓨란-2-일카보닐)하이드라조노]메틸}-1H-인돌-1-일)아세테이트, 이의 유사체를 유효성분으로 포함하는 암 예방 및 치료용 조성물 |
| WO2014175623A1 (ko) * | 2013-04-26 | 2014-10-30 | 한국생명공학연구원 | 신규 튜불린 중합 저해제 및 그 합성방법 |
Also Published As
| Publication number | Publication date |
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| EP3418271A1 (en) | 2018-12-26 |
| KR20170098170A (ko) | 2017-08-29 |
| US20210292306A1 (en) | 2021-09-23 |
| WO2017142269A1 (ko) | 2017-08-24 |
| AU2017221673A1 (en) | 2018-08-30 |
| AU2017221673B2 (en) | 2021-06-17 |
| CN109071437A (zh) | 2018-12-21 |
| JP2019509273A (ja) | 2019-04-04 |
| EP3418271A4 (en) | 2019-10-30 |
| KR101790193B1 (ko) | 2017-10-25 |
| JP6917634B2 (ja) | 2021-08-11 |
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