CN102206203B - 含有苯并咪唑的萘酰亚胺衍生物的合成及其在抗肿瘤上的应用 - Google Patents
含有苯并咪唑的萘酰亚胺衍生物的合成及其在抗肿瘤上的应用 Download PDFInfo
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Abstract
本发明涉及一类含有苯并咪唑的萘酰亚胺衍生物的合成及其在抗肿瘤方面的应用,属于有机合成及药物化学技术领域。所述的衍生物是在萘酰亚胺的萘环4位连接上苯并咪唑基团后获得的。该类萘酰亚胺衍生物对肿瘤细胞的增殖抑制实验是选用四氮唑盐还原法,针对MCF-7人乳腺癌细胞、Hela人宫颈癌细胞、PC12大鼠肾上腺髓质嗜铬瘤分化细胞进行的。结果表明,该类萘酰亚胺衍生物对肿瘤细胞具有良好的抑制活性和选择性。
Description
技术领域
本发明涉及一种4-(1H-苯并咪唑-2-y1)-1,8-萘酰亚胺类化合物的合成及在肿瘤细胞中的应用,属于有机合成和药物化学技术领域。
背景技术
萘酰亚胺是良好的DNA嵌入剂母体,是近几年来研究的热点。其中最著名的已进行临床应用的衍生物是amonafide(N-(β-二甲基氨基乙基)-3-胺基-1,8-萘酰亚胺)和mitonafide(N-(β-二甲基氨基乙基)-3-硝基-1,8-萘酰亚胺),但因为其神经毒副作用没有进入临床III期。为了改善毒副作用和提高抗肿瘤活性,对萘酰亚胺活性位点进行改造合成新型萘酰亚胺衍生物层出不穷。国外Brana研究组报道了一系列咪唑并萘酰亚胺衍生物,这类衍生物对人结肠癌细胞(HT-29)和人子宫癌(Hela)的抑制活性比amonafide有了稍微地提高(BranaM F,CachoM,Garcia M A,et al.J.Med.Chem.,2002,45,5813-5816)。国内对萘酰亚胺也做了诸多修饰并取得良好的抗肿瘤效果,例如:在2,3位并入各种功能性含硫芳香杂环,其IC50比amonafide低很多,可达到nm数量级(Li Z G,Yang Q,Qian X H.Bioorg.Med.Chem.Lett.15,2005,1769-1772)。
在萘酰亚胺母体上以单键连接芳香杂环化合物的研究比较少,我们研究组对萘酰亚胺3位、4位分别引入苯基三唑芳香环,其抗肿瘤活性较amonafide高,说明对萘酰亚胺以单键连接芳香杂环的改造将有助于发掘出高效、低毒、高选择性的抗肿瘤先导化合物,推动药物化学和生命科学的发展。
发明内容
本发明是以单键连接苯并咪唑到萘酰亚胺的4位,药效团苯并咪唑可以改善萘酰亚胺的药理活性,提高其肿瘤细胞增殖抑制效果。
本发明的技术方案是:含有苯并咪唑的萘酰亚胺衍生物具有以下的化学分子结构通式:
式中:R为
其中:R1、R2同为甲基或乙基,R1+R2为哌嗪环、吗啉环、甲基哌嗪环或硫代吗啉环,R3、R4为H、CF3或NO2,n=2~4。
这类萘酰亚胺衍生物的合成方法,是以苊为原料,经过vilsmeier反应使苊的四位带上醛基,此中间体与邻苯二胺在DMF溶剂中,氮气保护下,100℃加热2hr,得到一中间体,该中间体在冰醋酸溶剂中,与重铬酸钠通过氧化反应得到萘酐中间体,萘酐中间体与R1NH2在乙醇中回流3个小时,得到所述的萘酰亚胺类衍生物。
该类衍生物对肿瘤细胞体外抑制生长活性实验采用四氮唑盐(microculture tetrozolium,MTT)还原法对MCF-7人乳腺癌细胞、Hela人宫颈癌细胞、PC12大鼠肾上腺髓质嗜铬瘤分化细胞进行体外抗肿瘤活性测试。将所述的萘酰亚胺类衍生物用细胞培养液配制成不同浓度的药液,用MCF-7人乳腺癌细胞、Hela人宫颈癌细胞、PC12大鼠肾上腺髓质嗜铬瘤分化细胞进行体外抗肿瘤活性测试。方法是:取处于对数生长期1/3-1/2的细胞,消化后反复吹打成悬浮状。通过细胞计数法确定细胞密度,按所需密度接种于96孔板细胞培养板中,每孔200μL。在37℃、5%CO2的细胞培养箱中温育24h后,加入不同浓度梯度的药物,终浓度从10-8到10-5M,每个浓度均为6个复孔。另设无细胞调零孔、如果药物有颜色要做相应药物浓度无细胞调零孔。继续培养48小时,使药物与细胞充分作用。每孔加入MTT溶液(5mg/ml)20μl,孵育3-4小时后,小心吸尽培养基。每孔加入200μL DMSO,振荡10分钟,使紫色结晶物完全溶解。用酶标仪上测定波长为570nm处的OD值,按下列公式计算被测物对癌细胞生长的抑制率:肿瘤抑制率=(对照组OD值一治疗组OD值)/对照组OD值×100%。
所述含有苯并咪唑的萘酰亚胺衍生物分别为N-(N‘N’-二甲基氨基乙基)-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物1)、N-(N‘N’-二乙基氨基乙基)-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物2)、N-丁基-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物3)、N-(N‘N’-二甲基氨基丙基)-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物4)、N-(2’-哌嗪基乙基)-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物5)、N-(3-三氟甲基苯基)-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物6)。这类萘酰亚胺衍生物的合成路线如下:
本发明的有益效果为:在萘酰亚胺母体环4-位,以单键连接苯并咪唑药效团,并引入多种类型的侧链基团,得到一类新型的萘酰亚胺类衍生物。该类衍生物的体外抗肿瘤活性测试,选用四氮唑盐还原法,针对MCF-7人乳腺癌细胞、Hela人宫颈癌细胞、PC12神经瘤细胞进行。测试结果表明,该类衍生物具有良好的肿瘤抑制活性和细胞选择性。
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-丁基-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物3)的合成
(1)1,2-二氢苊烯-5-羰醛(2)的合成
零度冰水浴中,向100mL干燥的双口瓶中加入10mL(1.3mol)无水DMF(氢化钙处理),磁力搅拌下,用恒压滴液漏斗向反应体系中缓慢滴加10mL(1.0mol)POC13,撤掉冰水浴,常温反应1hr,将4.0g(26.0mmol)苊溶于15mL无水DMF中,滴加到反应体系内,滴加完毕后升温至100℃,继续反应8hr,TLC跟踪至反应完全。冷却至室温,剧烈搅拌下缓慢倒入200mL冰水中,析出灰色沉淀,过滤,干燥,得灰色针状固体4.2g,产率:88.9%。产物较纯,可直接用于下面合成。
(2)2-(1,2-二氢苊烯-5-y1)-1H-苯并[d]咪唑(3)
将4.0g(22.0mmol)化合物(2)和2.4g(22.2mmol)邻苯二胺溶于20mLDMF中,磁力搅拌,加入3.4g(28.8mmol)亚硫酸氢钠,氮气保护,100℃加热2hr,反应体系冷却至室温后倒入冷水中,静置,析出灰褐色沉淀3.1g,产率:67.4%。
(3)4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酐(4)
在50mL双口瓶中,加入化合物(3)3.0g(11.1mmol),二水合重铬酸钠7.6g(25.5mmol)和20mL冰醋酸,回流下磁力搅拌3hr后,冷却,反应液倒入冰水中,析出大量黄色沉淀,静置,过滤、干燥,得2.5g目标化合物,产率:71.7%。
(4)N-丁基-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物3)
在25mL双口瓶中,加入0.1g(0.31mmol)化合物(4),正丁胺57μL(0.57mmol),乙醇溶剂10mL,磁力搅拌下加热回流3hr,TLC跟踪至反应完全,倒入水中,静置一夜,得深绿色沉淀,热石油醚洗涤两次,水洗涤两次,除去残余的正丁胺,干燥,得深绿色出产品0.1g,粗产率:89.0%。硅胶柱层析分离(柱层析洗脱液为:CH2Cl2∶CH3OH=80∶1)得黄绿色固体M1。熔点:104.1-104.9℃.
HR-MS(m/z):C23H19N3O2,计算值:369.1477,实测值:369.1482。
1HNMR(d6-DMSO,400MHz):δ(ppm):13.22(s,1H),8.74(d,J=8.2Hz,1H),8.62(d,J=8.0Hz,1H),8.56(d,J=7.2Hz,1H),8.35(d,J=7.6Hz,1H),7.99(dd,J1=7.6Hz,J2=8.0Hz,1H),7.84(d,J=7.6Hz,1H),7.64(d,J=7.6Hz,1H),7.33(m,2H),4.06(t,J=8.0Hz,2H),1.65(m,2H),1.37(m,2H),0.94(t,J=7.2Hz,3H).
实施例2
N-(N‘,N’-二甲基氨基乙基)-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物1)
除用N,N-二甲基乙二胺代替正丁胺,其它制备及提纯方法与实例1相同。经硅胶柱层析分离(柱层析洗脱液为:CH2Cl2∶CH3OH=20∶1)得化合物M1,为黄色固体,产率:88.9%。熔点:93.2-93.8℃。
HR-MS(m/z):C23H20N4O2,计算值:384.1586,实测值:384.1588。
1HNMR(d6-DMSO,400MHz):δ(ppm):13.35(s,1H),8.76(d,J=8.8Hz,1H),8.63(d,J=7.6Hz,1H),8.58(d,J=6.8Hz,1H),8.37(d,J=7.6Hz,1H),8.00(dd,J1=6.0Hz,J2=5.6Hz,1H),7.74(m,2H),7.33(m,2H),4.19(t,J=7.2Hz,2H),2.60(t,J=7.2Hz,2H),2.27(s,3H).
实施例3
N-(N‘N’-二乙基氨基乙基)-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物2)
除用N,N-二乙基乙二胺替代正丁胺外,其它合成及提纯方法同实例1,经硅胶柱分离(柱层析洗脱液为CH2Cl2∶CH3OH=20∶1)得到目标化合物M2,黄绿色固体,产率81.7%,熔点:149.9-150.6℃。
HR-MS(m/z):C25H24N4O2,计算值:412.1899,实测值:412.1895。
1HNMR(d6-DMSO,400MHz):δ(ppm):13.22(s,1H),9.75(d,J=8.0Hz,1H),8.63(d,J=8.0Hz,1H),8.58(d,J=8.0Hz,1H),8.37(d,J=7.6Hz,1H),7.99(dd,J1=J2=8.0Hz,1H),7.84(d,J=7.6Hz,1H),7.66(d,J=7.6Hz,1H),7.32(m,2H),4.16(t,J=8.0Hz,2H),2.73(t,J=8.0Hz,2H),2.60(m,4H),0.99(s,6H).
实施例4
N-(N‘N’-二甲基氨基丙基)-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物4)
除用N,N-二甲基丙二胺替代正丁胺外,其它合成及提纯方法同实例1,经硅胶柱分离(柱层析洗脱液为CH2Cl2∶CH3OH=9∶1)得到目标化合物M4,黄绿色固体,产率70.6%,熔点:176.7-177.1℃。
HR-MS(m/z):C23H19N3O2,计算值:398.1743,实测值:398.1742。
1HNMR(d6-DMSO,400MHz):δ(ppm):13.50(s,1H),9.77(d,J=7.8Hz,1H),9.63(d,J=6.4Hz,1H),8.56(d,J=6.4Hz,1H),8.41(d,J=6.8Hz,1H),8.00(t,J1=6.2Hz,J2=7.2Hz,1H),7.82(d,J=6.8Hz,1H),7.67(d,J=6.8Hz,1H),7.32(m,2H),4.13(t,J=8.0Hz,2H),2.94(t,J=8.0Hz,2H),2.57(s,6H),2.02(m,2H)
实施例5
N-(2’-哌嗪基乙基)-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物5)
除用1-(2-氨基乙基)哌嗪替代正丁胺外,其它合成及提纯方法同实例1,经硅胶柱分离(柱层析洗脱液为CH2Cl2∶CH3OH=7∶1)得到目标化合物M5,黄绿色固体,产率69.1%,熔点:186.8-188.0℃。
HR-MS(m/z):C23H23N3O2,计算值:425.1852,实测值:425.1844。
1HNMR(d6-DMSO,400MHz):δ(ppm):1HNMR(d6-DMSO,400MHz):δ(ppm):9.76(d,J=7.8Hz,1H),8.64(d,J=6.4Hz,1H),8.59(d,J=6.4Hz,1H),8.38(d,J=6.8Hz,1H),8.00(t,J1=J2=7.2Hz,1H),7.75(d,J=6.8Hz,2H),7.31(d,J=6.8Hz,2H),7.32(m,2H),4.20(t,J=8.0Hz,2H),2.72(m,4H),2.56(t,2H),2.46(m,4H)
实施例6
N-(3-三氟甲基苯基)-4-(1H-苯并[d]咪唑-2-y1)-1,8-萘酰亚胺(衍生物6)
除用间三氟甲基苯胺替代正丁胺外,其它合成及提纯方法同实例1,经硅胶柱分离(柱层析洗脱液为CH2Cl2∶CH3OH=100∶1)得到目标化合物S4,深黄色固体,产率89.3%,熔点:293.0-294.1℃。
HR-MS(m/z):C26H14N3O2F3,计算值:457.1038,实测值:457.1043。
1HNMR(d6-DMSO,400MHz):δ(ppm):13.38(s,1H),9.81(d,J=8.0Hz,1H),8.67(d,J=8.0Hz,1H),8.62(d,J=6.8Hz,1H),8.41(d,J=7.6Hz,1H),8.50(t,J1=J2=8.0Hz,1H),7.94(d,J=7.6Hz,1H),7.87(d,J=4.4Hz,1H),7.81(m,2H),7.70(m,2H)7.35(m,2H).
实施例7
测定衍生物的体外抑制肿瘤细胞生长活性:
用四氮唑盐(microculture tetrozolium,MTT)还原法对MCF-7人乳腺癌细胞、Hela人宫颈癌细胞、PC12大鼠肾上腺髓质嗜铬瘤分化细胞进行体外抑制肿瘤细胞生长活性测定。四氮唑盐(MTT)还原法的具体操作是:取处于对数生长期1/3-1/2的细胞,胰酶消化后反复吹打成悬浮状。通过细胞计数法确定细胞密度,按所需密度接种于96孔板细胞培养板中,每孔200μL。在37℃、5%CO2的细胞培养箱中温育24h后,加入不同浓度梯度的药物,终浓度从10-8到10-5M,每个浓度均为6个复孔。另设无细胞调零孔、如果药物有颜色要做相应药物浓度无细胞调零孔。继续培养48h,使药物与细胞充分作用。每孔加入MTT溶液(5mg/ml)20μl,孵育3-4h后,小心吸尽培养基。每孔加入200μL DMSO,振荡10分钟,使紫色结晶物完全溶解。用酶标仪上测定波长为570nm处的OD值,按下列公式计算被测物对癌细胞生长的抑制率:
肿瘤抑制率=(对照组OD值治疗组OD值)/对照组OD值×100%
从列表数据中可以看出,这6个新型萘内酰胺衍生物除带正丁胺侧链的都对这三种细胞表现出良好的抗肿瘤活性,尤其是衍生物1、2、5,其IC50可部分达到10-7M。它们在10-5浓度下对肿瘤细胞生长的抑制率大多可大于90%。这种新型衍生物对MCF-7、Hela细胞的抗肿瘤活性要明显高于PC12。
表一 衍生物对MCF-7人乳腺癌细胞生长的抑制率%
表二 衍生物对Hela人宫颈癌细胞生长的抑制率%
表三 衍生物对PC12大鼠肾上腺髓质嗜铬瘤分化细胞生长的抑制率%
Claims (1)
1.一类含有苯并咪唑的萘酰亚胺衍生物,其特征是:结构式依次如下所示:
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