CN113694062A - 一种含吡啶的化合物的抗肿瘤用途 - Google Patents
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Abstract
本申请涉及一种含吡啶的化合物的抗肿瘤用途。所述含吡啶的化合物为化合物JKW‑14，能够对多种肿瘤细胞具有抗增殖的作用。
Description
技术领域
本文涉及药物化学领域，尤指一种含吡啶的化合物的抗肿瘤用途。
背景技术
以阿司匹林为代表的非甾体抗炎药的应用已有百年历史，其作用机制主要是通过抑制环氧化酶(COX-1和COX-2等)合成前列腺素而发挥抗炎镇痛效果。其中，COX-2在正常状态下表达量极低，只有在受到炎症刺激等条件下才会出现表达增强并促进炎症反应的现象。传统的非甾体抗炎药目前仍是临床上治疗炎症最主要的药物，但它们大多对于COX-1和COX-2没有选择性，容易导致严重的胃肠道副作用，甚至因此而危及生命。因此，找到特异性强、活性高的COX-2抑制剂是研究非甾体抗炎药的主要方向。
发明人曾在具有消炎、消包块的昆虫类中药琵琶甲虫中分离提纯了一种具有抗炎活性的化合物JKW-14(CN109810049A)
发明内容
化合物JKW-14在琵琶甲虫中含量较低，用天然原料提取难以满足后续实验和生产需要。发明人利用Suzuki反应，完成了该化合物的体外化学合成。
因此，在本申请的第一方面，提供了化合物JKW-14的合成方法。化合物JKW-14的合成路线如路线1所示。
路线1.合成化合物JKW-14的试剂和条件：(a)三苯基膦钯，碳酸氢钠，1,4-二氧六环，90℃反应8小时,收率89％；(b)三溴化硼，二氯甲烷，室温反应4h，收率57％。
发明人通过进一步研究发现，化合物JKW-14还具有良好的抗肿瘤活性，能够对多种肿瘤细胞起到抗增殖作用。因此，在第二方面，本申请提供了化合物JKW-14或其药学上可接受的衍生物及其盐用于预防或治疗肿瘤的用途。
本申请的其它特征和优点将在随后的说明书中阐述，并且，部分地从说明书中变得显而易见，或者通过实施本申请而了解。本申请的其他优点可通过在说明书以及附图中所描述的方案来实现和获得。
附图说明
附图用来提供对本申请技术方案的理解，并且构成说明书的一部分，与本申请的实施例一起用于解释本申请的技术方案，并不构成对本申请技术方案的限制。
图1示出了化合物JKW-14对MDA-MB-231细胞周期的影响。
图2示出了化合物JKW-14对MDA-MB-231细胞有丝分裂指数的影响。
具体实施方式
在本申请的第一方面，提供了化合物JKW-14的合成方法。所述的合成方法包括在三苯基膦钯和碳酸氢钠的存在下，3,4-二甲氧基苯基硼酸和3,5-二溴吡啶在1,4-二氧六环中90℃反应8h，得到中间体1；以二氯甲烷为溶剂，中间体1与三溴化硼室温反应4h，生成目标化合物JKW-14。然后，化合物JKW-14可以通过本领域常用手段形成药学上可接受的衍生物和盐。
在第二方面，本申请提供了化合物JKW-14或其药学上可接受的衍生物及其盐、或其药物组合物用于预防或治疗肿瘤的用途。
在一些实施方案中，所述药物组合物包含化合物JKW-14或其药学上可接受的衍生物及其盐，任选地，所述药物组合物还包含药学上可接受的赋形剂。
在一些实施方案中，所述化合物JKW-14或其药学上可接受的衍生物及其盐，或者其药物组合物可以适于口服、鼻内、直肠内、舌下、经颊或胃肠道外施用，施用的剂量为0.1mg-5g/次，可以每天一次或多次，也可以两天或三天一次。在一些实施方案中，药物组合物可以是片剂、胶囊、糖锭剂、锭剂、胃肠道外剂型、液体或粉剂，但不限于这些剂型。通常，预期口服剂型是最方便的。所有的剂型可利用本领域已知的标准方法制备。
在一些实施方案中，所述药物组合物还包含药学上可接受的赋形剂，例如滑石粉、阿拉伯胶、乳糖、淀粉、硬脂酸镁、可可脂、水性或非水性溶剂、油类、石蜡油衍生物、二醇类等。色素或调味剂也可加入为口服施用设计的制剂中。可利用水或生理学相容的有机溶剂制备溶液，例如乙醇、1-2丙二醇、聚乙二醇类、二甲基亚砜、脂肪醇类、甘油三酯类、甘油偏酯类等。胃肠道组合物可利用常规技术制备，且包括无菌等渗盐水、水、1,3-丁二醇、乙醇、1,2-丙二醇、与水混合的聚乙二醇等。
发明人发现，化合物JKW-14能够将细胞周期抑制在G2/M期。因此，预期化合物JKW-14能够抑制多种类型的癌症，例如但不限于神经系统癌症、脑癌、甲状腺癌、头颈癌、黑素瘤、白血病、多发性骨髓瘤、霍奇金病、乳腺癌、膀胱癌、前列腺癌、结肠直肠癌癌、结肠癌、肾癌、肾细胞癌、胰腺癌、食管癌、肺癌、间皮瘤、卵巢癌、宫颈癌、子宫内膜癌、子宫癌、生殖细胞肿瘤、睾丸癌、胃癌、骨肉瘤或其他癌症。
在一些实施方案中，化合物JKW-14能够抑制乳腺癌和骨肉瘤，特别是人乳腺癌MCF-7、T47D、MDA-MB-231及人骨肉瘤U2OS细胞系。
实施例1：化合物JKW-14的合成
将7.28g的3,4-二甲氧基苯硼酸与4.68g的3,5-二溴吡啶溶于150mL二氧六环中，搅拌均匀，氩气鼓泡除去体系中空气。然后加入1.15g的四三苯基膦钯和5mL饱和碳酸氢钠溶液，继续用氩气鼓泡5分钟。在氩气气氛保护下，90℃反应8小时以上，待薄层色谱检测到原料消失，恢复至室温，过滤，滤渣用二氧六环洗涤两次，合并滤液，减压蒸馏除去溶剂，所得残余物用乙酸乙酯和饱和食盐水萃取，有机相用饱和食盐水洗涤两次，无水硫酸钠干燥后减压蒸馏除去溶剂，得淡黄色固体6.24g，即化合物1，产率89％。
将351mg化合物1溶解于加入25ml无水二氯甲烷中，氩气鼓泡除去体系中空气，边搅拌边冷却至-10℃，用注射器缓慢滴加三溴化硼的二氯甲烷溶液(1.1g三溴化硼溶于25mL二氯甲烷)，滴毕，自然升温至室温反应4小时以上，待薄层色谱跟踪显示原料消失，将反应液缓慢加入到不断搅拌的冰水混合物中，缓慢加入饱和碳酸氢钠溶液至溶液显中性，二氯甲烷(10mL×3)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。减压浓缩得黄色的固体，粗产物经柱层析分离(DCM/MeOH,20:1～10:1)得168.1mg黄色固体，即JKW-14，产率57％。ESIMS m/z 296[M+H]+；HRESIMS m/z 296.0919[M+H]+(calcd for C17H13NO4,296.0917)；1H NMR(500MHz,MeOD)δH 8.58(d,J＝2.1Hz,1H),8.05(d,J＝2.1Hz,1H),7.12(d,J＝2.2Hz,2H),7.05(dd,J＝8.2,2.2Hz,2H),6.91(d,J＝8.2Hz,2H)；13C NMR(125MHz,MeOD)δC147.3,147.1,145.6,138.7,133.3,130.3,119.8,117.1,115.0.
实施例2：体外抗肿瘤活性测试
细胞及其培养条件
DMEM培养基、胎牛血清及0.25％胰酶(Trypsin-EDTA)均购自Hyclone公司。双抗(青霉素-链霉素)购自Gemini公司。体外抗肿瘤活性实验所使用的CellTiter
MTS细胞增殖试剂盒购自Promega公司。
所有肿瘤细胞均在37℃5％CO2细胞培养箱中培养。待细胞铺满培养皿底部约80-90％后，吸除原培养基，沿培养皿侧边缓慢加入约5mL的1×PBS缓冲液润洗细胞。吸除PBS，加入1mL 0.25％胰蛋白酶，轻摇培养皿使其铺满整个皿底并与细胞充分接触，吸除胰蛋白酶。将培养皿置于培养箱中，消化2-3min。加入合适体积的新培养基终止细胞消化，轻轻吹打细胞，使细胞在培养基中单个悬浮分散。吸取1mL细胞悬液传至新的培养皿中，补齐培养皿中培养基到10mL。轻摇培养皿使细胞分散均匀，放入培养箱中培养。
细胞毒活性实验
该实验使用CellTiter
AQueous One Solution Cell Proliferation Assay试剂盒(Promega)。待测化合物事先配成104μM的DMSO溶液，-20℃保存，解冻后使用，用培养基稀释至所需浓度。实验数据均为三次独立平行实验计算所得。
按上述细胞传代方法制得细胞悬液，5×103/well的密度接种于96孔培养板中，留出两个孔作为空白，其余每孔加入90μL细胞悬液。在培养箱中培养24h后，吸除旧培养基，空白及本底孔加入100μL新培养基，其余孔加入配好的待测化合物的培养基溶液，放入培养箱中继续培养72h。预先将冷冻保存的MTS溶液在室温下解冻，向96孔培养板每孔加入20μLMTS溶液，放入培养箱2h，使用酶标仪(Molecular Devices SpectraMax M5)检测492nm波长处各孔的吸光值(OD值)。按如下公式计算细胞增殖抑制率(Cell proliferationinhibition)：
Cell proliferation inhibition(％)＝[1-(ODcell+test compound-ODblank)/(ODcell+CM-ODblank)]×100％
其中ODcell+test compound、ODcell+CM、ODblank值分别代表在492nm波长下测试组、空白组以及本底组的吸光值。通过SPSS 20for Windows软件绘制抑制率的S型曲线，计算化合物的半抑制浓度(IC50)。
采用MTS法测定了目标化合物对肿瘤细胞的细胞毒活性，结果见表1。以上市的抗肿瘤药物5-氟尿嘧啶(5-FU)为阳性对照，测定了化合物JKW-14对于人乳腺癌MCF-7、T47D、MDA-MB-231及骨肉瘤U2OS等细胞系的半抑制浓度(IC50)。结果表明，JKW-14对于以上几种肿瘤细胞系均有良好的抗增殖活性，且明显优于阳性对照。
表1.化合物JKW-14在MCF-7、T47D、MDA-MB-231和U2OS细胞中的IC50值。
细胞周期实验
采用碘化丙啶染色法和荧光激活分选测定细胞周期分布。首先根据需要设置不同浓度待测化合物配成培养基溶液。然后将细胞按照6×105/well的密度接种于六孔盘中，放入培养箱培养24h。吸除原培养基，加入配好的培养基溶液，并用新培养基补齐到每孔1.5-2mL。加药处理24h后，收集培养基，每孔加入200μL 0.25％胰蛋白酶，消化2-3min。加入之前手机的培养基终止细胞消化，轻轻吹打细胞，全部收集于离心管中，4℃1500g离心2min。弃上清液，加1mL冷的PBS重悬细胞，4℃1500g离心2min后吸除。加200μL冷的PBS重悬细胞，缓慢加入200μL冷的无水乙醇，吹打混匀，重复加乙醇两次，使乙醇的终浓度为75％。在4℃层析柜中固定12h后可以上机测试。
测试前离心固定好的细胞(4℃，1500g，2min)，弃除上清液，敞口放置使乙醇尽量挥干。加1mL PBS重悬细胞，4℃1500g离心2min，吸除上清液，如此洗涤细胞两次。用PBS稀释RNase A(10mg/mL,l:100)和PI(2mg/mL,1:200)，每个样品管加400μL的RNase A和PI染色剂稀释液，37℃水浴避光染色30min。
染色完成后，轻轻吹打使得细胞分散均匀。用500目筛过滤细胞，防止未吹散的细胞团堵塞仪器管路，然后用流式细胞仪(BD
C6)检测样品。
实验结果在图1中示出。用不同浓度的JKW-14处理MDA-MB-231细胞24h，采用流式细胞术分析了不同细胞时相的分布，同时设不加药处理的DMSO溶剂组。结果发现，JKW-14能够显著地将细胞周期阻滞在G2/M期，即使在最小浓度下(1μM)，处于G2/M期细胞的比例也高达90％。
有丝分裂指数
将细胞按照2×105/well的密度接种于六孔盘中，待细胞贴壁生长后，加药处理不同时长。按照细胞周期的方法收集并固定细胞。离心固定好的细胞(4℃，1500g，2min)，弃上清液，加1mL 0.1％PBST洗涤细胞两次，离心，弃去上清液。加入500μL blocking buffer(2％BSA,0.1％PBST)，室温封闭30min。注意要每隔10min轻摇离心管，使沉淀细胞重悬，以便与BSA充分接触。离心(4℃，1500g，2min)，吸除上清液。加入500μL稀释好的一抗H3pS10，37℃水浴孵育45min。离心(4℃，1500g，2min)，弃去上清液。加1mL 0.1％PBST洗涤细胞两次，加入150μL稀释好的二抗FITC，37℃水浴避光孵育30min。离心(4℃，1500g，2min)，弃去上清液。加1mL PBST洗涤细胞两次，每样品管加400μL的RNase A和PI染色剂的PBS稀释液，37℃水浴避光染色30min。流式细胞仪(BD
C6)检测样品，上机测试前需用500目筛过滤细胞，防止未吹散的细胞团堵塞仪器管路。
采用流式细胞术测试了化合物JKW-14对MDA-MB-231细胞有丝分裂指数的影响。用10μM浓度的JKW-14处理MDA-MB-231细胞不同的时间，从图2可见，随着处理时间从3h延长到16h，处于M期的细胞明显增多，有丝分裂指数显著提高。结果提示，JKW-14可促进HeLa细胞越过G2/M检验点，通过激活纺锤体装配检验点，将细胞周期阻滞在M期。
本申请描述了多个实施例，但是该描述是示例性的，而不是限制性的，并且对于本领域的普通技术人员来说显而易见的是，在本申请所描述的实施例包含的范围内可以有更多的实施例和实现方案。尽管在附图中示出了许多可能的特征组合，并在具体实施方式中进行了讨论，但是所公开的特征的许多其它组合方式也是可能的。除非特意加以限制的情况以外，任何实施例的任何特征或元件可以与任何其它实施例中的任何其他特征或元件结合使用，或可以替代任何其它实施例中的任何其他特征或元件。
本申请包括并设想了与本领域普通技术人员已知的特征和要素的组合。本申请已经公开的实施例、特征和要素也可以与任何常规特征或要素组合，以形成由权利要求限定的独特的发明方案。任何实施例的任何特征或要素也可以与来自其它发明方案的特征或要素组合，以形成另一个由权利要求限定的独特的发明方案。因此，应当理解，在本申请中示出和/或讨论的任何特征可以单独地或以任何适当的组合来实现。因此，除了根据所附权利要求及其等同替换所做的限制以外，实施例不受其它限制。此外，可以在所附权利要求的保护范围内进行各种修改和改变。
Claims (7)
1.化合物JKW-14
或其药学上可接受的衍生物或其盐，或其药物组合物在制备预防或治疗肿瘤的药物中的用途。
2.根据权利要求1所述的用途，其中所述化合物JKW-14或其药学上可接受的衍生物或其盐，或者其药物组合物通过口服、鼻内、直肠内、舌下、经颊或胃肠道外施用。
3.根据权利要求1所述的用途，其中所述药物组合物还包含药学上可接受的赋形剂。
4.根据权利要求3所述的用途，其中所述药物组合物是片剂、胶囊、糖锭剂、锭剂、胃肠道外剂型、液体或粉剂。
5.根据权利要求4所述的用途，其中所述药学上可接受的赋形剂为滑石粉、阿拉伯胶、乳糖、淀粉、硬脂酸镁、可可脂、水性或非水性溶剂、油类、石蜡油衍生物、二醇类中的一种或更多种，任选地，所述药学上可接受的赋形剂还包括色素或调味剂。
6.根据权利要求1至5中任一项所述的用途，其中所述肿瘤选自神经系统癌症、脑癌、甲状腺癌、头颈癌、黑素瘤、白血病、多发性骨髓瘤、霍奇金病、乳腺癌、膀胱癌、前列腺癌、结肠直肠癌癌、结肠癌、肾癌、肾细胞癌、胰腺癌、食管癌、肺癌、间皮瘤、卵巢癌、宫颈癌、子宫内膜癌、子宫癌、生殖细胞肿瘤、睾丸癌、胃癌、骨肉瘤或其他癌症。
7.根据权利要求6所述的用途，其中所述肿瘤为乳腺癌和骨肉瘤，特别是人乳腺癌和人骨肉瘤。
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