新型拓扑异构酶抑制剂的发现、优化设计和生物活性评价
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摘要
DNA拓扑异构酶(Topoisomerase, Top)是真核细胞体内必需酶,主要功能是负责解决DNA拓扑结构问题,广泛参与DNA复制、转录、重组和染色体组装和分离等生命活动。Top分为Topl和Top2,它们通过DNA切断和连接,维持DNA正常拓扑结构和代谢过程。由于Top在DNA代谢过程的重要作用,干扰Top的催化活性或者诱导产生Top介导的DNA损伤已经成为抗肿瘤治疗的重要策略。Top被誉为最重要抗肿瘤药物靶点之一,临床上有近50%的治疗方法要依赖于使用一种或几种Top抑制剂。
本论文以开发新型Top抑制剂为主要研究方向,以基于结构的虚拟筛选为手段,着重进行全新结构Top1和Top2抑制剂的发现、优化设计和抗肿瘤机制研究。
一、新型Top1抑制剂的虚拟筛选和生物活性研究
通过基于分子对接的虚拟筛选从Specs库中筛选得到23个化合物,14个化合物具有Top1抑制活性,其中化合物A1酶抑制活性与喜树碱相当。体外抗肿瘤活性测试结果表明,A1、A14、A20、A21和A23表现出中等以上的抗肿瘤活性,其中A1活性最好,IC50值为0.50-43μM。化合物A1和A20(吴茱萸碱)适合作为先导化合物进行进一步优化研究。
二、新型吴茱萸碱衍生物的设计、合成和抗肿瘤作用机制研究
吴茱萸碱是从传统中药吴茱萸中提取分离得到的一种生物碱,前期研究发现它具有Top1抑制活性和体外抗肿瘤活性,是一个理想的抗肿瘤先导化合物。本研究设计合成了51个全新结构的吴茱萸碱衍生物,发现大部分化合物体外抗肿瘤活性得到明显提高,部分化合物(B4、B5、B38和B39)GI50值小于3nM。细胞凋亡实验显示,高活性化合物(B4、B38、B39、B41和B45)能够诱导A549肿瘤细胞凋亡,使细胞停滞在G2/M期。机制研究和分子模拟表明吴茱萸碱衍生物为Top1和Top2双重抑制剂。体内小鼠移植瘤实验显示,10-羟基吴茱萸碱(B38)和3-氨基-10-羟基吴茱萸碱(B45)在1mg/kg和2mg/kg剂量下抑瘤率分别为44.43%和52.71%,并表现出低毒性和高耐受性的特点,有希望作为候选药物进行开发。
三、4-取代蒽并[1,2-c][1,2,5]噻二唑-6,11-二酮的设计、合成和抗肿瘤活性研究
化合物4-(对甲苯磺酰基)蒽并[1,2-c][1,2,5]噻二唑-6,11-二酮(A1)是前期虚拟筛选发现的新型Topl抑制剂。本研究设计合成54个4-取代蒽并[1,2-c][1,2,5]噻二唑-6,11-二酮衍生物,从结构上分为两类：4-含硫侧链衍生物和4-含氮侧链衍生物。前者因其溶解性差,体外抗肿瘤活性表现不佳,仅有部分化合物(D14和D15)表现出较好的肿瘤生长抑制活性；后者在溶解性和体外抗肿瘤活性上均有较大提高,其中化合物E1、E6和E19表现出与喜树碱相当的体外抗肿瘤活性。
四、新型Top2抑制剂的虚拟筛选和生物活性研究
研究发现Top2催化性抑制剂毒性较低,并有望克服肿瘤耐药性,而ATPase抑制剂是一类非常重要的Top2催化性抑制剂。本研究通过虚拟筛选,以ATPase为作用位点,筛选得到37个化合物。研究发现,19个化合物具有Top2抑制活性,其中化合物F2、F8、F15、F17、F26和F27对Top2抑制活性强于依托泊苷。体外抗肿瘤活性实验显示,化合物F8对肺癌肿瘤株抑制活性明显超过依托泊苷,F20对三个肿瘤株的抑制活性均超过依托泊苷。机制研究表明,高活性化合物F8和F20能微弱的稳定Top2-DNA复合物。分子对接研究预示两者能够很好结合于ATPase活性腔,为ATPase抑制剂。综上所述,F8和F20适合作为先导化合物进行进一步优化研究。
综上所述,本研究对抗肿瘤重要药靶Topl和Top2开展了虚拟筛选研究,成功发现多类全新结构的抑制剂(活性化合物的命中率分别为60.9%和51.4%)。在此基础上开展了优化设计研究,设计合成得到了105个新化合物,从中发现多个高活性化合物在分子、细胞和动物水平显示了优秀抗肿瘤活性。首次采用现代药物设计技术对我国传统有效成分吴茱萸碱进行了靶标发现和结构创新,发现吴茱萸碱衍生物是Topl/Top2双重抑制剂,深入探讨了该类化合物作用机制,并获得了高效、低毒和广谱的吴茱萸碱类抗肿瘤新化学实体,为开发具有自主知识产权的抗肿瘤原创药物奠定了基础。
DNA topoisomerases (Tops) are essential enzymes that regulate the cellular processes such as replication, transcription, recombination, chromatin and chromosomal segregation by altering DNA topology. DNA Tops can be classified into two types, topoisomerase Ⅰ (Top1) and topoisomerase Ⅱ (Top2). They catalyze the breakage and religation of DNA, maintaining the topological changes of DNA and various DNA metabolic processes. Due to their important role in DNA metabolism, the ability to interfere with the functions of Tops or generating Top-mediated DNA damage is an effective strategy for cancer chemotherapy. Tops have been considered as the most important targets for tumor chemotherapy. Clinically, approximately50%of the chemotherapy regimens contain at least one Top inhibitor.
The present dissertation aims to identify novel Top inhibitors as antitumor agents. A series of novel Top1and Top2inhibitors were identified by structure-based virtual screening. The structure-activity relationships, antitumor activity and mechanism of action of evodiamine derivatives and4-substituted anthra[2,1-c][1,2,5]thiadiazole-6,11-dione analogs were investigated, which led to the discovery of highly potent antitumor agents.
1. Discovery and biological evaluation of novel topoisomerase I inhibitors by structure-based virtual screening
Structure-based virtual screening was applied to the discovery of structurally diverse Top1inhibitors. From23compounds selected by virtual screening from the Specs database, a total of14compounds were found to be topoisomerase I inhibitors. Five hits (compounds Al, A14, A20, A21, and A23) also showed moderate to good in vitro antitumor activity. Compound Al showed excellent cytotoxicity with IC50values in the range of0.5-25μM. Compounds Al and A20(evodiamine) were considered as good starting points for the development of new antitumor lead compounds.
2. Design, synthesis and antitumor mechanism of novel evodiamine derivatives
Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, evodiamine was identified as potent topoisomerase I inhibitor by structure-based virtual screening and showed moderate in vitro antitumor activity. It was also considered as a new antitumor lead compound. Herein,51novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives (B4, B5, B38and B39) showed substantial increase of the antitumor activity, with GI50values lower than3nM. Moreover, these highly potent compounds (B4, B38, B39, B41and B45) can effectively induce the apoptosis and G2/M arrest of A549cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases Ⅰ and Ⅱ. Moreover, several hydroxyl derivatives, such as10-hydroxyl evodiamine (B38) and3-amino-10-hydroxyl evodiamine (B45), also showed good in vivo antitumor efficacy with low toxicity and good tolerance. At the dose of1mg/kg or2mg/kg, B38and B45reduced44.43%and52.71%tumor growth, respectively. They represent promising candidates for the development of novel antitumor agents.
3.4-Substituted anthra[2,1-c][1,2,5]thiadiazole-6,11-dione derivatives: design, synthesis and antitumor potency.
Previously,4-tosylanthra[1,2-c][1,2,5]thiadiazole-6,11-dione (Al) was identified as potent topoisomerase I inhibitor by structure-based virtual screening and showed good antitumor activity in vitro. Based on the structure of Al,54novel analogs were designed and synthesized, which can be classed into two types,4-thio and4-amine substituted derivatives. The former series exhibited weak antitumor activity because of their poor solubility. Only few compounds (D14and D15) showed moderate to good in vitro antitumor activity. The latter series were proved to have stronger antitumor activity with better solubility. Three compounds (El, E6and E19) showed high cytotoxicity similar to that of camptothecin.
4. Discovery and biological evaluation of novel topoisomerase Ⅱ inhibitors by structure-based virtual screening
Top2catalytic inhibitors have the advantages of modulating the cytotoxic effects of topoisomerase II poisons and overcoming the multidrug resistance (MDR). ATP binding site (ATPase) binders represent an important class of Top2catalytic inhibitors. On the basis of the crystal structures of ATPase, docking-based virtual screening was applied to the discover novel Top2inhibitors. From37compounds selected by virtual screening, a total of19compounds were found to be Top2inhibitors. Six hits (compounds F2, F8, F15, F17, F26and F27) were more active than etoposide at the concentration of100μM. In particular, compound F8exhibited better antitumor activity than etoposide in A549cancer cells. Compound F20showed good antitumor activity against all the three cancer cells. The biological assay indicated that compounds F8and F20could stabilize the Top2-DNA cleaved complex slightly. Molecular docking predicted that compounds F8and F20might bind at the ATP binding site. They were considered as good starting points for the development of new antitumor lead compounds targeting Top2.
In summary, structure-based virtual screening were successfully used to discover novel Top1and Top2inhibitors with a hit rate of60.9%and51.4%, respectively. On the basis of the identified lead compounds, a total of105new derivatives were designed and synthesized. Among them, several highly active antitumor compounds were identified which showed excellent activity at molecular, cellular and in vivo level. Target identification and structural optimization of traditional Chinese medicine evodiamine were performed for the first time using the modern drug design techonologies. Evodiamine derivatives were proved to be dual Top1/Top2inhibitors and several of them showed excellent antitumor potency with low toxicity, which provided basis for the development of novel antitumor agents.
本论文以开发新型Top抑制剂为主要研究方向,以基于结构的虚拟筛选为手段,着重进行全新结构Top1和Top2抑制剂的发现、优化设计和抗肿瘤机制研究。
一、新型Top1抑制剂的虚拟筛选和生物活性研究
通过基于分子对接的虚拟筛选从Specs库中筛选得到23个化合物,14个化合物具有Top1抑制活性,其中化合物A1酶抑制活性与喜树碱相当。体外抗肿瘤活性测试结果表明,A1、A14、A20、A21和A23表现出中等以上的抗肿瘤活性,其中A1活性最好,IC50值为0.50-43μM。化合物A1和A20(吴茱萸碱)适合作为先导化合物进行进一步优化研究。
二、新型吴茱萸碱衍生物的设计、合成和抗肿瘤作用机制研究
吴茱萸碱是从传统中药吴茱萸中提取分离得到的一种生物碱,前期研究发现它具有Top1抑制活性和体外抗肿瘤活性,是一个理想的抗肿瘤先导化合物。本研究设计合成了51个全新结构的吴茱萸碱衍生物,发现大部分化合物体外抗肿瘤活性得到明显提高,部分化合物(B4、B5、B38和B39)GI50值小于3nM。细胞凋亡实验显示,高活性化合物(B4、B38、B39、B41和B45)能够诱导A549肿瘤细胞凋亡,使细胞停滞在G2/M期。机制研究和分子模拟表明吴茱萸碱衍生物为Top1和Top2双重抑制剂。体内小鼠移植瘤实验显示,10-羟基吴茱萸碱(B38)和3-氨基-10-羟基吴茱萸碱(B45)在1mg/kg和2mg/kg剂量下抑瘤率分别为44.43%和52.71%,并表现出低毒性和高耐受性的特点,有希望作为候选药物进行开发。
三、4-取代蒽并[1,2-c][1,2,5]噻二唑-6,11-二酮的设计、合成和抗肿瘤活性研究
化合物4-(对甲苯磺酰基)蒽并[1,2-c][1,2,5]噻二唑-6,11-二酮(A1)是前期虚拟筛选发现的新型Topl抑制剂。本研究设计合成54个4-取代蒽并[1,2-c][1,2,5]噻二唑-6,11-二酮衍生物,从结构上分为两类：4-含硫侧链衍生物和4-含氮侧链衍生物。前者因其溶解性差,体外抗肿瘤活性表现不佳,仅有部分化合物(D14和D15)表现出较好的肿瘤生长抑制活性；后者在溶解性和体外抗肿瘤活性上均有较大提高,其中化合物E1、E6和E19表现出与喜树碱相当的体外抗肿瘤活性。
四、新型Top2抑制剂的虚拟筛选和生物活性研究
研究发现Top2催化性抑制剂毒性较低,并有望克服肿瘤耐药性,而ATPase抑制剂是一类非常重要的Top2催化性抑制剂。本研究通过虚拟筛选,以ATPase为作用位点,筛选得到37个化合物。研究发现,19个化合物具有Top2抑制活性,其中化合物F2、F8、F15、F17、F26和F27对Top2抑制活性强于依托泊苷。体外抗肿瘤活性实验显示,化合物F8对肺癌肿瘤株抑制活性明显超过依托泊苷,F20对三个肿瘤株的抑制活性均超过依托泊苷。机制研究表明,高活性化合物F8和F20能微弱的稳定Top2-DNA复合物。分子对接研究预示两者能够很好结合于ATPase活性腔,为ATPase抑制剂。综上所述,F8和F20适合作为先导化合物进行进一步优化研究。
综上所述,本研究对抗肿瘤重要药靶Topl和Top2开展了虚拟筛选研究,成功发现多类全新结构的抑制剂(活性化合物的命中率分别为60.9%和51.4%)。在此基础上开展了优化设计研究,设计合成得到了105个新化合物,从中发现多个高活性化合物在分子、细胞和动物水平显示了优秀抗肿瘤活性。首次采用现代药物设计技术对我国传统有效成分吴茱萸碱进行了靶标发现和结构创新,发现吴茱萸碱衍生物是Topl/Top2双重抑制剂,深入探讨了该类化合物作用机制,并获得了高效、低毒和广谱的吴茱萸碱类抗肿瘤新化学实体,为开发具有自主知识产权的抗肿瘤原创药物奠定了基础。
DNA topoisomerases (Tops) are essential enzymes that regulate the cellular processes such as replication, transcription, recombination, chromatin and chromosomal segregation by altering DNA topology. DNA Tops can be classified into two types, topoisomerase Ⅰ (Top1) and topoisomerase Ⅱ (Top2). They catalyze the breakage and religation of DNA, maintaining the topological changes of DNA and various DNA metabolic processes. Due to their important role in DNA metabolism, the ability to interfere with the functions of Tops or generating Top-mediated DNA damage is an effective strategy for cancer chemotherapy. Tops have been considered as the most important targets for tumor chemotherapy. Clinically, approximately50%of the chemotherapy regimens contain at least one Top inhibitor.
The present dissertation aims to identify novel Top inhibitors as antitumor agents. A series of novel Top1and Top2inhibitors were identified by structure-based virtual screening. The structure-activity relationships, antitumor activity and mechanism of action of evodiamine derivatives and4-substituted anthra[2,1-c][1,2,5]thiadiazole-6,11-dione analogs were investigated, which led to the discovery of highly potent antitumor agents.
1. Discovery and biological evaluation of novel topoisomerase I inhibitors by structure-based virtual screening
Structure-based virtual screening was applied to the discovery of structurally diverse Top1inhibitors. From23compounds selected by virtual screening from the Specs database, a total of14compounds were found to be topoisomerase I inhibitors. Five hits (compounds Al, A14, A20, A21, and A23) also showed moderate to good in vitro antitumor activity. Compound Al showed excellent cytotoxicity with IC50values in the range of0.5-25μM. Compounds Al and A20(evodiamine) were considered as good starting points for the development of new antitumor lead compounds.
2. Design, synthesis and antitumor mechanism of novel evodiamine derivatives
Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, evodiamine was identified as potent topoisomerase I inhibitor by structure-based virtual screening and showed moderate in vitro antitumor activity. It was also considered as a new antitumor lead compound. Herein,51novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives (B4, B5, B38and B39) showed substantial increase of the antitumor activity, with GI50values lower than3nM. Moreover, these highly potent compounds (B4, B38, B39, B41and B45) can effectively induce the apoptosis and G2/M arrest of A549cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases Ⅰ and Ⅱ. Moreover, several hydroxyl derivatives, such as10-hydroxyl evodiamine (B38) and3-amino-10-hydroxyl evodiamine (B45), also showed good in vivo antitumor efficacy with low toxicity and good tolerance. At the dose of1mg/kg or2mg/kg, B38and B45reduced44.43%and52.71%tumor growth, respectively. They represent promising candidates for the development of novel antitumor agents.
3.4-Substituted anthra[2,1-c][1,2,5]thiadiazole-6,11-dione derivatives: design, synthesis and antitumor potency.
Previously,4-tosylanthra[1,2-c][1,2,5]thiadiazole-6,11-dione (Al) was identified as potent topoisomerase I inhibitor by structure-based virtual screening and showed good antitumor activity in vitro. Based on the structure of Al,54novel analogs were designed and synthesized, which can be classed into two types,4-thio and4-amine substituted derivatives. The former series exhibited weak antitumor activity because of their poor solubility. Only few compounds (D14and D15) showed moderate to good in vitro antitumor activity. The latter series were proved to have stronger antitumor activity with better solubility. Three compounds (El, E6and E19) showed high cytotoxicity similar to that of camptothecin.
4. Discovery and biological evaluation of novel topoisomerase Ⅱ inhibitors by structure-based virtual screening
Top2catalytic inhibitors have the advantages of modulating the cytotoxic effects of topoisomerase II poisons and overcoming the multidrug resistance (MDR). ATP binding site (ATPase) binders represent an important class of Top2catalytic inhibitors. On the basis of the crystal structures of ATPase, docking-based virtual screening was applied to the discover novel Top2inhibitors. From37compounds selected by virtual screening, a total of19compounds were found to be Top2inhibitors. Six hits (compounds F2, F8, F15, F17, F26and F27) were more active than etoposide at the concentration of100μM. In particular, compound F8exhibited better antitumor activity than etoposide in A549cancer cells. Compound F20showed good antitumor activity against all the three cancer cells. The biological assay indicated that compounds F8and F20could stabilize the Top2-DNA cleaved complex slightly. Molecular docking predicted that compounds F8and F20might bind at the ATP binding site. They were considered as good starting points for the development of new antitumor lead compounds targeting Top2.
In summary, structure-based virtual screening were successfully used to discover novel Top1and Top2inhibitors with a hit rate of60.9%and51.4%, respectively. On the basis of the identified lead compounds, a total of105new derivatives were designed and synthesized. Among them, several highly active antitumor compounds were identified which showed excellent activity at molecular, cellular and in vivo level. Target identification and structural optimization of traditional Chinese medicine evodiamine were performed for the first time using the modern drug design techonologies. Evodiamine derivatives were proved to be dual Top1/Top2inhibitors and several of them showed excellent antitumor potency with low toxicity, which provided basis for the development of novel antitumor agents.
引文
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