双氟喹诺酮类查尔酮衍生物的合成与抗肿瘤活性研究

发布时间：2019-06-06 17:36

【摘要】：目前随着多种因素的影响,肿瘤的发病率逐年攀升,已是威胁人类生命健康的常见病、多发病。现如今的抗肿瘤药物在提高患者生存时间和改善生活质量方面取得了重大的突破性进展,但是这些抗肿瘤药物因选择性差而导致严重的毒副作用,同时耐药性的产生等缺点极大地影响了抗肿瘤药物的临床疗效。因此,寻求更加理想的抗肿瘤药物,已经成为全世界科学工作者正在积极探索研究的重大课题。喹诺酮类药物是以喹啉-4-酮-3-羧酸为结构特征的抗感染药,因抗菌氟喹诺酮(FQ)的作用靶酶-拓扑异构酶(TOPO)与哺乳动物细胞内的TOPO在结构和功能上的相似性,因此可将其抗菌活性转化为抗肿瘤活性。近年来对喹诺酮类药物进行了大量的结构修饰,获得具有潜在抗肿瘤活性的候选化合物,但由于体内毒性或生物利用度或稳定性等生物学问题而未进入临床评价。因此,寻找新的结构修饰方法,获得高效、低毒的先导化合物,是目前抗肿瘤氟喹诺酮药物研究面临的新挑战。肿瘤发病机制虽然有多种,但DNA拓扑异构酶(TOPO)和蛋白酪氨酸激酶(PTK)的过度表达与肿瘤的发生、发展和转移等密切相关,这两种酶已成为目前抗肿瘤药物的重要靶标,许多作用于这两种靶点的抑制剂已经有效地应用于临床肿瘤的化学治疗。因此,基于机制或结构的理性药物设计方法,在现有药物结构的基础上,如何设计作用于TOPO或(和)PTK靶的先导化合物,对抗肿瘤药物的创新发展具有重要的意义。一方面,参考抗肿瘤PTK抑制剂—舒尼替尼是由吲哚酮和吡咯酰胺骨架构筑的α,β-不饱和酮结构特征的“类查尔酮”分子;另一方面,基于以α,β-不饱和酮骨架为结构特征查尔酮类化合物广泛存在于药用天然产物中,并具有较强的抗肿瘤活性。为此,本论文结合查尔酮及FQ的结构特征,利用药效团拼合和骨架迁越药物分子构建策略,巧妙地设计了新的双氟喹诺酮“类查尔酮”衍生物。最后通过体外药理活性筛选得出初步的构-效关系,为抗肿瘤氟喹诺酮“类查尔酮”先导化合物的设计提供新途径和方法。1.目标化合物的设计与合成首先把FQ转化为氟喹诺酮醛和二氢氟喹诺酮,然后氟喹诺酮醛与二氢氟喹诺酮通过Claisen-Schmidt缩合反应形成活化烯甲基连接链,得到双氟喹诺酮类查尔酮衍生物,产物经过MS、1H NMR光谱数据表征。2.体外抗肿瘤活性评价采用MTT实验方法评价双氟喹诺酮类查尔酮衍生物对人胰腺癌Panc、膀胱癌T24、胃癌HGC823、前列腺癌PU145、胃癌HGC27、胰腺癌Capan-1细胞的抗增殖活性。结果表明,所得目标化合物的抗肿瘤活性都显著强于所对应的母体化合物的活性,在对胰腺癌Capan-1的抗增殖抑制活性中,化合物E5、E6、F1、F4、F5、F6的IC50值在0.13~0.69μΜ之间。3.结论本文设计合成了24个双氟喹诺酮类查尔酮衍生物,其结构经过光谱数据得到了确证。体外抗肿瘤活性结果表明,目标化合物的抗肿瘤活性都显著强于所对应的母体化合物的活性。因此,氟喹诺酮醛与二氢氟喹诺酮通过活化烯甲基连接链,得到的新型双氟喹诺酮类查尔酮类化合物具有发展为先导化合物的前景,具有进一步研究的价值。
[Abstract]:At present, with the influence of various factors, the incidence of the tumor is increasing year by year, and has been a common disease that threatens the health of human life. The present anti-tumor medicine has made great breakthrough in improving the survival time of the patient and improving the quality of life, but the anti-tumor drugs cause serious side effects due to the selective difference, Meanwhile, the defects of the drug resistance and the like greatly influence the clinical curative effect of the anti-tumor medicament. Therefore, seeking a more ideal anti-tumor drug has become a major task of the world's scientific workers to actively explore the research. The invention relates to an anti-infective agent which is characterized by the following components in the structure and function of a target enzyme-topoisomerase (TOPO) and a TOPO in a mammalian cell due to the action of the anti-bacterial florfenone (FQ) and the TOPO in the mammalian cell, So that its antibacterial activity can be converted into anti-tumor activity. In recent years, a large amount of structural modification has been carried out on the Leninone drug to obtain the candidate compound having the potential anti-tumor activity, but not to the clinical evaluation due to the biological problems such as in vivo toxicity or bioavailability or stability. Therefore, the new structure modification method is found, and the high-efficiency and low-toxic lead compound is obtained, which is a new challenge facing the research of the anti-tumor flurolenin drug. Although there are various mechanisms of tumor pathogenesis, the overexpression of DNA topoisomerase (TOPO) and protein tyrosine kinase (PTK) is closely related to the occurrence, development and metastasis of tumor. Many of the inhibitors acting on these two targets have been effectively applied to the chemotherapy of clinical tumors. Therefore, on the basis of the existing drug structure, it is of great significance to design the leading compound which acts on TOPO or (and) PTK target based on the existing drug structure. On the one hand, reference to the anti-tumor PTK inhibitor, psunitinib, is a "chalcone" molecule of the structure of the antigen, the p-unsaturated ketone, which is constructed from the framework of the donor and the alicyclic amine, and on the other hand, on the basis of the formula, The 1-unsaturated ketone framework is a structural characteristic, and the chalcone compound is widely present in the medicinal natural product, and has strong anti-tumor activity. To this end, the structure of chalcone and FQ is combined with the structure of chalcone and FQ, and the new difluoro-noone "chalcone" derivatives are skillfully designed by means of the combination of the pharmacophore and the molecular construction of the framework. And finally, the initial structure-effect relationship is obtained through the in-vitro pharmacological activity screening, and a new approach and a method are provided for the design of the anti-tumor fluoxolone "chalcone" lead compound. The design and synthesis of the target compound first converts the FQ into a fluoromethyl-ketone aldehyde and a dihydro-fluoromethyl ketone, and then the fluoronorone aldehyde and the dihydro-fluoromethyl-ketone are subjected to a Claisen-Schmidt condensation reaction to form an activated alkene methyl connecting chain to obtain a difluoro-noone-like chalcone derivative, and the product is subjected to an MS, 1H NMR spectral data characterization. In vitro anti-tumor activity was evaluated by MTT assay to evaluate the anti-proliferative activity of the difluoro-1-type chalcone derivatives on human pancreatic cancer Panc, bladder cancer T24, gastric cancer HGC823, prostate cancer PU145, gastric cancer HGC27, and pancreatic cancer Capan-1 cells. The results showed that the anti-tumor activity of the obtained target compound was stronger than that of the corresponding parent compound, and the IC50 value of the compounds E5, E6, F1, F4, F5 and F6 was between 0.13 and 0.69. m Conclusion The structure of 24 difluoro-one-like chalcone derivatives has been synthesized and its structure is confirmed by the spectral data. The results of in vitro anti-tumor activity show that the anti-tumor activity of the target compound is stronger than that of the corresponding parent compound. Therefore, the novel difluoro-one-like chalcone compound has the prospect of development as a lead compound, and has the value of further research.
【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R914;R96

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