吲哚马来酰亚胺类蛋白激酶C抑制剂的合成及其抗肿瘤活性的研究
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摘要
通过对星型孢菌素进行结构改造而得到的一系列吲哚马来酰亚胺类化合物是一类新型蛋白激酶C抑制剂。本文首先总结和概述了近年来吲哚马来酰亚胺类化合物的在结构修饰、合成和生物活性等方面取得的研究进展。介绍了吲哚马来酰亚胺类化合物的合成方法,并讨论了各种合成方法的优缺点。在本课题组前期研究工作的基础上,我们根据吲哚马来酰亚胺类化合物与蛋白激酶C的作用模型,进行化合物的设计、合成与抗肿瘤活性研究,本论文工作主要包括以下方面:
1)我们以琥珀酰亚胺为起始原料,经溴化、碘甲烷甲基化,并在镁粉和溴乙烷作用下与吲哚发生加成反应等步骤分别合成了3-溴-4-吲哚马来酰亚胺类化合物和3-溴-4-吲哚-N-甲基马来酰亚胺类化合物,并研究了其与各种氨基醇、胺和氰化亚铜的反应,制备了3-氨基-4-吲哚马来酰亚胺和3-氰基-4-吲哚马来酰亚胺类化合物。
2)较为系统的研究了3-溴-4-吲哚马来酰亚胺和3-溴-4-吲哚-N-甲基马来酰亚胺与胺类化合物的亲核取代反应,得到了3-氨基醇取代的吲哚马来酰亚胺和3-氨基醇-N-烷基取代的吲哚马来酰亚胺类化合物,发现了区域选择性开环反应,并对其反应机理进行了讨论。研究了双吲哚马来酰亚胺与水合肼的开环反应,得到了1-氨基双吲哚马来酰亚胺类化合物,而未获得双吲哚哒嗪类化合物。
3)在乙酸乙酯和丙酮(1:1)的混合溶剂中进行单晶培养,获得了3-二甲胺基-4-吲哚马来酰亚胺和3-(2-羟乙基胺基)-4-吲哚-N-(2-羟乙基)马来酰亚胺类的单晶,前者为单斜晶系,后者为三斜晶系,通过分子间氢键相互作用形成三维空间结构,对单晶结构进行了解析。
4)通过实验我们合成出了3-氨基醇、3-胺基、3-氰基等取代的吲哚马来酰亚胺类和3-氨基醇-N-烷基取代的吲哚马来酰亚胺类及双吲哚马来酰亚胺类共12个目标化合物,并通过质谱、核磁共振氢谱以及红外光谱确证其结构,其中11个为未见文献报道的新化合物。
5)采用MTT法对本文所合成的化合物的抗肿瘤活性进行了研究。测定了7个目标化合物在体外对人宫颈癌Hela细胞株的杀伤作用,药理研究表明:目标化合物在10μM浓度下,对人宫颈癌Hela细胞株均有不同程度的抑制作用。目标化合物对其它肿瘤细胞株如白血病K562等的抑制作用和进一步的抗肿瘤活性和作用机理研究正在进行之中。
Indolylmaleimides,derived from staurosporine,is a specific class of protein kinase C inhibitors.The structure modification,synthesis and biological activity of indolylmaleimide derivatives have been reviewed in this paper.The synthetic routes are also introduced,both merits and limitations of the synthetic methods have been discussed.
Recently,our research group is interested in the synthesis and development of indolylmaleimide derivatives as anticancer agents.In our continued research program directed toward the synthesis of novel indolylmaleimide derivatives in this area.A series of novel 3-amino-4-indolylmaleimides have been designed and synthesized.This thesis includes the following part:
1) 2-Bromo-3-(1H-indol-3-y1)-N-methylmaleimide as the key intermediate could be easily synthesized from succinimide by bromination with bromine,methylation with methyl idodide and the adduction of indole with 2,3-dibromo-N-methyl-maleimide in the presence of magnesium and ethyl bromide in 35%overyield for three steps.2-Bromo-3-(1H-indol-3-y1)maleimide was obtained from the 2,3-bromomaleimide by the adduction of indole with 2,3-dibromo-N-methylmaleimide in the presence of magnesium and ethyl bromide in 49%all yield for two steps.With the 2,3-dibromo-N-methylmaleimide and 2-Bromo-3-(1H-indol-3-y1)maleimide in hand, it was treated with different amines in DMF to give 3-amino-4-indolylmaleimides and 3-amino-4-indolyl-N-methylmaleimides as red crystal.3-Cyano-4-indolylmaleimides were obtained by treating 3-bromo-4-indolylmaleimides with copper cyanide.
2) 2,3-Dibromo-4-indolyl-N-methylmaleimide,2,3-dibromo-4-indolylmaleimide bisindolylmaleimide,prepared by the reaction of indole with 3,4-dibromo-N-methyl-maleimide in the presence of magnesium and ethyl bromide,were used as the substrate. They were subjeced to the regioselective amination with substituted amines to provide 3-aminoindolylmaleimides,3-amino-N-alkylated indolylmaleimides and N-alkylated bisindolylmaleimides in good yields.Based on the experimental results,a plausible mechanism can be proposed.The resulting indolylmaleimides represent a new class of potentially bioactive compounds.
3) Two single crystals for 3-(dimethylamino)-4-indolylmaleimides and 3-(2-hydroxyethylamino)-N-(2-hydroxyethyl)-4-indolylmaleimide were obtained by dissolving the compounds in ethyl acetate and ethanol(1:1),and evaporating the solvent slowly at room temperature.X-Ray single crystals were solved by direct methods with SHELX-97.They are monoclinic and triclinic,respectively.
4) Totally,twelve compounds were synthezied in this paper.Eleven of them were not reported in the literature.Their structures have been confirmed by IR,~1H-NMR and MS.
5) The cytotoxicities of these compounds were evaluated against various cancer cell lines by standard MTT assay in vitro.The pharmacological results showed that some of the compounds displayed moderate or high cytotoxic activity against the tested cell lines.Structure-activity relationships are discussed based on the experimental data obtained.A hydroxyalkylamino group at 3-position in the side chain of indolylmaleimide is associated with an increase in cytotoxicity.
1)我们以琥珀酰亚胺为起始原料,经溴化、碘甲烷甲基化,并在镁粉和溴乙烷作用下与吲哚发生加成反应等步骤分别合成了3-溴-4-吲哚马来酰亚胺类化合物和3-溴-4-吲哚-N-甲基马来酰亚胺类化合物,并研究了其与各种氨基醇、胺和氰化亚铜的反应,制备了3-氨基-4-吲哚马来酰亚胺和3-氰基-4-吲哚马来酰亚胺类化合物。
2)较为系统的研究了3-溴-4-吲哚马来酰亚胺和3-溴-4-吲哚-N-甲基马来酰亚胺与胺类化合物的亲核取代反应,得到了3-氨基醇取代的吲哚马来酰亚胺和3-氨基醇-N-烷基取代的吲哚马来酰亚胺类化合物,发现了区域选择性开环反应,并对其反应机理进行了讨论。研究了双吲哚马来酰亚胺与水合肼的开环反应,得到了1-氨基双吲哚马来酰亚胺类化合物,而未获得双吲哚哒嗪类化合物。
3)在乙酸乙酯和丙酮(1:1)的混合溶剂中进行单晶培养,获得了3-二甲胺基-4-吲哚马来酰亚胺和3-(2-羟乙基胺基)-4-吲哚-N-(2-羟乙基)马来酰亚胺类的单晶,前者为单斜晶系,后者为三斜晶系,通过分子间氢键相互作用形成三维空间结构,对单晶结构进行了解析。
4)通过实验我们合成出了3-氨基醇、3-胺基、3-氰基等取代的吲哚马来酰亚胺类和3-氨基醇-N-烷基取代的吲哚马来酰亚胺类及双吲哚马来酰亚胺类共12个目标化合物,并通过质谱、核磁共振氢谱以及红外光谱确证其结构,其中11个为未见文献报道的新化合物。
5)采用MTT法对本文所合成的化合物的抗肿瘤活性进行了研究。测定了7个目标化合物在体外对人宫颈癌Hela细胞株的杀伤作用,药理研究表明:目标化合物在10μM浓度下,对人宫颈癌Hela细胞株均有不同程度的抑制作用。目标化合物对其它肿瘤细胞株如白血病K562等的抑制作用和进一步的抗肿瘤活性和作用机理研究正在进行之中。
Indolylmaleimides,derived from staurosporine,is a specific class of protein kinase C inhibitors.The structure modification,synthesis and biological activity of indolylmaleimide derivatives have been reviewed in this paper.The synthetic routes are also introduced,both merits and limitations of the synthetic methods have been discussed.
Recently,our research group is interested in the synthesis and development of indolylmaleimide derivatives as anticancer agents.In our continued research program directed toward the synthesis of novel indolylmaleimide derivatives in this area.A series of novel 3-amino-4-indolylmaleimides have been designed and synthesized.This thesis includes the following part:
1) 2-Bromo-3-(1H-indol-3-y1)-N-methylmaleimide as the key intermediate could be easily synthesized from succinimide by bromination with bromine,methylation with methyl idodide and the adduction of indole with 2,3-dibromo-N-methyl-maleimide in the presence of magnesium and ethyl bromide in 35%overyield for three steps.2-Bromo-3-(1H-indol-3-y1)maleimide was obtained from the 2,3-bromomaleimide by the adduction of indole with 2,3-dibromo-N-methylmaleimide in the presence of magnesium and ethyl bromide in 49%all yield for two steps.With the 2,3-dibromo-N-methylmaleimide and 2-Bromo-3-(1H-indol-3-y1)maleimide in hand, it was treated with different amines in DMF to give 3-amino-4-indolylmaleimides and 3-amino-4-indolyl-N-methylmaleimides as red crystal.3-Cyano-4-indolylmaleimides were obtained by treating 3-bromo-4-indolylmaleimides with copper cyanide.
2) 2,3-Dibromo-4-indolyl-N-methylmaleimide,2,3-dibromo-4-indolylmaleimide bisindolylmaleimide,prepared by the reaction of indole with 3,4-dibromo-N-methyl-maleimide in the presence of magnesium and ethyl bromide,were used as the substrate. They were subjeced to the regioselective amination with substituted amines to provide 3-aminoindolylmaleimides,3-amino-N-alkylated indolylmaleimides and N-alkylated bisindolylmaleimides in good yields.Based on the experimental results,a plausible mechanism can be proposed.The resulting indolylmaleimides represent a new class of potentially bioactive compounds.
3) Two single crystals for 3-(dimethylamino)-4-indolylmaleimides and 3-(2-hydroxyethylamino)-N-(2-hydroxyethyl)-4-indolylmaleimide were obtained by dissolving the compounds in ethyl acetate and ethanol(1:1),and evaporating the solvent slowly at room temperature.X-Ray single crystals were solved by direct methods with SHELX-97.They are monoclinic and triclinic,respectively.
4) Totally,twelve compounds were synthezied in this paper.Eleven of them were not reported in the literature.Their structures have been confirmed by IR,~1H-NMR and MS.
5) The cytotoxicities of these compounds were evaluated against various cancer cell lines by standard MTT assay in vitro.The pharmacological results showed that some of the compounds displayed moderate or high cytotoxic activity against the tested cell lines.Structure-activity relationships are discussed based on the experimental data obtained.A hydroxyalkylamino group at 3-position in the side chain of indolylmaleimide is associated with an increase in cytotoxicity.
引文
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