CN111848498B - 哌啶及2,6-哌啶二酮类秋水仙碱位点抑制剂及其制备方法和应用 - Google Patents

哌啶及2,6-哌啶二酮类秋水仙碱位点抑制剂及其制备方法和应用 Download PDF

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CN111848498B
CN111848498B CN202010750283.7A CN202010750283A CN111848498B CN 111848498 B CN111848498 B CN 111848498B CN 202010750283 A CN202010750283 A CN 202010750283A CN 111848498 B CN111848498 B CN 111848498B
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李军
付冬君
张云封
常安琪
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Abstract

本发明公开了一类基于哌啶及2,6‑哌啶二酮的秋水仙碱位点抑制剂、其制备方法及作为抗***癌药物的应用，属于药物化学领域。本发明化合物的结构通式如下：

Description

哌啶及2,6-哌啶二酮类秋水仙碱位点抑制剂及其制备方法和 应用
技术领域
本发明涉及药物化学领域，具体涉及一类哌啶及2,6-哌啶二酮类秋水仙碱位点抑制剂及其制备方法和作为一类新的抗***癌药物的应用。
背景技术
***癌是指发生在***的上皮性恶性肿瘤，在男性致死性癌症中居第二位，其发病率及死亡率仅次于肺癌。研发安全有效的抗***癌药物具有重要的科学意义及临床意义。国内外对哌啶及2,6-哌啶二酮类化合物均有大量的研究报道，这类药物的生物活性非常广泛，而唯独对于***癌方面却鲜有研究报道。
基于微管蛋白靶点的抗肿瘤药物分为秋水仙碱位点抑制剂、长春碱位点抑制剂、laulimalide结合位点抑制剂和紫杉烷结合位点抑制剂。与其他三种微管抑制剂相比，秋水仙碱位点抑制剂具有如下优点：(1)能够克服多药耐药；(2)有较好的药代动力学性质与水溶性；(3)可以避免表面活性剂带来的过敏反应等副作用。秋水仙碱位点抑制剂能够抑制***癌的增殖并诱导***癌细胞凋亡，但目前仍没有被FDA批准上市的秋水仙碱位点抑制剂类抗癌药物。因此，研究开发新型的秋水仙碱位点抑制剂具有重要意义。基于哌啶及2,6-哌啶二酮设计合成秋水仙碱位点抑制剂，应用于抗***癌药物，具有一定的研究价值，目前没见相关文献报道。
发明内容
本发明目的在于提供系列对抗***癌活性好的新型秋水仙碱位点抑制剂。
本发明的另一个目的在于提供其简单高效，绿色环保的合成方法。
本发明的再一个目的在于提供所述化合物在制备抗***癌药物中的应用。
为实现本发明目的，本发明以3,4,5-三甲氧基苯胺和对甲氧基苄氯为原料，经三步反应制备哌啶及2,6-哌啶二酮类衍生物。
所述一类哌啶及2,6-哌啶二酮类秋水仙碱位点抑制剂结构通式如下：
Figure BDA0002609846110000021
R1，R5分别代表氢或羰基，取代基同时相同；R2，R4代表氢或甲基，取代同时相同或不同；R3代表氢，环戊基，甲基双取代。
优选如下化合物：
Figure BDA0002609846110000031
本发明所述哌啶及2,6-哌啶二酮类秋水仙碱位点抑制剂主要通过下列步骤制得：
Figure BDA0002609846110000032
二甲基甲酰胺溶剂中，加入3,4,5-三甲氧基苯胺和对甲氧基苄氯，三乙胺，室温搅拌反应，制备化合物3。取化合物3溶于l丙酮中，加入碳酸钾，氯乙酰氯，室温搅拌反应，反应结束后，萃取浓缩，重结晶得化合物4。取化合物4溶于二氯甲烷中，加入哌啶或其衍生物，氢氧化钠，室温搅拌反应，反应结束后，抽滤得化合物目标物。
本发明优点：首次合成了一类哌啶及2,6-哌啶二酮类秋水仙碱位点抑制剂。合成路线简短，收率高，达45％以上且成本低廉。实验证明，此类化合物具备广谱抗肿瘤活性，特别是化合物I-1～I-6，例如化合物I-1诱导***癌PC3细胞凋亡，对PC3细胞的活性为810nM，并直接结合在***癌PC3细胞的秋水仙碱位点。该类秋水仙碱位点抑制剂对研究微管蛋白的生物学功能及新型抗***癌药物具有重要的意义。
附图说明
图1为本发明化合物I-1的电泳图片。
具体实施方式
为了对本发明进行更好的说明，举实施例如下：
实施例通式(I-1～I-6)的制备
50ml二甲基甲酰胺溶剂中，加入0.01mol的3,4,5-三甲氧基苯胺和0.01mol的对甲氧基苄氯，0.02mol的三乙胺，室温搅拌反应2小时，制备化合物3。取0.01mol化合物3，溶于10ml丙酮中，加入0.02mol碳酸钾，0.02mol氯乙酰氯，室温搅拌3小时，萃取浓缩，2ml乙醇重结晶得化合物4。取1mmol化合物4溶于10ml二氯甲烷中，加入1.2mmol哌啶或其衍生物，2mmol氢氧化钠，室温搅拌，抽滤得化合物I-1～I-6。
所述哌啶衍生物为2,6-哌啶二酮、3,3-四亚甲基戊二酰亚胺、3,3-二甲基谷酰胺、3-甲基哌啶、3,5-二甲基哌啶。
通式(I-1～I-6)结构表征如下：
I-1：收率:62％.白色固体,m.p.:156～158℃.1H NMR(400MHz,CDCl3)δ7.05(d,J＝8.5Hz,2H),6.74(d,J＝8.6Hz,2H),6.22(s,2H),4.69(s,2H),4.26(s,2H),3.76(s,3H),3.71(s,3H),3.66(s,6H),2.64(t,J＝6.5Hz,4H),1.99–1.90(m,2H).13C NMR(100MHz,CDCl3)δ171.35,165.46,158.02,152.59,136.88,135.29,129.35,128.31,112.72,104.74,59.92,55.19,54.26,51.65,40.23,31.45,16.02.HRMS(m/z)[M+H]+calcd for C24H29N2O7,457.1975；found,457.1979.
I-2：收率:52％.白色固体,m.p.:95～97℃.1H NMR(400MHz,CDCl3)δ7.04(d,J＝8.5Hz,2H),6.73(d,J＝8.5Hz,2H),6.21(s,2H),4.70(s,2H),4.25(s,2H),3.76(s,3H),3.71(s,3H),3.65(s,6H),2.58(s,4H),1.66(t,J＝6.8Hz,4H),1.54(d,J＝6.4Hz,4H).13CNMR(100MHz,CDCl3)δ171.11,165.45,158.01,152.57,136.86,135.27,129.37,128.32,112.71,104.77,59.91,55.18,54.25,51.52,43.35,40.22,38.59,36.65,23.10.HRMS(m/z)[M+H]+calcd for C28H35N2O7,511.2444；found,511.2448.
I-3：收率:46％.白色固体,m.p.:141～143℃.1H NMR(400MHz,CDCl3)δ7.04(d,J＝8.5Hz,2H),6.73(d,J＝8.6Hz,2H),6.21(s,2H),4.70(s,2H),4.26(s,2H),3.76(s,3H),3.71(s,3H),3.65(s,6H),2.49(s,4H),1.11(s,6H).13C NMR(100MHz,CDCl3)δ170.88,165.52,158.01,152.58,136.87,135.26,129.37,128.31,112.71,104.76,59.91,55.18,54.25,51.53,45.03,40.13,28.32,26.77.HRMS(m/z)[M+H]+calcd for C26H33N2O7,485.2288；found,485.2289.
I-4：收率:61％.白色固体,m.p.:75～77℃.1H NMR(400MHz,CDCl3)δ7.08(d,J＝8.5Hz,2H),6.72(d,J＝8.5Hz,2H),6.04(s,2H),4.69(s,2H),3.78(s,3H),3.71(s,3H),3.63(s,6H),2.85(s,2H),2.35(s,4H),1.57–1.42(m,4H),1.32(s,2H).13C NMR(100MHz,CDCl3)δ168.38,157.96,152.34,136.60,136.20,129.57,128.93,112.59,104.88,59.95,59.30,55.13,54.25,53.61,51.28,24.86,22.98.HRMS(m/z)[M+H]+calcd for C24H33N2O5,429.2389；found,429.2392.
I-5：收率:80％.白色固体,m.p.:72～74℃.1H NMR(400MHz,CDCl3)δ7.08(d,J＝8.5Hz,2H),6.72(d,J＝8.4Hz,2H),6.04(s,2H),4.69(s,2H),3.78(s,3H),3.71(s,3H),3.63(s,6H),2.86(s,2H),2.74(s,2H),1.85(s,1H),1.59(d,J＝10.3Hz,3H),1.51(s,2H),0.75(s,1H),0.75(d,J＝5.6Hz,3H).13C NMR(100MHz,CDCl3)δ168.44,157.97,152.34,136.60,136.20,129.58,128.93,112.59,104.89,61.00,59.95,59.09,55.13,54.25,53.04,51.27,31.65,30.06,24.50,18.64.HRMS(m/z)[M+H]+calcd for C25H35N2O5,443.2546；found,443.2548.
I-6：收率:62％.白色固体,m.p.:96～98℃.1H NMR(400MHz,CDCl3)δ7.08(d,J＝8.4Hz,2H),6.72(d,J＝8.4Hz,2H),6.04(s,2H),4.70(s,2H),3.78(s,3H),3.71(s,3H),3.63(s,6H),2.87(s,2H),2.74(d,J＝9.5Hz,2H),1.61(s,2H),1.58(s,1H),1.48(s,2H),0.74(d,J＝6.3Hz,6H),0.40(q,J＝11.8Hz,1H).13C NMR(100MHz,CDCl3)δ168.43,157.98,152.35,136.61,136.15,129.60,128.92,112.59,104.88,60.52,59.95,58.79,55.12,54.25,51.27,40.79,30.02,18.51.HRMS(m/z)[M+H]+calcd for C26H37N2O5,457.2702；found,457.2706.
上述化合物的抗肿瘤活性测定：
称取2mg本发明化合物置于2mL EP管中，然后用DMSO配制成浓度是128×103μg/mL的溶液，4℃保存放置，实验时根据所需浓度用培养基稀释。取对数生长期的细胞，消化计数后，用培养基调整细胞密度，接种至96孔板中，培养24h后，弃去培养基，加入用培养基稀释好的药物(0.5μg/mL、1μg/mL、2μg/mL、4μg/mL、8μg/mL、16μg/mL、32μg/mL、50μg/mL)，每个浓度设6个复孔，另设空白对照组及阴性对照组。药物作用48h后，每孔加入20μL MTT，继续培养4h后，吸去液体，加入150mL的DMSO，振荡均匀，酶标仪490nm处检测吸光度值，计算抑制率。试验结果采用SPSS软件计算IC50值和相关系数。实验结果如下：
表1上述化合物对三种肿瘤细胞的抗肿瘤活性评价数据
Figure BDA0002609846110000071
a胃癌细胞b***癌细胞c乳腺癌细胞d临床对照药：5-氟尿嘧啶
化合物I-1对***癌细胞PC3的凋亡诱导作用：
收集化合物I-1处理的***癌细胞PC3，用预冷的PBS洗涤细胞2次，吸弃PBS。加入5μL Annexin V-FITC和10μL PI染色液，轻轻混匀。避光、室温反应15min。加入400μLBinding Buffer，混匀后放置于冰上，样品在1小时内用流式细胞仪检测。化合物I-1对***癌细胞PC3的凋亡诱导作用见下表：
Figure BDA0002609846110000081
化合物I-1直接结合在***癌PC3细胞的秋水仙碱位点：
***癌PC3细胞接种于6孔板中，培养24小时。***癌PC3细胞分别用化合物I-1孵化,秋水仙碱(10μM)或二甲基亚砜处理2小时，然后加入N,N’-乙双(碘乙酰胺)(EBI)(100μM)孵育2小时。然后,收集细胞并裂解，进行western blotting分析，实验结果见图1。可以看出，该类化合物有利于后期开发新型抗***癌药物。

Claims (6)

1.一类哌啶及2,6-哌啶二酮的秋水仙碱位点抑制剂，其特征在于，具有如下所示结构：
Figure 402936DEST_PATH_IMAGE001
取代基R1，R5分别代表氢或羰基，取代基同时相同；取代基R2，R4代表氢或甲基，取代基同时相同或不同；取代基R3代表氢或甲基双取代。
2.一类哌啶及2,6-哌啶二酮的秋水仙碱位点抑制剂，其特征在于，选自如下化合物之一：
Figure 743918DEST_PATH_IMAGE002
。
3.如权利要求1或2所述的一类哌啶及2,6-哌啶二酮的秋水仙碱位点抑制剂的应用，其特征在于，将其作为活性成分用于制备抗肿瘤药物。
4.如权利要求3所述的一类哌啶及2,6-哌啶二酮的秋水仙碱位点抑制剂的应用，其特征在于，将其作为活性成分用于制备抗***癌药物。
5.制备如权利要求1所述的一类哌啶及2,6-哌啶二酮的秋水仙碱位点抑制剂的方法，其特征在于：通过如下步骤实现，
Figure 268440DEST_PATH_IMAGE003
二甲基甲酰胺溶剂中，加入3,4,5-三甲氧基苯胺和对甲氧基苄氯，三乙胺，室温搅拌反应，制备化合物3；取化合物3溶于丙酮中，加入碳酸钾，氯乙酰氯，室温搅拌反应，反应结束后，萃取浓缩，重结晶得化合物4；取化合物4溶于二氯甲烷中，加入哌啶或其衍生物，氢氧化钠，室温搅拌反应，反应结束后，抽滤得目标化合物。
6.如权利要求5所述的一类哌啶及2,6-哌啶二酮的秋水仙碱位点抑制剂制备方法，其特征在于：所述哌啶衍生物为2,6-哌啶二酮、3,3-二甲基谷酰胺、3-甲基哌啶或3,5-二甲基哌啶。
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