CN101671278B - 氨基甲酸紫草素酯及其制备方法和用途 - Google Patents
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Abstract
本发明公开了一种氨基甲酸紫草素酯及其制备方法和用途。它是1摩尔紫草素和1~2摩尔的异氰酸酯在甲苯中反应,反应温度为80~100℃,反应时间为10~15小时,柱层析分离得到氨基甲酸紫草素酯。氨基甲酸紫草素酯用于制备具有抗肿瘤活性以及耐药性的药物。本发明通过简单易行的方法制备氨基甲酸紫草素酯,并对氨基甲酸紫草素酯进行抗肿瘤活性和耐药性进行考察,发现其对肿瘤细胞株具有强烈的抑制作用,并证明具有很好的耐药性,是具有前途的抗肿瘤药物。
Description
技术领域
本发明涉及化合物及其制备方法,尤其涉及一种氨基甲酸紫草素酯及其制备方法和用途。
背景技术
5,8-二氢萘醌类化合物已被美国国家癌症研究所确定为具有抗肿瘤活性的物质,紫草素(SH)是该类化合物的典型代表。紫草素具有广泛的生物活性包括:抗菌、抗艾滋病、促进烧伤伤口愈合、抗肿瘤等,备受研究者的关注。近年来对对紫草素的研究主要关注于以下的方面:紫草素的新药效研究,紫草素的全合成和对紫草素改性衍生化等研究。
本身抗肿瘤活性较弱且水溶性不佳等因素使得紫草素不能成为很好的抗肿瘤药物,为此很多研究者对紫草素进行了修饰,合成了多类紫草素衍生物。研究表明5,8-二氢萘醌结构是紫草素抗肿瘤活性的关键,因此绝大部分的紫草衍生物都是1’-位羟基进行修饰的,这类衍生物比紫草素本身具有更好的抗肿瘤活性,如1’-O-乙酰紫草素,1’-O-呋喃甲酰紫草素,1’-O-异戊酰紫草素,侧链氮原子取代的紫草素类似物。
1.V.P.Papageorgiou,A.N.Assimopoulou,E.A.Couladouros,D.Hepworth,K.C.Nicolaou.Angew.Chem.Int.Ed.1999,38,270.
2.W.J.Wang,J.Y.Bai,D.P.Liu,L M..Xue,X.Y.Zhu.Yaoxue Xuebao,1994,29,161
3.Q.Lu,W.J.Liu,J.Ding,J.C.Cai,W.H.Duan.Bioorg.Med.Chem Lett.2002,12,1375.
4.F.Yang,Y.Chen,W.H.Duan,C.Zhang,H.Zhu,J.Ding.Int.J.Cancer.2006,119,1184.
为了寻找更好活性的紫草素衍生物,我们设计了紫草素乙酰糖的衍生物,我们发现这一类化合物比紫草素具有更好的抗肿瘤活性,同时具备良好的耐药性,并未见有文献报道。
发明内容
本发明的目的是克服现有技术的不足,提供一种氨基甲酸紫草素酯及其制备方法和用途。
氨基甲酸紫草素酯的通式如下:
其中R=含有取代基团的直连烷烃或芳香基。
所述的氨基甲酸紫草素酯为:
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-苯基氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-甲基苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-甲基苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-环己基氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-氯苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N(2-氯乙基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-溴苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-甲氧基苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-乙酰基苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(2-O-乙酰基乙基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-硝基苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-氟苯基)氨基甲酸酯或
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(三氯乙酰基)氨基甲酸酯。
氨基甲酸紫草素酯的制备方法是:1摩尔紫草素和1~2摩尔的异氰酸酯在甲苯中反应,反应温度为80~100℃,反应时间为10~15小时,柱层析分离得到氨基甲酸紫草素酯。
氨基甲酸紫草素酯用于制备具有抗肿瘤活性以及耐药性的药物。
本发明通过简单易行的方法制备氨基甲酸紫草素酯,并对氨基甲酸紫草素酯进行抗肿瘤活性和耐药性进行考察,发现其对肿瘤细胞株具有强烈的抑制作用,并证明具有很好的耐药性,是具有前途的抗肿瘤药物。
具体实施方式
本发明氨基甲酸紫草素酯的通式如下:
其中R=含有取代基团的直连烷烃或芳香基,优选化合物如下:
本发明的反应式如下:
本发明制备的氨基甲酸紫草素酯在细胞毒实验中发现对肿瘤细胞株具有强烈的抑制作用,并证明具有很好的耐药性,是具有前途的抗肿瘤药物。
抗肿瘤活性测定:
K562细胞使用添加10%胎牛血清的RPMI-1640培养液,K562/ADR细胞使用添加10%胎牛血清和1ug/mL阿霉素的RPMI-1640培养液,培养于含5%CO2的饱和湿度37℃恒温培养箱中。所有的化合物用DMSO溶解制成浓度为20mM的储备液,使用前用新鲜培养基稀释成相应的浓度。3000/孔的MCF-7和K562和K562/ADR的种板密度分别为8000和3000/孔,种板后直接用化合物处理。恒温箱中培养72小时后,每孔加20uL的5mg/mL的MTT(过滤除菌,遮光,4℃保存),37℃孵育4小时后,倾倒培养板内液体,每孔加入150uLDMSO,以溶解MTT形成的蓝紫色甲簪结晶,在570nm波长下用酶标仪检测吸光度值,计算不同化合物对各细胞的生长抑制率。
表1氨基甲酸紫草素酯细胞毒性
编号 | K562 | K562/Adr | Ratio |
Ar-sh | 4.91 | 4.92 | 1.002037 |
MT-sh | 3.76 | 4.8 | 1.276596 |
PT-sh | 4.9 | 4.86 | 0.991837 |
Hex-sh | 1.55 | 2.72 | 1.754839 |
3Chlo-sh | 2.1 | 2.16 | 1.028571 |
ChlEt-sh | 2.64 | 2.67 | 1.011364 |
3Brom-sh | 4 | 2.7 | 0.675 |
4Ome-sh | 4.32 | 2.8 | 0.648148 |
3Acp-sh | 2.43 | 3.68 | 1.514403 |
EtAc-sh | 3 | >5(~5) | |
4Flu-sh | 4.47 | 4.77 | 1.067114 |
Trichl-sh | 1.55 | 1.58 | 1.019355 |
实施例1
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-苯基氨基甲酸酯(Ar-sh)0.288g(1mmol)紫草素和异氰酸苯酯0.119g(1mmol)溶于10mL甲苯中,在80℃下反应15小时,蒸除溶剂,残余物柱层析分离,得到0.28g(69%)具有如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.60(s,1H),12.41(s,1H),7.37(d,J=8.0Hz,2H),7.31(m,2H),7.16(s,2H),7.06(m,2H),6.84(s,1H),6.03(m,1H),5.17(1H),2.66(m,1H),2.49(m,1H),1.70(s,3H),1.59(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ177.7,176.2,167.6,167.1,152.0,148.2,137.2,135.9,132.8,132.6,131.2,129.0,123.7,118.5,117.6,111.7,111.5,70.4,32.8,25.6,17.9ppm;
实施例2
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-甲基苯基)氨基甲酸酯(Mt-sh)
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-苯基氨基甲酸酯(Ar-sh)0.288g(1mmol)紫草素和异氰酸-3-甲基苯酯0.266g(2mmol)溶于10mL甲苯中,在100℃下反应10小时,蒸除溶剂,残余物柱层析分离,得到0.28g(69%)具有如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.61(s,1H),12.4(s,1H),7.18(m,5H),7.05(s,1H),6.90(m,1H),6.74(s,1H),6.03(m,1H),5.18(m,1H),2.68(m,1H),2.53(m,1H),2.32(s,3H),1.71(s,3H),1.60(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ177.4,175.9,167.2,166.7,151.7,147.9,138.6,136.8,135.6,132.4,132.3,130.8,128.4,124.1,118.8,117.3,115.2,111.4,111.1,70.0,32.5,25.3,21.0,17.5ppm;
实施例3
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-甲基苯基)氨基甲酸酯(Pt-sh)
操作同实施例1
1H NMR(400MHz,CDCl3):δ12.59(s,1H),12.42(s,1H),7.25(m,2H),7.16(m,2H),7.08(m,3H),6.80(s,1H),6.03(m,1H),5.17(m,1H),2.65(m,1H),2.52(m,1H),2.29(s,3H),1.69(s,3H),1.59(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ178.1,176.6,167.5,167.0,152.2,148.5,136.0,134.7,133.4,132.8,132.7,131.3,129.6,118.6,117.8,111.8,111.6,70.4,33.0,25.8,20.7,18.0ppm;
实施例4
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-环己基氨基甲酸酯(Hex-sh)操作同实施例1
1H NMR(400MHz,CDCl3):δ12.59(s,1H),12.45(s,1H),7.18(s,2H),6.98(s,1H),5.93(m,1H),5.13(m,1H),4.72(d,J=8Hz,1H),3.44(t,J=4Hz,1H),2.63(m,1H),2.46(m,1H),1.94(m,2H),1.69(m,5H),1.56(m,4H),1.31(m,2H),1.17(m,3H)ppm;
13C NMR(100MHz,CDCl3):δ178.9,177.4,165.9,165.4,153.8,148.9,135.2,131.9,131.8,131.2,117.5,111.4,111.1,69.2,49.6,32.9,32.5,25.3,24.9,24.3,17.5ppm;
实施例5
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-氯苯基)氨基甲酸酯(3Chl-sh)
操作同实施例1
1H NMR(400MHz,CDCl3):δ12.59(s,1H),12.41(s,1H),750(s,1H),7.17(m,4H),7.02(m,2H),6.91(s,1H),6.03(m,1H),5.16(m,1H),2.65(m,1H),2.53(m,1H),1.70(s,3H),1.59(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ177.1,175.6,168.4,167.9,151.9,147.9,138.5,136.2,134.8,133.2,133.0,131.1,130.0,123.8,118.7,117.6,116.5,111.8,111.6,70.8,32.9,25.8,18.0ppm;
实施例6
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N(2-氯乙基)氨基甲酸酯(Chlet-sh)
操作同实施例1
1H NMR(400MHz,CDCl3):δ12.58(s,1H),12.43(s,1H),7.18(s,2H),7.00(s,1H),5.96(dd,J=4.86.4Hz,1H),5.29(m,1H),5.13(t,J=7.2Hz,1H),3.63(m,2H),3.53(m,2H),2.61(m,1H),2.48(m,1H),1.69(s,3H),1.57(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ178.4,176.9,167.2,166.6,155.0,148.6,136.0,132.7,132.6,131.4,117.7,111.8,111.5,70.3,43.9,42.8,32.9,25.7,17.9ppm;
实施例7
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-溴苯基)氨基甲酸酯(3Brom-sh)
操作同实施例1
1H NMR(400MHz,CDCl3):δ12.59(s,1H),12.41(s,1H),7.40(m,2H),7.28(m,2H),7.17(s,2H),7.04(s,1H),6.87(s,1H),6.03(m,1H),5.16(m,1H),2.67(m,1H),2.50(m,1H),1.69(s,3H),1.59(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ177.2,175.6,168.3,167.8,152.0,147.9,136.5,136.2,133.1,132.9,131.9,131.9,131.1,120.0,117.6,117.5,116.3,111.8,111.5,70.7,32.9,25.7,18.0ppm;
实施例8
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-甲氧基苯基)氨基甲酸酯(4OMe-sh)
操作同实施例1
1H NMR(400MHz,CDCl3):δ12.60(s,1H),12.43(s,1H),7.29(m,2H),717(s,2H),7.05(s,1H),6.85(m,2H),6.71(s,1H),6.02(m,1H),5.17(m,1H),3.77(s,3H),2.66(m,1H),2.53(m,1H),1.70(s,3H),1.59(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ178.2,176.6,167.5,166.9,148.5,136.0,132.8,132.7,131.4,130.4,120.5,117.8,114.2,114.2,111.8,111.6,70.4,55.5,32.9,25.8,18.0ppm;
实施例9
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-乙酰基苯基)氨基甲酸酯(3Acp-sh)
操作同实施例1
1H NMR(400MHz,CDCl3):δ12.60(s,1H),12.41(s,1H),7.97(m,1H),7.64(m,2H),7.42(m,1H),7.17(m,3H),7.06(s,1H),6.05(m,1H),5.17(m,1H),2.66(m,1H),2.60(s,3H),2.53(m,1H),1.69(s,3H),1.59(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ197.8,177.4,175.9,168.1,167.6,152.2,148.0,138.0,137.8,136.2,133.1,132.9,131.2,129.4,123.6,123.0,118.1,117.6,111.8,111.6,70.7,32.9,26.7,25.8,18.0ppm;
实施例10
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(2-O-乙酰基乙基)氨基甲酸酯(Etac-sh)
操作同实施例1
1H NMR(400MHz,CDCl3):δ12.56(s,1H),12.42(s,1H),7.16(s,2H),7.01(s,1H),5.92(m,1H),5.40(t,J=5.2Hz,1H),5.13(t,J=6.8Hz,1H),4.22(m,2H),3.94(m,2H),2.60(m,1H),2.48(m,1H),1.68(s,3H),1.56(s,3H),1.27(t,J=7.2Hz,3H)ppm;
13C NMR(100MHz,CDCl3):δ178.6,177.1,169.7,167.0,166.5,155.0,148.7,135.9,132.7,132.5,131.5,117.7,111.8,111.6,70.5,61.6,42.8,32.9,25.7,17.9,14.1ppm;
实施例11
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-氟苯基)氨基甲酸酯(4Flu-sh)
操作同实施例1
1H NMR(400MHz,CDCl3):δ12.60(s,1H),12.42(s,1H),7.33(m,2H),7.17(s,2H),7.01(m,3H),6.81(s,1H),6.03(m,1H),5.16(m,1H),2.65(m,1H),2.52(m,1H),1.70(s,3H),1.59(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ177.6,176.1,167.9,167.4,152.3,148.2,136.1,133.3,133.0,132.9,131.2,120.4,117.6,115.8,115.6,111.8,111.6,70.6,32.9,25.8,18.0ppm;
实施例12
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(三氯乙酰基)氨基甲酸酯(Trichl-sh)
操作同实施例1
1H NMR(400MHz,CDCl3):δ12.57(s,1H),12.44(s,1H),8.52(s,1H),7.17(m,2H),7.14(s,1H),6.15(m,1H),5.13(t,J=7.2Hz,1H),2.70(m,1H),2.60(m,1H),1.69(s,3H),1.59(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ175.5,173.8,169.8,169.4,157.5,149.0,145.6,137.0,133.8,133.6,131.4,116.7,111.7,111.6,91.6,73.0,32.7,25.8,17.9ppm;
Claims (1)
1.一种氨基甲酸紫草素酯的制备方法,其特征在于1摩尔紫草素和1~2摩尔的异氰酸酯在甲苯中反应,反应温度为80~100℃,反应时间为10~15小时,柱层析分离得到氨基甲酸紫草素酯;所述的氨基甲酸紫草素酯为:
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-苯基氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-甲基苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-甲基苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-氯苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N(2-氯乙基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-溴苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-甲氧基苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(3-乙酰基苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(2-O-乙酰基乙基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-硝基苯基)氨基甲酸酯、
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(4-氟苯基)氨基甲酸酯或
1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊烯基-N-(三氯乙酰基)氨基甲酸酯。
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DE2831786A1 (de) * | 1978-07-19 | 1980-02-07 | Papageorgiou Vassilios | P-dihydroxynaphtochinonderivate und verfahren zu ihrer herstellung |
CN1112363A (zh) * | 1993-07-14 | 1995-11-22 | 安丙浚 | 制备5,8-二氢萘醌衍生物的方法,新的5,8-二氢萘醌衍生物和它们作为抗癌药的用途 |
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DE2831786A1 (de) * | 1978-07-19 | 1980-02-07 | Papageorgiou Vassilios | P-dihydroxynaphtochinonderivate und verfahren zu ihrer herstellung |
CN1112363A (zh) * | 1993-07-14 | 1995-11-22 | 安丙浚 | 制备5,8-二氢萘醌衍生物的方法,新的5,8-二氢萘醌衍生物和它们作为抗癌药的用途 |
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Vassilios P. Papageorgiou et al.The chemistry and biology of alkannin,shikonin,and related naphthazarin natural products.《Angewandte Chemie International Edition》.1999,第38卷(第3期),270-300. * |
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