CN109516926B - 一种荜茇明碱衍生物制备及用途 - Google Patents
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- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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Abstract
本发明公开了一种荜茇明碱衍生物结构式，该化合物为新结构，还公开了该化合物的制备方法及其用途，在化合物对胰腺癌、宫颈癌、结肠癌、恶性黑色素瘤、肝癌、肺腺癌、白血病、卵巢癌等肿瘤细胞具有明显抑制作用。该化合物结构式为
Description
技术领域
本发明涉及一种抗肿瘤天然产物衍生物的制备及用途，属于医药技术领域
背景技术
恶性肿瘤已经成为严重危害人类生命健康的主要疾病，是人类健康的头号杀手。虽然世界卫生组织、各国政府和科研机构始终把攻克癌症列为一项首要任务，但是时至今日仍是一场“没有获胜的战争”。而小分子抗肿瘤药物是肿瘤治疗的重要部分，寻找和开发新型的小分子抗肿瘤药物是征服恶性肿瘤的重要举措。天然产物对小分子抗肿瘤药物发现领域有着深刻影响。天然产物经过进化预选以及其他一些生物或非生物因素的共同作用,其防御体系和代谢系统高度发达，具有结构新颖，多样，活性独特等特点。天然产物及衍生物也是肿瘤治疗和化学领域的主要候选药物来源，例如紫杉醇，喜树碱，长春新碱，斑蝥素等均成为临床应用的抗肿瘤化学治疗的明星药物。它所含有的核心骨架成为人们寻找生物活性化合物的最佳向导。
荜茇明碱(Piplartine)，是一种生物碱类化合物。最初在胡椒科植物荜茇Piperlongum Linn.中被发现，后来发现长柄胡椒P.sylvaticumRoxb.和瘤突胡椒P.tuberculatum Jacq.的根中也存在该化合物。荜茇明碱被认为是荜茇药材的主要药效成分。药理学研究发现荜茇明碱有着多种药理学活性。其中我们最感兴趣的是其抗肿瘤活性。研究表明，荜茇明碱能够抑制肿瘤细胞的增殖，促进肿瘤细胞凋亡，对多种肿瘤产生抑制作。来自《nature》的一篇关于荜茇明碱抗肿瘤研究报道更加鼓舞人心，该研究显示荜茇明碱对肿瘤细胞具有选择性杀伤作用，而对正常细胞无影响。在浓度为10μmol/L的条件下对肿瘤细胞即可表现出非常强的细胞毒作用，但即使是在15μmol/L的浓度下对正常细胞的生存力影响仍然很小。不管是原癌基因突变还是抑癌基因突变造成的细胞恶性转化，通常都会造成细胞应激反应的增强，如氧化、复制、代谢、蛋白毒性应激和DNA损伤等。癌细胞要生存下去就必须适应这种应激性的表型，这就导致癌细胞对某些非原癌基因因素的依赖性，而正常细胞则不具有这种依赖性，因此如果靶向特异性破坏这种恶性转化表型中的非原癌基因因素，就可以选择性的杀死癌细胞。因此荜茇明碱是一种具有良好开发前景的抗肿瘤药物的先导化合物。以荜茇明碱为先导进行结构改造和修饰，合成结构多样的衍生物可以克服荜茇明碱来源有限的和成药性不佳的问题。
发明内容
本发明提供了一种α，β不饱和苯丙酰胺结构的荜茇明碱衍生物，其化学结构式如下式I所示
本发明的化合物可以一种或多种异构体的形式存在。异构体包括对映异构体、非对映异构体、几何异构体。如本发明的式I所示的化合物，由于一个碳原子上连接四个不同的取代基而形成立体异构体(分别以R和S来表示不同的构型)，本发明包括R型异构体和S型异构体以及它们任何比例的混合物。
本发明提供N-十四烷基-3,4,5-三甲氧基苯丙酰胺的制备和抗肿瘤用途。
具体实施方式
下面结合具体实施，进一步阐明本发明。这些实施例应理解为仅用于说明本发明而不是用于限制本发明的保护范围。在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等效变化和修饰同样落入本发明权利要求书所限定的范围。
化合物N-十四烷基-3,4,5-三甲氧基苯丙烯酰胺的制备
3,4,5-三甲氧基苯丙烯酸的制备。将3,4,5-三甲氧基苯甲醛(0.1mol，19.60g)、丙二酸(0.1mol，10.40g)与催化剂乙醇胺(0.1mol,6.11g)溶于25mL水中,于100mL圆底烧瓶中回流反应,TLC监测反应进行状况，待反应结束后冷却后放置过夜待结晶。用布氏漏斗过滤,用0℃水25mL,水洗2次,得粗品,所得产物经50mL乙醇+水[V(乙醇)：V(水)＝6：4]重结晶，即得相应的纯品，产率91％。
3,4,5-三甲氧基苯丙烯酰氯的制备。将SOCl2(0.1mol，11.79g)缓慢加入含有3,4,5-三甲氧基苯丙烯酸(0.1mol，23.81g)的CH2Cl2中溶液中，室温搅拌过夜，旋干，无需分离，备用。
N-十四烷基-3,4,5-三甲氧基苯丙酰胺的制备将十四烷基胺(0.1mol，19.92g)溶于200ml无水处理的CH2Cl2中加入0.11mol三乙胺，N2保护，边搅拌缓慢地加入上一步反应的干燥处理的烧瓶中，0℃搅拌2小时。TLC检测反应结束后，将反应物倒入500ml水中，然后搅拌萃取，分离有机层，旋干，得粗品，再用CH2Cl2重结晶即得纯品，产率95％。
N-十四烷基-3,4,5-三甲氧基苯丙烯酰胺的化学表征如下：(E)-N-tetradecyl-3-(3,4,5-trimethoxyphenyl)acrylamide，1H-NMR(DMSO)δ：7.55(d，J＝1.5Hz，1H，AR-CH)7.17(s，2H，AR-H3-6)6.30(s，1H，NH),6.19(d，J＝15.6Hz，1H，C＝O-CH)，3.99(s，6H，AR-3,5-OCH3)，3.93(s，3H，AR-4-OCH3),3.26(m，2H，N-CH2)，1.53(m，2H，CH2)，1.29(m，24H，CH2)，0.96(m，3H，CH3)；EI-MS m/z:434.31[M+1]+,calcd for C26H43NO4：433.32。
细胞培养将本实验需要的人胰腺癌细胞PANC-1、人宫颈癌细胞Hela、人结肠癌细胞HCT116、人恶性黑色素瘤细胞A375、人肝癌细胞HepG2、人肺腺癌细胞A549、人白血病细胞K562、人卵巢癌细胞SKOV-3等8种肿瘤细胞株用含12.5％马血清、2.5％胎牛血清、青霉素100U/ml、链霉素100U/ml的DMEM培养液培养，于37℃、5％CO2孵化箱中孵化，待细胞贴壁生长时进行传代处理，传代期间2～3天更换培养液，选取对数生长期细胞进行实验。
抗肿瘤活性测试取对数生长期各肿瘤细胞接种于96孔细胞培养板，密度为5×104个/ml。药物处理组和细胞对照组分别加入每孔100μl细胞悬液，并将每组设3个平行孔，空白对照组只加入DMEM全培养基，每孔100μl，同样设3个平行孔。细胞培养24h后，药物处理组分别加入终浓度为20μg/ml的药物溶液100ul，细胞对照组和空白对照组加入与处理组等量细胞培养液。将96孔培养板置于37℃、5％CO2培养箱培养24h后，加入10μl MTT(5mg/ml)溶液，继续培养4h，每孔加入100μl DMSO溶解液，直至完全溶解。置于酶标仪，用空白矫正基线，测定570nm的吸光度(A)值，按照下示公式[抑制率＝(1-实验组A值/对照组A值)×100％]计算抑制率。
结果显示，我们合成的化合物对人胰腺癌细胞PANC-1、人宫颈癌细胞Hela、人结肠癌细胞HCT116、人恶性黑色素瘤细胞A375、人肝癌细胞HepG2、人肺腺癌细胞A549、人白血病细胞K562、人卵巢癌细胞SKOV-3等8种肿瘤细胞株具有不同程度的抑制作用，10μM时抑制率在18.3％-96.7％不等，其中对人结肠癌细胞HCT116抑制率最高，达96.7％。
表1本发明化合物浓度为10μM时对多种肿瘤细胞株的抑制率
半数抑制率IC50的测试按照上述方法，测定0.01μM、0.1μM、0.5μM、1μM、5μM、10μM、20μM、40μM浓度下该化合物的对HCT116细胞的抑制率，利用GraphPad Prism 5软件计算化合物对HCT116的半数抑制IC50值。结果显示该化合物对HCT116的IC50值为0.77μM，高于天然产物荜茇明碱的6.82μM。
N-十四烷基-3,4,5-三甲氧基苯丙烯酰胺具对多种肿瘤细胞具有抑制作用，可用于制备抗肿瘤药物。
Claims (4)
1.一种荜茇明碱衍生物或其药学上可接受的盐，其中所述的荜茇明碱衍生物具有以下结构
2.一种权利要求1所述的荜茇明碱衍生物的制备方法，其合成路线为：
3.一种权利要求1所述的荜茇明碱衍生物或其药学上可接受盐的用途，其特征在于：所述化合物在制备用于治疗肿瘤疾病药物中的应用。
4.如权利要求3所述的用途，其中所述的肿瘤疾病为胰腺癌、宫颈癌、结肠癌、恶性黑色素瘤、肝癌、肺腺癌、白血病、卵巢癌中的任意一种。
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