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前列腺癌药物的应用，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前列腺癌药物的应用。
背景技术
前列腺癌是指发生在前列腺的上皮性恶性肿瘤，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。研发安全有效的抗前列腺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，而唯独对于前列腺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前列腺癌的增殖并诱导前列腺癌细胞凋亡，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，应用于抗前列腺癌药物，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前列腺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前列腺癌药物中的应用。
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诱导前列腺癌PC3细胞凋亡，对PC3细胞的活性为810nM，并直接结合在前列腺癌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前列腺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前列腺癌细胞c乳腺癌细胞d临床对照药：5-氟尿嘧啶
化合物I-1对前列腺癌细胞PC3的凋亡诱导作用：
收集化合物I-1处理的前列腺癌细胞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对前列腺癌细胞PC3的凋亡诱导作用见下表：
Figure BDA0002609846110000081
化合物I-1直接结合在前列腺癌PC3细胞的秋水仙碱位点：
前列腺癌PC3细胞接种于6孔板中，培养24小时。前列腺癌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前列腺癌药物。

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前列腺癌药物。
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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