CN106167490B - 一类含吲哚的咪唑并萘酰亚胺类衍生物及其合成和应用 - Google Patents
一类含吲哚的咪唑并萘酰亚胺类衍生物及其合成和应用 Download PDFInfo
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Abstract
本发明公开了一类含吲哚的咪唑并萘酰亚胺类衍生物、其制备方法及应用,属于生物有机合成领域。本发明结构在萘酰亚胺上引入有抗癌活性的吲哚药效团,以增加共轭面积,提高分子的生物学活性,从而增加抗肿瘤效果。本发明所述的含吲哚的咪唑并萘酰亚胺类衍生物制备方法,是以4‑溴‑1,8‑萘酐为原料,通过硝化,还原等步骤合成中间体3,4‑二氨基‑1,8‑萘酐,之后与吲哚‑3‑甲醛发生缩合反应,得到中间体9‑(3’‑1H‑吲哚‑基)咪唑并萘酰亚胺,再引入不同的侧链基团,在制备抑制肿瘤细胞药物中具有重要的应用。
Description
技术领域
本发明涉及生物有机合成领域中的一类含吲哚的咪唑并萘酰亚胺类衍生物的合成及应用。
背景技术
DNA作为生命遗传最基本的物质,已经成为众多抗肿瘤药物的首选靶点。DNA靶向药物的发展已经成为大势所趋。DNA嵌入剂可以嵌入DNA碱基对中,改变其构象,导致DNA链解旋增长,改变DNA复制过程,表现出显著的抗肿瘤活性。萘酰亚胺是一种具有三环平面结构的芳香族杂环化合物,最早由Brana团队报道可作为DNA嵌入剂。该类嵌入剂的典型代表是氨萘非特(Amonafide)和米托萘胺(Mitonafide),临床表现出高效抗肿瘤活性,据报道它们的作用机制为:嵌入DNA碱基对之间并且抑制DNA拓扑异构酶II的活性,引起DNA链断裂。在萘酰亚胺母体上并入具有抗肿瘤生物活性的芳香环,既可以增大分子的共轭面积,增强其嵌入DNA碱基对之间的能力,又可以通过引入并入体系的功能性芳香环改变整个分子的静电性或者电荷分布,从而影响分子的选择性和抗肿瘤活性。吲哚类衍生物是一种常见的酪氨酸及酶抑制剂,其中舒尼替尼、SU6668已经进入临床研究,许多新型的吲哚类抗肿瘤酶抑制剂也纷纷被设计合成。因此,将萘酰亚胺与吲哚类小分子组合在同一个分子上设计合成新的具有耐药性的DNA靶向抗肿瘤药物是非常具有意义的。
发明内容
本发明提供一类含吲哚的咪唑并萘酰亚胺类衍生物的合成及应用。目的是在萘酰亚胺上引入有抗癌活性的吲哚药效团,以增加共轭面积,提高分子的生物学活性,从而增加抗肿瘤效果。
本发明解决上述技术问题所采用的技术方案是:一类含吲哚的咪唑并萘酰亚胺类衍生物,其化学分子结构通式如下:
通式A中:
R”为‐NH(CH2)7CH3、‐NHCH2CH3、
本发明提供上述的含吲哚的咪唑并萘酰亚胺类衍生物的制备方法,是以4-溴-1,8-萘酐为原料,通过硝化,还原步骤合成中间体3,4-二氨基-1,8-萘酐,之后与吲哚-3-甲醛发生缩合反应,得到中间体9-(3’-1H-吲哚-基)咪唑并萘酰亚胺,之后再加入R引入不同的侧链基团,R选自N,N-二甲基乙二胺、N,N-二乙基乙二胺、正丙醇胺、N,N-二甲基丙二胺、正辛胺、乙胺、苯胺、1,4-二氨基-苯胺。
进一步地,在上述技术方案中,以4-溴-1,8-萘酐为原料,在浓硫酸中,加入硝酸钠冰浴条件下硝化反应3小时,再加入叠氮化钠发生叠氮取代反应,用无水氯化亚锡溶解在浓盐酸中做还原剂,78℃反应2.5小时还原硝基,得到中间体3,4-二氨基-1,8-萘酐,取3,4-二氨基-1,8-萘酐和吲哚-3-甲醛摩尔比1~1.1:1.2反应DMF作为溶剂,以碳酸氢钠作催化剂在100℃下反应3小时,得中间体9-(3’-1H-吲哚-基)咪唑并萘酰亚胺,加入R引入不同的侧链基团,R选自N,N-二甲基乙二胺、N,N-二乙基乙二胺、正丙醇胺、N,N-二甲基丙二胺、正辛胺、乙胺、苯胺、1,4-二氨基-苯得到权利要求1所述化合物。
上述的含吲哚的咪唑并萘酰亚胺类衍生物的合成路线如下:
本发明提供上述的含吲哚的咪唑并萘酰亚胺类衍生物在抑制肿瘤细胞药物中的应用。
进一步地,在上述技术方案中,所述的肿瘤为乳腺癌MCF-7细胞、人体胃癌BCG-823细胞。
用上述合成的含吲哚的咪唑并萘酰亚胺类衍生物用MTT还原法对乳腺癌MCF-7细胞、人宫胃癌BGC-823细胞和肝细胞HL7702进行体外抑制肿瘤细胞生长活性的测定,结果表明,该类化合物对胃癌、乳腺癌等癌细胞具有抑制生长的效果。
用四氮唑盐还原法对乳腺癌MCF-7细胞、人宫颈癌Hela细胞和肝细胞HL7702以4000-5000个/孔接种于96孔培养板内,培养12-16h后加入梯度浓度药液100μL/孔,对每个肿瘤细胞株,设置6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5mg/mL的MTT液继续培养4h后,加入DMSO溶解结晶,然后用酶标仪测OD570值,利用寇式改良法计算被测物对癌细胞生长的IC50值。
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
(1)中间体3-硝基-4-溴-1,8-萘酐的合成:
冰浴条件下,取100mL双颈圆底烧瓶加入98%浓硫酸24mL,缓慢搅拌,分批少量加入5.54g(20mmol)4-溴-1,8-萘酐,使之溶解在浓硫酸中,接着分批少量加入2g硝酸钠,在冰浴条件下反应3小时,之后撤去冰浴,室温反应1小时,将混合物倒入200mL冰水中,析出大量的淡黄色沉淀,过滤,洗涤,真空干燥,得到产物4.84g,产率75.00%。
(2)中间体3-硝基-4-叠氮-1,8-萘酐的合成:
取100mL双颈圆底烧瓶,加入50mlDMF,搅拌状态下分批少量加入4.83g(15mmol)3-硝基-4-溴-1,8-萘酐。称取1.5g叠氮化钠,溶解在3mL水中,之后用滴管将溶液缓缓滴入反应体系中,室温反应3小时后,将混合液倒入冰水中,析出大量的红褐色沉淀,得到粗产物4g,产率93.89%。
(3)中间体3,4-二氨基-1,8-萘酐的合成:
取10g无水氯化亚锡溶解在15mL浓盐酸中(先加入浓盐酸,后缓缓加入无水氯化亚锡),之后分批少量加入3.2g(11.3mmol)3-硝基-4-叠氮-1,8-萘酐,过程中产生大量泡,可加入2-3mL乙醇帮助搅拌,全部加完之后加入10mL乙醇,升温至78℃反应2.5小时,TLC跟踪至反应结束,冷却到室温,直接抽滤得到橙红色固体2.4g,产率93.15%。
(4)中间体9-(3’-1H-吲哚-基)咪唑并萘酰亚胺的合成:
取2g(8.8mmol)3,4-二氨基-1,8-萘酐,1.45g(10mmol)吲哚-3-甲醛置于100mL双颈圆底烧瓶中,加入30mL DMF作为溶剂,加入催化剂量的碳酸氢钠,在100℃下反应3小时,TLC跟踪至原料点消失,停止反应,冷却到室温,析出红色沉淀,直接抽滤,真空干燥得到2.4g粗产物,产率77.68%。
(5)终产物Z1N-(N’,N’-二甲基胺基乙基)-9-(3’-1H-吲哚-基)咪唑并萘酰亚胺的合成:
50mL双颈圆底烧瓶中加入0.36g(1mmol)2-(3’-1H-吲哚-基)咪唑并萘酰亚胺,0.095mL(1mmol)N’N-二甲基乙二胺,15mL乙醇,搅拌,升温回流3小时,TLC跟踪至原料点消失,停止反应,冷却至室温,倒入50mL冰水中,析出橙红色沉淀,柱层析提纯(洗脱剂:CH2Cl2:MeOH=4:1),得到产物0.23g,产率54.71%。熔点:300.8-301.5℃。
+ESI MS(M+H):C25H21N5O2,计算值:423.4665,实测值:423.1760。
1H NMR(400MHz,DMSO)δ11.83(d,J=26.2Hz,1H),8.96(d,J=7.6Hz,1H),8.62(d,J=34.1Hz,2H),8.50–8.23(m,2H),7.89(t,J=7.7Hz,1H),7.60–7.46(m,1H),7.26(s,2H),4.19(t,J=6.5Hz,2H),2.75–2.55(m,2H),2.30(s,6H).
13C NMR(126MHz,DMSO)δ163.79,163.65,136.58,128.04,127.33,126.16,125.11,124.36,122.47,122.16,121.40,120.66,112.09,105.90,56.38,55.99,45.10,37.30,18.52.
实施例2
终产物Z2N-(N’,N’-二乙基胺基乙基)-9-(3’-1H-吲哚-基)咪唑并萘酰亚胺的合成:
用0.14mL(1mmol)N’N-二乙基乙二胺代替0.095mL(1mmol)N’N-二甲基乙二胺,洗脱剂改为CH2Cl2:MeOH=5:1,其余合成过程同上,得到产物0.25g,产率55.43%。熔点:274.9-275.6℃。
+ESI MS(M+H):C27H25N5O2,计算值:451.5197,实测值:451.2080。
1H NMR(400MHz,DMSO)δ11.86(s,1H),8.95(d,J=8.0Hz,1H),8.61(d,J=44.5Hz,2H),8.45–8.27(m,2H),7.86(t,J=7.7Hz,1H),7.62–7.46(m,1H),7.25(d,J=2.8Hz,2H),4.12(s,2H),2.96(d,J=6.9Hz,2H),1.13(t,J=7.2Hz,4H),1.01(dt,J=13.5,6.9Hz,6H).
13C NMR(126MHz,DMSO)δ163.74,163.60,136.59,128.05,127.39,126.09,125.15,124.31,122.43,122.17,121.44,120.61,112.07,105.94,49.08,46.90,45.48,11.59,8.86.
实施例3
终产物Z3N-(3’-羟基-丙基)-9-(3’-1H-吲哚-基)咪唑并萘酰亚胺的合成:
用0.075mL(1mmol)正丙醇胺代替0.095mL(1mmol)N’N-二甲基乙二胺,甲醇重结晶,其余合成过程同上,得到产物0.20g,产率48.87%。熔点:364.5-365.2℃。
+ESI MS(M+H):C24H18N4O3,计算值:410.4247,实测值:410.1451。
1H NMR(400MHz,DMSO)δ11.95(s,1H),9.02(s,1H),8.66(s,3H),8.41(d,J=7.1Hz,1H),7.86(t,J=7.7Hz,1H),7.55(dd,J=6.3,2.6Hz,1H),7.27(dd,J=5.8,3.1Hz,2H),4.56(s,1H),4.21–4.01(m,2H),3.52(d,J=4.2Hz,2H),1.91–1.72(m,2H).
13C NMR(126MHz,DMSO)δ163.88,163.78,136.59,128.09,127.75,126.11,125.18,124.38,122.37,122.31,121.46,120.55,112.07,105.95,59.02,37.49,31.15.
实施例4
终产物Z4N-(N’,N’-二甲基胺基丙基)-9-(3’-1H-吲哚-基)咪唑并萘酰亚胺的合成:
用0.085mL(1mmol)N’N-二甲基丙二胺代替0.095mL(1mmol)N’N-二甲基乙二胺,洗脱剂改为CH2Cl2:MeOH=4:1,其余合成过程同上,得到产物0.22g,产率50.34%。熔点:303.4-304.8℃。
+ESI MS(M+H):C26H23N5O2,计算值:437.4931,实测值:437.1916。
1H NMR(400MHz,DMSO)δ11.91(s,1H),9.04(s,1H),8.67(s,2H),8.45(d,J=7.2Hz,2H),7.98–7.86(m,1H),7.66–7.48(m,1H),7.28(dd,J=5.9,3.1Hz,2H),4.12(t,J=7.2Hz,2H),2.92(q,J=7.1Hz,6H),2.60(t,J=7.0Hz,2H),1.97–1.78(m,2H).
13C NMR(126MHz,DMSO)δ146.98,136.08,127.35,127.17,126.91,125.71,124.65,123.86,122.25,121.93,121.68,120.36,110.19,55.99,18.52,15.31.
实施例5
为了检测目标化合物的潜在抗肿瘤活性,本实验采用MTT比色法进行了体外抗肿瘤活性测试。MTT全称为3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,是一种黄颜色的染料。MTT比色法是一种检测活细胞存活和生长的方法,它的检测原理是存在于活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为非水溶性的蓝紫色结晶甲瓒(Formazan)并且沉积在细胞中,而死细胞无此功能。二甲基亚砜(DMSO)能溶解细胞中沉积的甲瓒,用酶联免疫检测仪在490nm、625nm波长处测定其光吸收值,可间接地反映活细胞数量。在一定细胞数范围内,甲瓒的沉积量与细胞的数目是成正比的。目前该方法已广泛用于一些生物活性因子的活性检测、大规模的抗肿瘤药物筛选、细胞毒性试验以及肿瘤放射敏感性测定等。
本实验选用人体乳腺癌细胞MCF-7,人体胃癌细胞BCG-823和人体肝脏细胞HL7702三种细胞株进行体外抗肿瘤活性的测试。实验步骤如下:
(1)接种细胞从液氮中取出相应细胞株的冻存管,对细胞株进行细胞复苏,之后加入培养液培养并且传代,待到细胞生长到对数期之后,用培养液稀释细胞悬浮液,取无菌96孔板接种细胞,内60个孔内每孔加入100μL细胞悬浮液,约5000个细胞。外围36个加入PBS缓冲液。之后将96孔板置于37℃,5%CO2条件的恒温培养箱中培养12-16小时,保证细胞贴壁生长。
(2)加药取母液浓度为1×10-3mol/L的化合物溶液(溶剂为DMSO)稀释成四个梯度浓度,分别为100μM、50μM、25μM、12.5μM,每孔加入100μL药物(由于孔中原有100μL培养液,故而实际作用的药物浓度是说配置药物浓度的一半),每个药物浓度设置6个复孔以减小误差。最外侧设置空白对照空,只加入100μL培养液。加药结束之后将96孔板置于37℃,5%CO2条件的恒温培养箱中培养24小时。
(3)MTT还原MTT粉末用PBS配制为5mg/mL的溶液,在避光条件下,每孔加入20μLMTT溶液,置于培养箱中作用4小时,之后用移液枪小心地吸出上清液,每孔加入150μLDMSO溶解甲瓒结晶。将处理好的96孔板置于水平摇床震荡10分钟,在酶联免疫检测仪测定490nm、570nm、625nm下各个孔的吸光值。
(4)IC50计算目标化合物对于细胞生长的IC50值是指细胞被抑制一半时抑制剂的浓度,其计算采用寇式改良公式:lgIC50=Xm-I[P-(3-Pm-Pn)/4],其中Xm=lg(最大浓度),I=lg(最大浓度/相邻浓度),P=抑制率之和,Pm=最大抑制率,Pn=最小抑制率。
化合物Z1-Z4对MCF-7,BGC-823癌细胞和肝细胞HL7702的IC50值
化合物Z1-Z4对于两种肿瘤细胞都表现出明显的抗肿瘤效果,而且相较于MCF-7,对于胃癌细胞BGC-823的抑制作用更加明显,具有更好的选择性。针对MCF-7,化合物Z2(含有N,N-二乙基氨基乙基侧链)表现出最佳的抗肿瘤活性(IC50=23.74μM),其余三者的抑制作用大小为Z3>Z4>Z1。针对BGC-823,可明显看出该系列化合物对于此细胞株有较好的选择性。其中Z2抑制效果最为明显(IC50=8.20μM),这一点与化合物对于MCF-7的抑制效果类似。其余三种化合物也具有非常好的抑制效果,其大小分别为Z1>Z4>Z3。针对细胞HL7702,化合物Z3表现出最小毒性,其IC50值为48.67μM。
Claims (5)
1.一类含吲哚的咪唑并萘酰亚胺类衍生物,其特征在于其具有通式A结构的化合物:
通式A中:
R”选自
2.如权利要求1所述的含吲哚的咪唑并萘酰亚胺类衍生物的制备方法,是以4-溴-1,8-萘酐为原料,通过硝化,还原步骤合成中间体3,4-二氨基-1,8-萘酐,之后与吲哚-3-甲醛发生缩合反应,得到中间体9-(3’-1H-吲哚-基)咪唑并萘酐,之后再加入R引入不同的侧链基团,R选自N,N-二甲基乙二胺、N,N-二乙基乙二胺、正丙醇胺、N,N-二甲基丙二胺。
3.根据权利要求2所述的含吲哚的咪唑并萘酰亚胺类衍生物的制备方法,其特征在于:以4-溴-1,8-萘酐为原料,在浓硫酸中,加入硝酸钠冰浴条件下硝化反应3小时,再加入叠氮化钠发生叠氮取代反应,用无水氯化亚锡溶解在浓盐酸中做还原剂,78℃反应2.5小时还原硝基,得到中间体3,4-二氨基-1,8-萘酐,取3,4-二氨基-1,8-萘酐和吲哚-3-甲醛摩尔比1~1.1:1.2反应DMF作为溶剂,以碳酸氢钠作催化剂在100℃下反应3小时,得中间体9-(3’-1H-吲哚-基)咪唑并萘酐,加入R引入不同的侧链基团,R选自N,N-二甲基乙二胺、N,N-二乙基乙二胺、正丙醇胺、N,N-二甲基丙二胺得到权利要求1所述化合物。
4.如权利要求1所述的含吲哚的咪唑并萘酰亚胺类衍生物在制备抑制肿瘤细胞药物中的应用。
5.根据权利要求4所述的应用,其特征在于所述的肿瘤为乳腺癌MCF-7细胞、人体胃癌BCG-823细胞。
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