CN107698648B - 含胆甾醇的萘酰亚胺类衍生物及其合成和应用 - Google Patents
含胆甾醇的萘酰亚胺类衍生物及其合成和应用 Download PDFInfo
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Abstract
发明公开了一种含胆甾醇的萘酰亚胺类衍生物及其合成和应用，属于生物有机合成领域，本发明利用分子杂交，将修饰后的胆甾醇引入萘酰亚胺母体，研发具有抗癌效果的新药。本发明所述的含胆甾醇的萘酰亚胺类衍生物，是用不同的环胺或脂肪胺基团取代萘酐末端的Br，研究药物分子的构效关系；以甘氨酸为桥链，将萘酰亚胺母体与胆甾醇通过DCC法发生酯化反应生成具有抗癌活性的新型含胆甾醇的萘酰亚胺类衍生物的目标化合物。
Description
技术领域
本发明涉及生物有机合成领域中的一类含胆甾醇的萘酰亚胺类衍生物的合成及应用。
背景技术
DNA嵌插剂作为靶向抗肿瘤药物一直是医药化学和分子生物学的研究热点。萘酰亚胺具有平面刚性结构、大π共轭体系、结构可修饰等优点，是DNA嵌入剂的典型嵌入母体，萘酰亚胺类化合物作为DNA嵌入剂已经被广泛地用于抗肿瘤、抗病毒、抗锥体虫等。胆甾醇与细胞膜、胆酸、维生素D的形成息息相关，对动物体作用重大，并且有些胆甾醇衍生物具有抗肿瘤、抗癌活性。容士宏等合成了羟基固醇类的水溶性衍生物对小鼠Krebs II具有强的抗癌作用。甘氨酸属于非必需氨基酸，结构简单，却参与了很多重要的与代谢有关的生理活性分子和蛋白质的合成，具有抗炎及免疫调节作用。治疗巴金森氏病的“L-多巴”以甘氨酸为主要合成中间体。
发明内容
本发明提供一类含胆甾醇的萘酰亚胺类衍生物的合成及应用。将修饰后的胆甾醇引入萘酰亚胺母体，研发具有抗癌效果的新药。
本发明所述的含胆甾醇的萘酰亚胺类衍生物，(1)用不同的环胺或脂肪胺基团取代萘酐末端的Br，研究药物分子的构效关系。(2)以甘氨酸为桥链，将萘酰亚胺母体与胆甾醇通过DCC法发生酯化反应生成具有抗癌活性的新型含胆甾醇的萘酰亚胺类衍生物的目标化合物。
本发明解决上述技术问题所采用的技术方案是：含胆甾醇的萘酰亚胺类衍生物，其化学分子结构通式D如下：
通式D中:
R选自N位取代的哌啶基、N位取代的吗啉基、N位取代的硫代吗啉基、N位取代的吡咯烷基、N,N-二甲基乙二胺基、N,N-二甲基丙二胺基、正丁胺基。
本发明提供上述含胆甾醇的萘酰亚胺类衍生物的制备方法，以4-溴-1,8萘酐为起始原料，与不同的环胺或链胺R’经溴代反应得到4-R-1,8-萘酐中间体，再与甘氨酸通过氨基缩合反应得到中间体N-(2’-羧基乙基)-4-R-1,8-萘酰亚胺，最后与胆甾醇通过(DCC法)发生酯化反应生成含胆甾醇的萘酰亚胺类衍生物的目标化合物。
所述R’选自哌啶、吗啉、硫代吗啉、吡咯烷、N,N-二甲基乙二胺、N,N-二甲基丙二胺、N,N-二乙基丙二胺、正丁胺。
上述的含胆甾醇的萘酰亚胺类衍生物的合成路线如下：
本发明提供上述含胆甾醇的萘酰亚胺类衍生物在抑制癌细胞药物中的应用。所述的癌细胞株为HepG2(人肝癌细胞)、Hela(人宫颈癌细胞)、MCF-7(乳腺癌细胞)、A549(肺癌细胞)，正常对照细胞株是RAW264.7(小鼠单核巨噬细胞)。
用上述合成的含胆甾醇的萘酰亚胺类衍生物用MTT比色法对HepG2(人肝癌细胞)、Hela(人宫颈癌细胞)、MCF-7(乳腺癌细胞)、A549(肺癌细胞)和RAW264.7(小鼠单核巨噬细胞)进行体外抑制肿瘤细胞生长活性的测定，结果表明，该类化合物对肝癌、宫颈癌、乳腺癌、肺癌等癌细胞具有抑制生长的效果。
用MTT比色法将HepG2(人肝癌细胞)、Hela(人宫颈癌细胞)、MCF-7(乳腺癌细胞)、A549(肺癌细胞)和RAW264.7(小鼠单核巨噬细胞)以5×103个细胞/孔接种于96孔板内，培养24h后加入梯度浓度药液200μL/孔，对每个肿瘤细胞株，设置5个复孔，另设无细胞调零孔；肿瘤细胞在37℃、5％CO2条件下培养24h后，加20μL的MTT液继续培养4h后，用移液枪小心地吸出上清液，加入DMSO溶解结晶，然后用酶标仪测OD490值，利用寇式改良法计算被测物对癌细胞生长的IC50值。
本发明所述的含胆甾醇的萘酰亚胺类衍生物具有液晶相，可用于液晶显示屏。
附图说明
图1为化合物D1的液晶相图；
图2为化合物D2的液晶相图。
具体实施方式
下面通过实施例对本发明作进一步的说明。
实施例1
N-(胆甾醇乙酸酯基)-4-吗啉基-1,8-萘酰亚胺(D1)的合成
(1)中间体4-R-1.8-萘酐的合成：
4-吗啉基-1.8-萘酐(中间体1)的合成:
在两口瓶中加入2.77g(10.0mmol)的4-溴-1,8萘酐，20mL
乙二醇单甲醚作溶剂，25℃搅拌，直至溶解。将0.96mL(11.0mmol)吗啉加入反应体系，油浴加热回流，TLC跟踪，4h后停止，冷却至室温，将反应液转移至盛水烧杯中，待黄色固体完全析出后过滤、干燥，得固体2.63g，黄色，产率：93.0％。熔点：210.0-212.0℃。
(2)中间体N-(2’-羧基乙基)-4-R-1,8-萘酰亚胺的合成:
N-(2’-羧基乙基)-4-吗啉基-1,8-萘酰亚胺(中间体2)的合成:
往双口瓶中加入0.57g(2.0mmol)中间体1和0.23g(3.0mmol)甘氨酸，15mL DMF作溶剂,100℃加热反应，TLC监测，9h后停止反应，自然冷却，将反应液转移至盛水烧杯中，待黄色固体完全析出后，过滤然后干燥，得固体0.58g，黄色，产率：85.0％。
(3)终产物N-(胆甾醇乙酸酯基)-4-吗啉基-1,8-萘酰亚胺(D1)的合成:
先将0.70g(1.81mmol)胆甾醇和0.51g(1.50mmol)中间体2的混合物溶于20mL干燥的二氯甲烷中，常温搅拌5min，然后加入0.02g(0.18mmol)DMAP(4-二甲氨基吡啶)和0.37g(1.81mmol)DCC(N,N'-二环己基碳二亚胺)在室温下继续反应，TLC跟踪，20h后停止。减压除去溶剂，柱层析提纯(洗脱液CH2Cl2)。得黄色固体D1 0.23g，收率：22.1％。
+ESI MS(M+Na):C45H60N2O5，计算值：708.4502，实测值：708.4352。
1H NMR(400MHz,CDCl3)δ8.61(dd,J＝7.3,1.1Hz,1H),8.56(d,J＝8.1Hz,1H),8.46(dd,J＝8.5,1.1Hz,1H),7.73(dd,J＝8.4,7.3Hz,1H),7.25(d,J＝8.1Hz,1H),5.38(d,J＝5.1Hz,1H),4.93(d,J＝5.9Hz,2H),4.73(tt,J＝10.5,5.3Hz,1H),4.06–4.02(m,4H),3.32–3.27(m,4H),2.46–2.33(m,2H),2.05–1.92(m,3H),1.90–1.80(m,2H),1.71–1.62(m,3H),1.58–1.41(m,6H),1.38–1.31(m,3H),1.27(s,2H),1.18–1.08(m,6H),1.02(s,4H),0.92(d,J＝6.5Hz,3H),0.88(dd,J＝6.6,1.7Hz,6H),0.69(d,J＝4.4Hz,3H).
13C NMR(126MHz,CDCl3)δ167.59(s),164.05(s),163.53(s),155.97(s),139.51(s),132.89(s),131.50(s),130.47(s),130.08(s),126.00(d,J＝43.6Hz),122.81(d,J＝13.4Hz),116.62(s),114.94(s),75.32(s),66.95(s),56.68(s),56.13(s),53.45(s),49.98(s),42.31(s),41.53(s),39.62(d,J＝26.0Hz),37.99(s),36.93(s),36.56(s),36.19(s),35.79(s),31.87(d,J＝7.7Hz),29.71(s),28.23(s),28.01(s),27.72(s),24.28(s),23.83(s),22.70(d,J＝32.3Hz),21.03(s),19.32(s),18.72(s),11.86(s).
化合物D1属于液晶分子，在60.8-156.7℃时出现液晶相如图1所示：
实施例2
N-(胆甾醇乙酸酯基)-4-吡咯烷基-1,8-萘酰亚胺(D2)的合成
(1)4-吡咯烷基-1.8-萘酐(中间体3)的合成：
除用0.90mL(11.0mmol)吡咯烷代替吗啉外，其它操作同实施例1中间体1的合成，得中间体3，黄色固体，产率90.8％。熔点：220.4-222.3℃。
(2)N-(2’-羧基乙基)-4-吡咯烷基-1,8-萘酰亚胺(中间体4)的合成：
除用中间体3代替实施例1中间体1，其它操作同实施例1中间体2，得黄色固体，产率：71.7％。
(3)终产物N-(胆甾醇乙酸酯基)-4-吡咯烷基-1,8-萘酰亚胺(D2)的合成：
除用中间体4代替中间体2外，其它操作同实施例1D1的合成，得目标化合物D2，黄色固体，产率：30.4％。
+ESI MS(M+H):C45H60N2O4，计算值：692.4553，实测值：692.4625。
1H NMR(400MHz,CDCl3)δ8.64–8.55(m,2H),8.43(d,J＝8.6Hz,1H),7.53(t,J＝7.9Hz,1H),6.81(d,J＝8.6Hz,1H),5.36(s,1H),4.91(s,2H),4.76–4.66(m,1H),3.79(s,4H),2.36(d,J＝13.0Hz,2H),2.11(s,4H),2.03–1.91(m,3H),1.85(d,J＝13.8Hz,2H),1.58(s,6H),1.29(d,J＝25.8Hz,8H),1.10(d,J＝7.0Hz,6H),1.01(s,4H),0.91(d,J＝6.3Hz,3H),0.86(d,J＝6.1Hz,6H),0.67(s,3H).
13C NMR(126MHz,CDCl3)δ167.96(s),164.57(s),163.58(s),152.89(s),139.62(s),133.76(s),132.33(s),131.42(d,J＝13.2Hz),122.97(s),122.62(d,J＝10.6Hz),122.04(s),110.01(s),108.50(s),75.13(s),56.69(s),56.13(s),53.20(s),49.99(s),42.31(s),41.49(s),39.73(s),39.52(s),38.00(s),36.95(s),36.57(s),36.19(s),35.79(s),31.87(d,J＝7.3Hz),28.23(s),28.01(s),27.72(s),26.08(s),24.28(s),23.83(s),22.82(s),22.57(s),21.03(s),19.32(s),18.72(s),11.85(s).
化合物D2属于液晶分子，如图2在120.1-149.8℃时具有液晶相。
应用例1：体外抗肿瘤活性抑制实验
本章实验选用HepG2(人肝癌细胞)、Hela(人宫颈癌细胞)、MCF-7(人乳腺癌细胞)、A549(人肺癌细胞)和RAW264.7(小鼠单核巨噬细胞)五种细胞对目标化合物D1-D2进行测试，其中RAW264.7是正常细胞，做阳性对照。采用MTT法计算相应的IC50值。
表2化合物D1-2对HepG2，Hela，MCF-7，A549和RAW264.7细胞株的IC50值
Tab.2 The values of IC50of compounds D1-2against HepG2,Hela,MCF-7,A549and RAW264.7
如上表所示，化合物D1、D2对四种癌细胞均表现出良好的抗肿瘤效果。二者均对乳腺癌细胞株MCF-7表现出最高抑制活性，IC50值接近，分别是18.44μΜ和17.58μΜ。在所有细胞株中，D1对正常细胞RAW264.7的细胞毒性均低于其它癌细胞株，特别是RAW264.7的IC50值是MCF-7的2倍，HepG2，Hela，A549的IC50值分别是MCF-7的1.7倍，1.9倍，1.4倍，具有较好的选择性。而D2对正常细胞RAW264.7的细胞毒性却高于HepG2和Hela。
Claims (3)
1.一类抗癌含胆甾醇的萘酰亚胺类衍生物，其特征在于该化合物具有通式D的化学结构式:
通式D中:
R选自N位取代的吗啉基、N位取代的吡咯烷基。
2.如权利要求1所述的含胆甾醇的萘酰亚胺类衍生物的制备方法，以4-溴-1,8萘酐为起始原料，与环胺经溴代反应得到4-R-1,8-萘酐中间体，再与甘氨酸通过氨基缩合反应得到中间体N-(2’-羧基亚甲基)-4-R-1,8-萘酰亚胺，最后与胆甾醇通过二环己基碳二亚胺脱水酯化法发生酯化反应生成含胆甾醇的萘酰亚胺类衍生物的目标化合物；
所述环胺选自吗啉、吡咯烷。
3.如权利要求1所述的含胆甾醇的萘酰亚胺类衍生物在制备抑制癌细胞药物中的应用；当R选自N位取代的吗啉基时，所述的癌细胞为人肝癌细胞HepG2、人宫颈癌细胞Hela、人乳腺癌细胞MCF-7、人肺癌细胞A549；当R选自N位取代的吡咯烷基时，所述的癌细胞为人乳腺癌细胞MCF-7、人肺癌细胞A549。
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