基于串联反应构建优势骨架和抗肿瘤药物发现
发布时间：2018-07-13 12:48
【摘要】：基于优势骨架的多样性导向合成(privileged-substructure-based diversity oriented synthesis,p DOS)是构建高质量类药性小分子化合物库的有效策略,发现和构建具有反应活性的优势骨架是该策略的关键。本论文基于多种串联反应构建了优势骨架并通过表型筛选发现了药物先导物,内容主要包括:(1)通过基于有机小分子催化的不对称串联反应构建了新型螺环吡唑酮抗肿瘤骨架并进行了抗肿瘤活性研究;(2)通过有机小分子催化的异罗丹宁与α,β-不饱和醛不对称Michael加成反应,发展了高效构建手性优势骨架4,5-二取代异罗丹宁的方法;(3)通过氧化还原-氨基化-芳构化-Friedel-Crafts酰基化串联反应快速构建了吡咯[1,2-b]异喹啉-10(5H)-酮优势骨架并发现了新型拓扑异构酶抑制剂。一、基于有机小分子催化的不对称串联反应构建新型螺环吡唑酮抗肿瘤骨架及其抗肿瘤活性研究(一)有机小分子催化的不对称串联反应构建新型螺环吡唑酮及其抗肿瘤构效关系研究表型筛选在药物发现中日益受到重视。相比于基于靶点的药物筛选,表型筛选可以直接评估化合物在细胞整体水平的活性。高质量的类药性小分子化合物库是表型筛选的物质基础,将高质量类药性小分子库与表型筛选相结合,以发现新的药物先导物,进而阐明其作用机制,有着有广阔的发展前景。为了构建高质量的小分子化合物库,本课题组前期将药物分子中普遍存在的优势骨架与发散性有机催化的串联反应整合,发展了发散性有机催化的不对称串联反应策略(DOCA)。通过简单易得的手性吡唑四氢吡喃半缩醛高效的合成了立体结构多样性的骨架,并成功发现了新型螺环吡唑酮抗肿瘤骨架。在此基础上,本课题通过设计合成了不同取代基、不同立体构型的新型螺环吡唑酮对其进行了初步构效关系研究,发现了一个高活性抗肿瘤化合物。(二)有机小分子催化的串联反应构建新型吡唑酮螺环己二烯酮骨架及其抗肿瘤活性研究通过简单易得的手性吡唑四氢吡喃半缩醛高效合成了新型吡唑酮螺环己二烯酮抗肿瘤骨架。通过对底物适用范围的探讨,确定了该底物的适用范围。选取部分目标产物进行了初步的体外抗肿瘤活性测试,其中化合物5s表现出最好的体外抗肿瘤活性,可用于发展新型抗肿瘤药物,具有深入研究的价值。二、有机小分子催化异罗丹宁与α,β-不饱和醛的不对称Michael加成反应构建药物分子中的手性模块有机小分子催化的不对称反应在有机合成中应用广泛,它可以环境友好地快速高效合成生物活性分子和天然产物,特别是不对称的Michael加成可以有效的构建具有立体选择性的C-C键。近年来,有机小分子催化的不对称Michael反应引起了化学家的广泛兴趣,大量的合成方法得到了发展。异罗丹宁骨架的具有广泛的生物活性,然而,有机催化的不对称合成异罗丹宁鲜见报道。为了高效的构建p DOS库,本课题组前期发展了发散性有机分子催化的串联反应策略(DOCA),通过简单易得的噻唑烷二酮及其类似物与α,β-不饱和醛反应得到了一系列多样性分子骨架。其中以异罗丹宁为底物,通过Michael-环合串联反应合成了骨架不同的骈合硫代吡喃骨架。基于以上研究,异罗丹宁可以互变异构化成烯醇式Michael供体,与二烯醛通过有机催化发生共轭加成反应,得到了一系列的高收率和中等到优秀对映选择性(ee值最高值99%)的4,5-双取代的异罗丹宁目标产物,该产物是快速合成手性异罗丹宁的构建模块,具有很好的应用前景。因异罗丹宁具有多样的生物活性,对4,5-双取代的异罗丹宁目标产物进行药理活性研究将有助于药物先导物的发现,具有深入研究的价值。三、基于氧化还原-氨基化-芳构化-Friedel-Crafts酰基化串联反应快速构建吡咯[1,2-b]异喹啉-10(5H)-酮骨架及新型拓扑异构酶抑制剂的发现吡咯[1,2-b]异喹啉酮骨架广泛分布于许多天然产物中,但目前合成该骨架的方法非常有限。通过文献调研,我们发展了一种新的氧化还原-氨基化-芳构化-Friedel-Crafts酰基化串联反应,快速构建了吡咯[1,2-b]异喹啉-10(5H)-酮骨架。通过对反应条件的优化,确定了最优反应条件,并在此基础上进行了底物适用性的探讨。研究结果表明,该串联反应底物适应性较好,目标产物能够通过一步反应得到,最高收率为96%。抑酶活性实验和体外抗肿瘤实验研究发现,化合物3h为Top1和Top2双重抑制剂,可以作为抗肿瘤先导化合物值得进一步研究。四、总结综上所述,本研究通过多种串联反应构建了4种优势骨架,并设计合成了160个首次报道的新化合物,通过生物活性评价发现了3种全新结构类型的抗肿瘤先导化合物。本论文将合成方法学与药物化学结合,发现了抗肿瘤先导结构,为开发具有自主知识产权的抗肿瘤创新药物奠定了基础。
[Abstract]:Privileged-substructure-based diversity oriented synthesis (P DOS) based on dominant skeleton is an effective strategy for building a high quality small molecular compound library, and the key to the discovery and construction of a dominant skeleton with reactive activity is the key of this strategy. Drug precursors were found through phenotypic screening, including: (1) the antitumor framework and anti-tumor activity of new spironazolone were constructed by asymmetric tandem reaction based on organic small molecular catalysis. (2) an asymmetric Michael addition reaction of isorodenin to alpha and beta unsaturated aldehydes, catalyzed by organic small molecules, was used. A highly efficient method for constructing the chiral dominant skeleton 4,5- two to replace ISO rodenning was developed. (3) a rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone backbone and a novel topoisomerase inhibitor by redox - aminoaromatization and aromatization series reaction were developed and a new type of topoisomerase inhibitor was found. Study on the construction of novel spiral pyrazolone against tumor skeleton and its antitumor activity (1) asymmetric tandem reaction of organic small molecular catalysis construction of novel spiral pyrazolone and its antitumor activity relationship study on phenotypic screening in drug discovery. Compared with drug screening based on target, phenotypic screening can be direct. The high quality small molecule compound library is the material basis for phenotypic screening, combining the high quality small molecule library with the phenotypic screening in order to discover new drug precursors and clarify its mechanism, which has broad prospects for development. In order to construct high quality small fraction, By integrating the dominant skeleton of the drug molecules with the series of divergent organic catalysis, the asymmetric series reaction strategy of divergent organic catalysis (DOCA) was developed. The framework of the stereostructural diversity was synthesized by a simple and easy chiral pyrazole four pyran semi acetal. A new novel spironazolone antitumor skeleton was successfully found. Based on this, the new type of new spironazolone with different stereotyping was designed and synthesized. A high active antitumor compound was found. (two) a new type of pyrazole was constructed by the series reaction of organic small molecules. The skeleton of ketone cyclohexadienone and its antitumor activity study the anti-tumor skeleton of a new pyrazolone cyclohexadienone by simple and easy chiral pyrazole four thiopria acetal. The scope of the substrate was determined by the scope of application of the substrate. A preliminary anti swelling in vitro was selected to select the target product. The tumor activity test, in which compound 5S shows the best antitumor activity in vitro, can be used to develop new antitumor drugs, and has the value of deep research. Two, the asymmetric Michael addition reaction of small organic molecules catalyzes the asymmetric addition of isorodenning to alpha and beta unsaturated aldehydes to construct asymmetric reaction of organic small molecules catalyzed by chiral modules in drug molecules. It should be widely used in organic synthesis, it can be environmentally friendly and fast and efficient synthesis of bioactive molecules and natural products, especially asymmetric Michael addition can effectively construct a stereoselective C-C bond. In recent years, the asymmetric Michael reaction catalyzed by organic small molecules should cause extensive interest of chemists and a large number of compounds. The method has been developed. The isrodenning framework has a wide range of biological activities. However, the asymmetric synthesis of isorodenin by organic catalysis is rare. In order to construct the P DOS library efficiently, the series of divergent organic molecules catalyzed series reaction (DOCA) was developed, and the simple and easy thiazolidane two ketone and its analogues were used. A series of diversity molecular skeletons were obtained with alpha, beta unsaturated aldehydes, in which different Luo Danning cytoskeleton cytoskeleton was synthesized by Michael- cyclization. Based on the above study, isosardenning could be transformed into enol Michael donor and conjugated with dienaldehyde through organic catalysis. In addition, a series of 4,5- biosuenin target products with high yield and excellent enantioselectivity (EE value 99%) were obtained. The product is a construction module for rapid synthesis of chiral isrodenannin. It has a good application prospect. The isosenannin has a variety of biological activity and the 4,5- biosubstituted isorodenning The research on the pharmacological activity of the target product will be helpful to the discovery of drug precursors. Three, the rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone skeleton and the discovery of pyrrole [1,2-b] isoquinolone based on the redox - aminoaromatization -Friedel-Crafts acylation reaction The skeleton is widely distributed in many natural products, but at present, the method of synthesizing the skeleton is very limited. Through literature research, we developed a new redox - aminoaromatization -Friedel-Crafts acylation series reaction and rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone framework. On the basis of the optimal reaction conditions, the substrate suitability was discussed. The results showed that the substrate was adaptable and the target product could be obtained by one step reaction. The highest yield was 96%. inhibition activity test and in vitro antitumor experimental study. Compound 3H was a double inhibitor of Top1 and Top2. Further research on antineoplastic precursor compounds is worth further research. Four, in summary, this study constructs 4 dominant skeletons through a variety of tandem reactions and designs and synthesizes 160 new compounds reported for the first time. Through Bioactivity Evaluation, 3 new structural types of antitumor precursor compounds have been found. This paper will synthesize methods and drugs. The combination of chemical discovery and anticancer precursor structure has laid the foundation for developing innovative anti-tumor drugs with independent intellectual property rights.
【学位授予单位】：第二军医大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914
，
本文编号：2119420
[Abstract]:Privileged-substructure-based diversity oriented synthesis (P DOS) based on dominant skeleton is an effective strategy for building a high quality small molecular compound library, and the key to the discovery and construction of a dominant skeleton with reactive activity is the key of this strategy. Drug precursors were found through phenotypic screening, including: (1) the antitumor framework and anti-tumor activity of new spironazolone were constructed by asymmetric tandem reaction based on organic small molecular catalysis. (2) an asymmetric Michael addition reaction of isorodenin to alpha and beta unsaturated aldehydes, catalyzed by organic small molecules, was used. A highly efficient method for constructing the chiral dominant skeleton 4,5- two to replace ISO rodenning was developed. (3) a rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone backbone and a novel topoisomerase inhibitor by redox - aminoaromatization and aromatization series reaction were developed and a new type of topoisomerase inhibitor was found. Study on the construction of novel spiral pyrazolone against tumor skeleton and its antitumor activity (1) asymmetric tandem reaction of organic small molecular catalysis construction of novel spiral pyrazolone and its antitumor activity relationship study on phenotypic screening in drug discovery. Compared with drug screening based on target, phenotypic screening can be direct. The high quality small molecule compound library is the material basis for phenotypic screening, combining the high quality small molecule library with the phenotypic screening in order to discover new drug precursors and clarify its mechanism, which has broad prospects for development. In order to construct high quality small fraction, By integrating the dominant skeleton of the drug molecules with the series of divergent organic catalysis, the asymmetric series reaction strategy of divergent organic catalysis (DOCA) was developed. The framework of the stereostructural diversity was synthesized by a simple and easy chiral pyrazole four pyran semi acetal. A new novel spironazolone antitumor skeleton was successfully found. Based on this, the new type of new spironazolone with different stereotyping was designed and synthesized. A high active antitumor compound was found. (two) a new type of pyrazole was constructed by the series reaction of organic small molecules. The skeleton of ketone cyclohexadienone and its antitumor activity study the anti-tumor skeleton of a new pyrazolone cyclohexadienone by simple and easy chiral pyrazole four thiopria acetal. The scope of the substrate was determined by the scope of application of the substrate. A preliminary anti swelling in vitro was selected to select the target product. The tumor activity test, in which compound 5S shows the best antitumor activity in vitro, can be used to develop new antitumor drugs, and has the value of deep research. Two, the asymmetric Michael addition reaction of small organic molecules catalyzes the asymmetric addition of isorodenning to alpha and beta unsaturated aldehydes to construct asymmetric reaction of organic small molecules catalyzed by chiral modules in drug molecules. It should be widely used in organic synthesis, it can be environmentally friendly and fast and efficient synthesis of bioactive molecules and natural products, especially asymmetric Michael addition can effectively construct a stereoselective C-C bond. In recent years, the asymmetric Michael reaction catalyzed by organic small molecules should cause extensive interest of chemists and a large number of compounds. The method has been developed. The isrodenning framework has a wide range of biological activities. However, the asymmetric synthesis of isorodenin by organic catalysis is rare. In order to construct the P DOS library efficiently, the series of divergent organic molecules catalyzed series reaction (DOCA) was developed, and the simple and easy thiazolidane two ketone and its analogues were used. A series of diversity molecular skeletons were obtained with alpha, beta unsaturated aldehydes, in which different Luo Danning cytoskeleton cytoskeleton was synthesized by Michael- cyclization. Based on the above study, isosardenning could be transformed into enol Michael donor and conjugated with dienaldehyde through organic catalysis. In addition, a series of 4,5- biosuenin target products with high yield and excellent enantioselectivity (EE value 99%) were obtained. The product is a construction module for rapid synthesis of chiral isrodenannin. It has a good application prospect. The isosenannin has a variety of biological activity and the 4,5- biosubstituted isorodenning The research on the pharmacological activity of the target product will be helpful to the discovery of drug precursors. Three, the rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone skeleton and the discovery of pyrrole [1,2-b] isoquinolone based on the redox - aminoaromatization -Friedel-Crafts acylation reaction The skeleton is widely distributed in many natural products, but at present, the method of synthesizing the skeleton is very limited. Through literature research, we developed a new redox - aminoaromatization -Friedel-Crafts acylation series reaction and rapid construction of pyrrole [1,2-b] isoquinoline -10 (5H) - ketone framework. On the basis of the optimal reaction conditions, the substrate suitability was discussed. The results showed that the substrate was adaptable and the target product could be obtained by one step reaction. The highest yield was 96%. inhibition activity test and in vitro antitumor experimental study. Compound 3H was a double inhibitor of Top1 and Top2. Further research on antineoplastic precursor compounds is worth further research. Four, in summary, this study constructs 4 dominant skeletons through a variety of tandem reactions and designs and synthesizes 160 new compounds reported for the first time. Through Bioactivity Evaluation, 3 new structural types of antitumor precursor compounds have been found. This paper will synthesize methods and drugs. The combination of chemical discovery and anticancer precursor structure has laid the foundation for developing innovative anti-tumor drugs with independent intellectual property rights.
【学位授予单位】：第二军医大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914
，
本文编号：2119420
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