抗真菌和抗肿瘤先导结构的发现和优化研究
发布时间：2018-08-09 18:06
【摘要】：先导化合物的发现和优化是新药研发的重要环节。本论文运用了多种策略来发现和优化抗真菌和抗肿瘤先导结构，主要包括：(1)通过基于结构的药物设计技术优化本实验室发现的高活性唑类抗真菌先导结构；(2)通过基于细胞的表型筛选技术发现咔啉类抗真菌先导结构，对其结构优化发现全新作用机制的抗真菌新化学实体；(3)通过药物结构优化技术，系统完成了传统中药有效成分吴茱萸碱的构效关系和药理活性研究，发现高活性抗肿瘤候选分子；(4)通过有机小分子催化的不对称串联反应技术，，发展了三项含硫骨架合成新方法，构建得到类药性分子库，并筛选发现具有广谱抗肿瘤活性的全新先导结构。 一、新型抗真菌先导结构的设计、合成与活性研究 (一)抗真菌靶标CYP51的同源模建和唑类先导结构的优化设计 真菌羊毛甾醇14α-去甲基化酶(CYP51)是抗真菌药物的重要靶点，其抑制剂唑类抗真菌药物已经广泛应用于临床。但由于真菌CYP51是跨膜蛋白，提取纯化比较困难，目前还没有晶体结构报道。本研究首次以人CYP51为模板，同源模建了白念珠菌CYP51(CA-CYP51)的三维模型，并进行了分子动力学优化。对CA-CYP51模建结构的准确度进行了系统的计算评价，包括蛋白的Pro-check、Profiles-3D、分子对接验证和富集性试验测试。结果表明，所建立的模型具有较高的精确性，可以用于指导新型唑类抗真菌药物的合理设计。 本课题组前期发现含有N-甲基侧链的唑类化合物表现出优秀的体外抗真菌活性。在此基础上，通过基于结构的药物设计技术对其进行了结构优化和构效关系研究，主要考察了含氮侧链上不同的取代基团对抗真菌活性的影响，设计合成了25个新化合物。构效关系表明，N上的取代基团以氢原子和甲基为最优，并且取代基团会影响侧链在CYP51活性位点中的伸展，进而影响抗真菌活性。其中化合物A1和A14较对照药氟康唑相比，表现出相当或更优的体外抗真菌活性。通过分子对接阐明了目标化合物与CA-CYP51的作用模式，并合理解释了构效关系，为进一步合理设计新型唑类抗真菌药物提供了有价值的信息。 (二)咔啉类抗真菌先导结构的发现、优化和生物活性研究 基于细胞表型或者功能的筛选是发现先导结构的重要途径。与针对具体靶点的分子水平筛选不同的是，细胞水平筛选不仅能够直接发现具有药理活性的分子，而且有可能发现全新结构类型和全新作用机制的先导结构，对新靶点和新药的发现具有重要作用。本研究中对课题组内部化合物库进行了体外抗真菌细胞水平的筛选，发现具有β-咔啉骨架结构的化合物表现出广谱的抗真菌活性。进一步对其进行结构优化，设计合成了27个新化合物。体外抗真菌测试表明，部分化合物的抗真菌活性优于先导结构。其中化合物C27活性最优，与对照药氟康唑相当。对其进行了深入的药理学评价，发现化合物C27对氟康唑敏感菌和耐药菌都具有杀真菌活性，能够有效抑制真菌生物被膜和真菌菌丝的形成，而氟康唑无此效应。协同抗真菌实验表明，化合物C27与氟康唑具有很好的协同抗真菌效果。采用透射电镜和GC-MS方法对C27的抗真菌作用机制进行了初步研究，发现该类化合物具有与氟康唑不同的作用机制，可能干扰了真菌细胞壁的生物合成途径。上述结果表明，对咔啉类抗真菌化合物进行深入研究，对于解决真菌的耐药性问题具有重要意义。 二、新型吴茱萸碱衍生物的设计、合成和抗肿瘤活性研究 天然产物一直是抗肿瘤新药研发的重要来源。在前期工作中，本课题组通过基于结构的虚拟筛选，首次报道了天然产物吴茱萸碱是拓扑异构酶的抑制剂。但它的体外抗肿瘤活性还比较低，分子作用靶点还不明确，有待深入的研究。 本研究对吴茱萸碱进行了系统的结构修饰，考察了引入取代基和改变分子骨架对抗肿瘤活性的影响，总共设计合成了139个新型吴茱萸碱衍生物，并在分子、细胞和动物水平进行了药理活性测试。结果显示，部分化合物对多种肿瘤株的GI50小于3nM，表现出广谱、高效的体外抗肿瘤活性。裸鼠体内肠癌和肺癌模型显示，部分高活性衍生物表现出很好的体内抗肿瘤效果。例如在裸鼠肠癌模型中，化合物E135在2mg/kg条件下抑瘤率达到50.39%，并表现低毒和高耐受性特点。细胞凋亡实验显示，高活性化合物(E38, E112和E133)能够诱导A549肿瘤细胞凋亡，使细胞周期阻滞于G2/M期。在分子作用靶点上，发现吴茱萸碱衍生物是首次报道的Top1/Top2/微管蛋白的三靶点抑制剂。其中化合物E112和E135对微管蛋白的抑制活性(IC50分别为5.3μM和4.5μM)优于对照药秋水仙碱(IC50为10.8μM)。吴茱萸碱衍生物多靶点抗肿瘤作用特点对于提高肿瘤化疗效果和克服肿瘤耐药性问题具有重要的意义。 三、基于有机合成方法学构建类药性骨架和抗肿瘤先导结构的发现 近年来，有机小分子催化的不对称串联反应发展迅速。这类反应仅需通过一步反应即能够以较好的反应收率和高立体选择性构建手性骨架，具有环境友好和原子经济性等特点，成为有机合成方法学的研究热点。 3,4-二氢-2H-硫代吡喃骨架是药物活性分子中的优势骨架。本研究首次采用有机小分子催化的硫-[3+3]环合反应，一步构建了含有两个手性中心的二氢硫代吡喃骨架。反应具有很好的反应收率(51%-84%)和较好的立体选择性(最高值20:1dr,99%ee)，并通过Nazarov反应构建得到含有四个手性中心的全新类药性骨架。 在此基础上，首次采用有机小分子催化的Michael-Michael串联反应，以较好的反应收率(58%-78%)、中等的非对映选择性(最高值为5.2:1dr)和高对映选择性(最高值99%ee)，一步构建了含有四个手性中心的四氢硫代吡喃骨架。通过简单的化学转化，能够得到结构更加复杂、骨架更加新颖的类药性分子。 螺吲哚酮骨架是天然产物和药物活性分子中的优势骨架，成为近年来药物研究的热点结构。采用有机小分子催化的方法将吲哚酮和四氢硫代吡喃骨架相结合，通过Michael-Michael串联反应一步构建了含有四个手性中心的吲哚酮螺四氢硫代吡喃骨架。反应具有很好的反应收率(55%-74%)和高立体选择性(dr30:1,ee≥99%)。通过简单的化学转化，能够得到骨架更加新颖、结构更加复杂的结构。 基于上述三类骨架建立了一个小型化合物库，并进行了体外抗肿瘤活性测试。结果表明，吲哚酮螺四氢硫代吡喃类衍生物表现出广谱的抗肿瘤活性。其中化合物3b的体外抗肿瘤活性总体要优于对照药nutlin-3，具有深入研究的价值。 在本部分研究中，通过发展有机合成方法学构建了三种含硫类药性骨架，并通过体外抗肿瘤活性筛选首次发现吲哚酮螺四氢硫代吡喃衍生物具有广谱抗肿瘤的特点。这项工作体现了有机合成方法学与药物化学的相结合，为新药发现提供了一种新思路，并为抗肿瘤化学生物研究提供了分子探针。 四、总结 综上所述，本研究将多种先导物发现和优化策略应用于抗真菌和抗肿瘤新药发现中，总共设计合成了191个新化合物，并发现四种结构类型的抗真菌或抗肿瘤活性化合物。本论文的创新性主要体现在如下三个方面：(1)首次发现咔啉类化合物是全新作用机制的抗真菌先导结构，发现化合物C27在克服真菌耐药性方面具有潜在的应用价值；(2)首次发现并证实吴茱萸碱衍生物是Top1/Top2/微管蛋白的三靶点抑制剂，并获得了高效、低毒和广谱的抗肿瘤新化学实体，为开发具有自主知识产权的抗肿瘤原创药物奠定了基础；(3)将有机合成方法学和药物化学紧密结合，提出了先导化合物发现新策略。通过有机小分子催化的不对称串联反应，快速构建了三类含硫优势分子骨架，并发现吲哚酮螺四氢硫代吡喃类衍生物具有广谱的抗肿瘤活性。本论文研究工作为开发具有自主知识产权的抗真菌和抗肿瘤创新药物奠定了基础。
[Abstract]:The discovery and optimization of pilot compounds is an important link in the development of new drugs. This paper uses a variety of strategies to discover and optimize antifungal and antitumor precursor structures, including: (1) optimize the antifungal precursor structure of the highly active azoles found in our laboratory through structural based drug design technology; (2) through cell based phenotype Screening techniques found the anti fungal precursor structure of carbazoline, optimized its structure and found a new antifungal entity with new mechanism. (3) through the optimization of drug structure, the structure-activity relationship and pharmacological activity of evodiazeroid from traditional Chinese medicine were systematically studied, and highly active antitumor candidate molecules were found; (4) through organic matter. Three new methods for the synthesis of sulphur containing skeletons have been developed by the small molecule catalyzed asymmetric series reaction technology, and the molecular library of drug like molecules has been constructed, and a new pilot structure with broad-spectrum antitumor activity has been screened.
1. Design, Synthesis and Activity of New Antifungal Pilot Structures
(1) Homology Modeling of Antifungal Target CYP51 and Optimization of Azole Pilot Structure
Fungi wool sterol 14 alpha demethylation enzyme (CYP51) is an important target for antifungal drugs, and its inhibitors, azole antifungal agents, have been widely used in clinical practice. However, because fungal CYP51 is a transmembrane protein, it is difficult to extract and purify the crystal structure. At present, there is no crystal structure report. This study was based on human CYP51 as a template for the first time, and a homologous model of Candida albicans C was built. The three-dimensional model of YP51 (CA-CYP51) was optimized by molecular dynamics. The accuracy of the CA-CYP51 model construction was evaluated systematically, including the protein Pro-check, Profiles-3D, molecular docking verification and enrichment test. The results show that the model has high accuracy and can be used to guide the new type of azole resistance. The rational design of fungal drugs.
The research group found that the azoles containing N- methyl side chain showed excellent antifungal activity in vitro. On this basis, structural optimization and structure-activity relationship were studied by structural based drug design technology, and the effect of different substituent groups on the nitrogen side chain was mainly investigated and the design and synthesis were designed. 25 new compounds. The structure-activity relationship shows that the substituent groups on N are optimal with hydrogen atoms and methyl groups, and the substituent groups affect the extension of the side chain in the CYP51 active site, and then affect the antifungal activity. The compounds A1 and A14 show the antifungal activity in phase or better in vitro compared with the control drug fluconazole. The mode of action of target compounds and CA-CYP51 is clarified, and the structure-activity relationship is explained reasonably, which provides valuable information for the further rational design of new azole antifungal drugs.
(2) Discovery, Optimization and Biological Activity of Caroline Antifungal Pilot Structures
Screening for phenotype or function based on cell phenotype is an important approach to the discovery of pilot structures. Unlike molecular level screening aimed at specific targets, cell level screening is not only able to detect molecules with pharmacological activity directly, but also may discover new structure types and new mechanisms, and new targets and new drugs. In this study, the level of antifungal cells in the compound library was screened in this study. It was found that the compounds with beta carbazoline skeleton structure showed broad-spectrum antifungal activity. Further, the structure was optimized and 27 new compounds were designed and synthesized. In vitro antifungal test showed that the compound was partial. The antifungal activity of the compound was superior to the pilot structure, in which the activity of compound C27 was the best, which was equivalent to the control drug fluconazole. The pharmacological evaluation of the compound was carried out. It was found that compound C27 had fungicidal activity to fluconazole sensitive and drug resistant bacteria, and could effectively inhibit the formation of fungal biofilm and fungal mycelium, and fluconazole had no such effect. Synergistic antifungal experiment showed that compound C27 had a good synergistic antifungal effect with fluconazole. The mechanism of anti fungal action of C27 was preliminarily studied by transmission electron microscope and GC-MS method. It was found that the compounds have different mechanisms of action with fluconazole, which may interfere with the biosynthesis pathway of the cell wall of fungi. The results showed that further study on carbaline antifungal compounds was of great significance to solve the problem of fungal resistance.
2. Design, Synthesis and Antitumor Activity of Novel Evodiamine Derivatives
Natural products have always been an important source of research and development of new antitumor drugs. In the early work, we first reported the natural product evodialkali as a topoisomerase inhibitor based on the structure based virtual screening. But its antitumor activity in vitro is still relatively low and the molecular target target is not clear.
In this study, the structure of evodiodipine was systematically modified, and the effects of introducing substituents and changing the molecular framework against the tumor activity were investigated. A total of 139 new evodiwood derivatives were designed and synthesized, and the pharmacological activities were tested at the molecular, cell and animal levels. The results showed that some of the compounds were GI50 in a variety of tumor strains. Less than 3nM, showing broad-spectrum and efficient antitumor activity in vitro. The model of colorectal cancer and lung cancer in nude mice showed that some highly active derivatives showed good antitumor effect in vivo. For example, in the nude mouse model, compound E135 was 50.39% under the condition of 2mg/kg, and showed low toxicity and high tolerance. The results showed that the highly active compounds (E38, E112 and E133) could induce apoptosis of A549 tumor cells and block the cell cycle in G2/M phase. At the molecular target, it was found that evodipine derivatives were the three target inhibitors of Top1/Top2/ microtubules for the first time. The inhibitory activity of compounds E112 and E135 to microtubule protein (IC50 was 5., respectively). 3 mu M and 4.5 mu M) are superior to the control drug colchicine (IC50 is 10.8 M). The antitumor characteristics of evodiine derivatives at multiple targets are of great significance in improving the effect of tumor chemotherapy and overcoming the problem of tumor resistance.
3. Discovery of Drug-like Skeleton and Antitumor Pilot Structures Based on Organic Synthesis Methodology
In recent years, the asymmetric series reaction catalyzed by small organic molecules has developed rapidly. This kind of reaction only needs to build chiral skeletons with good reaction yield and high stereoselectivity by one step reaction, which has the characteristics of environment-friendly and atomic economy. It has become a hot topic in the research of organic synthesis methodology.
3,4- two hydrogen -2H- thiothiolan skeleton is the dominant skeleton in drug active molecules. In this study, a sulfur -[3+3] cyclization reaction catalyzed by small organic molecules was used for the first time to construct a two hydrogen thiothiolan skeleton containing two chiral centers. The reaction has a good reaction yield (51%-84%) and a better stereoselectivity (maximum 20:1dr, 99%ee). A novel drug-like skeleton containing four chiral centers was constructed by Nazarov reaction.
On this basis, the Michael-Michael series reaction catalyzed by organic small molecules has been used for the first time, with a good reaction yield (58%-78%), medium non enantioselectivity (the maximum value of 5.2:1dr) and high enantioselectivity (the highest value 99%ee). One step is to construct a four thiothiolan skeleton containing four chiral centers. Drug-like molecules with more complex structure and novel skeleton can be obtained.
The cytoskeleton of spiro indolone is the dominant skeleton in natural products and drug active molecules. It has been a hot structure in drug research in recent years. Using organic small molecular catalysis, indolone and four thiothiolan skeleton were combined and four chiral centers containing four chiral centers were constructed by one step Michael-Michael series reaction. The cytoskeleton has a good reaction yield (55%-74%) and high stereoselectivity (dr30:1, EE > 99%). Through simple chemical conversion, a more novel structure and more complex structure of the skeleton can be obtained.
Based on the above three kinds of skeletons, a small compound library was established and the antitumor activity in vitro was tested. The results showed that the indolonone four thiothioparan derivatives showed broad-spectrum antitumor activity. The overall anti tumor activity of compound 3B was better than that of the control drug nutlin-3 in vitro, which was of great value for further study.
In this part, three kinds of sulfur containing insecticide skeleton were constructed by the development of organic synthesis method, and the characteristics of broad spectrum antitumor characteristics were found for the first time by the screening of anti tumor activity in vitro. This work embodies the combination of organic synthesis methodology and drug chemistry and the discovery of new drugs. It provides a new idea and a molecular probe for the study of anti-tumor chemistry and biology.
Four, summary
To sum up, a variety of pilot discovery and optimization strategies are applied to the discovery of antifungal and antitumor drugs. A total of 191 new compounds have been designed and four structural types of antifungal or antitumor compounds have been found. The innovation of this paper is mainly reflected in the following three aspects: (1) the first discovery of carbazolin The compound is an antifungal precursor structure of the new mechanism of action. It has been found that compound C27 has potential application value in overcoming fungal resistance. (2) it was first discovered and confirmed that evodipine derivatives are the three target inhibitors of microtubulin, and have obtained high efficient, low toxic and broad-spectrum anti-tumor chemical entities. The independent intellectual property rights have laid the foundation for antitumor original drugs; (3) a new strategy for the discovery of pilot compounds is proposed by combining organic synthesis methodology with drug chemistry. A rapid construction of three kinds of sulfur containing dominant molecular skeletons through asymmetric tandem reactions catalyzed by organic small molecules and the discovery of indolonone four hydrogen thiothioles derivatives are found. Biology has broad-spectrum antitumor activity. The research work of this paper lays a foundation for the development of innovative antifungal and antitumor 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】：2014
【分类号】：R914
本文编号：2174880
[Abstract]:The discovery and optimization of pilot compounds is an important link in the development of new drugs. This paper uses a variety of strategies to discover and optimize antifungal and antitumor precursor structures, including: (1) optimize the antifungal precursor structure of the highly active azoles found in our laboratory through structural based drug design technology; (2) through cell based phenotype Screening techniques found the anti fungal precursor structure of carbazoline, optimized its structure and found a new antifungal entity with new mechanism. (3) through the optimization of drug structure, the structure-activity relationship and pharmacological activity of evodiazeroid from traditional Chinese medicine were systematically studied, and highly active antitumor candidate molecules were found; (4) through organic matter. Three new methods for the synthesis of sulphur containing skeletons have been developed by the small molecule catalyzed asymmetric series reaction technology, and the molecular library of drug like molecules has been constructed, and a new pilot structure with broad-spectrum antitumor activity has been screened.
1. Design, Synthesis and Activity of New Antifungal Pilot Structures
(1) Homology Modeling of Antifungal Target CYP51 and Optimization of Azole Pilot Structure
Fungi wool sterol 14 alpha demethylation enzyme (CYP51) is an important target for antifungal drugs, and its inhibitors, azole antifungal agents, have been widely used in clinical practice. However, because fungal CYP51 is a transmembrane protein, it is difficult to extract and purify the crystal structure. At present, there is no crystal structure report. This study was based on human CYP51 as a template for the first time, and a homologous model of Candida albicans C was built. The three-dimensional model of YP51 (CA-CYP51) was optimized by molecular dynamics. The accuracy of the CA-CYP51 model construction was evaluated systematically, including the protein Pro-check, Profiles-3D, molecular docking verification and enrichment test. The results show that the model has high accuracy and can be used to guide the new type of azole resistance. The rational design of fungal drugs.
The research group found that the azoles containing N- methyl side chain showed excellent antifungal activity in vitro. On this basis, structural optimization and structure-activity relationship were studied by structural based drug design technology, and the effect of different substituent groups on the nitrogen side chain was mainly investigated and the design and synthesis were designed. 25 new compounds. The structure-activity relationship shows that the substituent groups on N are optimal with hydrogen atoms and methyl groups, and the substituent groups affect the extension of the side chain in the CYP51 active site, and then affect the antifungal activity. The compounds A1 and A14 show the antifungal activity in phase or better in vitro compared with the control drug fluconazole. The mode of action of target compounds and CA-CYP51 is clarified, and the structure-activity relationship is explained reasonably, which provides valuable information for the further rational design of new azole antifungal drugs.
(2) Discovery, Optimization and Biological Activity of Caroline Antifungal Pilot Structures
Screening for phenotype or function based on cell phenotype is an important approach to the discovery of pilot structures. Unlike molecular level screening aimed at specific targets, cell level screening is not only able to detect molecules with pharmacological activity directly, but also may discover new structure types and new mechanisms, and new targets and new drugs. In this study, the level of antifungal cells in the compound library was screened in this study. It was found that the compounds with beta carbazoline skeleton structure showed broad-spectrum antifungal activity. Further, the structure was optimized and 27 new compounds were designed and synthesized. In vitro antifungal test showed that the compound was partial. The antifungal activity of the compound was superior to the pilot structure, in which the activity of compound C27 was the best, which was equivalent to the control drug fluconazole. The pharmacological evaluation of the compound was carried out. It was found that compound C27 had fungicidal activity to fluconazole sensitive and drug resistant bacteria, and could effectively inhibit the formation of fungal biofilm and fungal mycelium, and fluconazole had no such effect. Synergistic antifungal experiment showed that compound C27 had a good synergistic antifungal effect with fluconazole. The mechanism of anti fungal action of C27 was preliminarily studied by transmission electron microscope and GC-MS method. It was found that the compounds have different mechanisms of action with fluconazole, which may interfere with the biosynthesis pathway of the cell wall of fungi. The results showed that further study on carbaline antifungal compounds was of great significance to solve the problem of fungal resistance.
2. Design, Synthesis and Antitumor Activity of Novel Evodiamine Derivatives
Natural products have always been an important source of research and development of new antitumor drugs. In the early work, we first reported the natural product evodialkali as a topoisomerase inhibitor based on the structure based virtual screening. But its antitumor activity in vitro is still relatively low and the molecular target target is not clear.
In this study, the structure of evodiodipine was systematically modified, and the effects of introducing substituents and changing the molecular framework against the tumor activity were investigated. A total of 139 new evodiwood derivatives were designed and synthesized, and the pharmacological activities were tested at the molecular, cell and animal levels. The results showed that some of the compounds were GI50 in a variety of tumor strains. Less than 3nM, showing broad-spectrum and efficient antitumor activity in vitro. The model of colorectal cancer and lung cancer in nude mice showed that some highly active derivatives showed good antitumor effect in vivo. For example, in the nude mouse model, compound E135 was 50.39% under the condition of 2mg/kg, and showed low toxicity and high tolerance. The results showed that the highly active compounds (E38, E112 and E133) could induce apoptosis of A549 tumor cells and block the cell cycle in G2/M phase. At the molecular target, it was found that evodipine derivatives were the three target inhibitors of Top1/Top2/ microtubules for the first time. The inhibitory activity of compounds E112 and E135 to microtubule protein (IC50 was 5., respectively). 3 mu M and 4.5 mu M) are superior to the control drug colchicine (IC50 is 10.8 M). The antitumor characteristics of evodiine derivatives at multiple targets are of great significance in improving the effect of tumor chemotherapy and overcoming the problem of tumor resistance.
3. Discovery of Drug-like Skeleton and Antitumor Pilot Structures Based on Organic Synthesis Methodology
In recent years, the asymmetric series reaction catalyzed by small organic molecules has developed rapidly. This kind of reaction only needs to build chiral skeletons with good reaction yield and high stereoselectivity by one step reaction, which has the characteristics of environment-friendly and atomic economy. It has become a hot topic in the research of organic synthesis methodology.
3,4- two hydrogen -2H- thiothiolan skeleton is the dominant skeleton in drug active molecules. In this study, a sulfur -[3+3] cyclization reaction catalyzed by small organic molecules was used for the first time to construct a two hydrogen thiothiolan skeleton containing two chiral centers. The reaction has a good reaction yield (51%-84%) and a better stereoselectivity (maximum 20:1dr, 99%ee). A novel drug-like skeleton containing four chiral centers was constructed by Nazarov reaction.
On this basis, the Michael-Michael series reaction catalyzed by organic small molecules has been used for the first time, with a good reaction yield (58%-78%), medium non enantioselectivity (the maximum value of 5.2:1dr) and high enantioselectivity (the highest value 99%ee). One step is to construct a four thiothiolan skeleton containing four chiral centers. Drug-like molecules with more complex structure and novel skeleton can be obtained.
The cytoskeleton of spiro indolone is the dominant skeleton in natural products and drug active molecules. It has been a hot structure in drug research in recent years. Using organic small molecular catalysis, indolone and four thiothiolan skeleton were combined and four chiral centers containing four chiral centers were constructed by one step Michael-Michael series reaction. The cytoskeleton has a good reaction yield (55%-74%) and high stereoselectivity (dr30:1, EE > 99%). Through simple chemical conversion, a more novel structure and more complex structure of the skeleton can be obtained.
Based on the above three kinds of skeletons, a small compound library was established and the antitumor activity in vitro was tested. The results showed that the indolonone four thiothioparan derivatives showed broad-spectrum antitumor activity. The overall anti tumor activity of compound 3B was better than that of the control drug nutlin-3 in vitro, which was of great value for further study.
In this part, three kinds of sulfur containing insecticide skeleton were constructed by the development of organic synthesis method, and the characteristics of broad spectrum antitumor characteristics were found for the first time by the screening of anti tumor activity in vitro. This work embodies the combination of organic synthesis methodology and drug chemistry and the discovery of new drugs. It provides a new idea and a molecular probe for the study of anti-tumor chemistry and biology.
Four, summary
To sum up, a variety of pilot discovery and optimization strategies are applied to the discovery of antifungal and antitumor drugs. A total of 191 new compounds have been designed and four structural types of antifungal or antitumor compounds have been found. The innovation of this paper is mainly reflected in the following three aspects: (1) the first discovery of carbazolin The compound is an antifungal precursor structure of the new mechanism of action. It has been found that compound C27 has potential application value in overcoming fungal resistance. (2) it was first discovered and confirmed that evodipine derivatives are the three target inhibitors of microtubulin, and have obtained high efficient, low toxic and broad-spectrum anti-tumor chemical entities. The independent intellectual property rights have laid the foundation for antitumor original drugs; (3) a new strategy for the discovery of pilot compounds is proposed by combining organic synthesis methodology with drug chemistry. A rapid construction of three kinds of sulfur containing dominant molecular skeletons through asymmetric tandem reactions catalyzed by organic small molecules and the discovery of indolonone four hydrogen thiothioles derivatives are found. Biology has broad-spectrum antitumor activity. The research work of this paper lays a foundation for the development of innovative antifungal and antitumor 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】：2014
【分类号】：R914
【参考文献】
相关期刊论文 前7条
1 陈坤成;冯思良;刘克良;;紫杉烷类抗肿瘤药物临床研究进展[J];国际药学研究杂志;2013年03期
2 郭晓鹏;冯思良;王金辉;俞腾飞;;拓扑异构酶1及其喜树碱类抑制剂的临床研究进展[J];国际药学研究杂志;2013年04期
3 胥彬;;高三尖杉酯碱(Homoharringtonine)抗癌研究新进展[J];肿瘤药学;2013年03期
4 张正智;关于我国发展电动汽车及代用燃料汽车的思考和建议[J];世界汽车;1997年03期
5 习利平;宋新波;张丽娟;;长春碱类抗肿瘤药的研究进展[J];药物评价研究;2011年01期
6 王超磊;孙炳峰;姚和权;吴晓明;徐进宜;;植物来源的抗肿瘤药物研究进展[J];药学进展;2011年05期
7 丁亚芳,包永明,安利佳;长春碱类抗肿瘤药物的研究进展[J];中国医药工业杂志;2005年07期
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