二氢氟喹诺酮查尔酮衍生物的合成及抗肿瘤活性研究

发布时间：2018-07-01 21:13

本文选题：氟喹诺酮 + 查尔酮　；参考：《河南大学》2014年硕士论文

【摘要】：查尔酮是以1,3-二苯基丙烯酮或含有α,β-不饱和酮为基本骨架、且广泛存在于多种药用植物中的一类化合物,因其具有多种药理活性而备受关注。对其结构的修饰除多集中于苯环取代基的变化外,用杂环或稠杂环替代经典的苯环以改善其药效学或药动学性质,促进其向成药性方向发展,已成为新查尔酮化合物研究的重点。氟喹诺酮类药物是以1-取代-6-氟-7-杂环-喹啉-4-酮-3-羧酸为结构特征的新型抗菌药。基于其作用靶拓扑异构酶(TOPO)也是抗肿瘤药物的重要靶点,企图转化其抗菌活性到抗肿瘤活性已成为氟喹诺酮发展面临的新挑战。然而,对抗肿瘤氟喹诺酮的研究多源于对抗菌氟喹诺酮N-1位和C-7位取代基及C-3位羧基生物等排体的变化,产生的候选化合物均因体内利用度或毒性或稳定性等亟待要解决的生物学问题而未进入临床评价。因此,寻找新的结构修饰途径和方法,获得新结构的先导化合物可能是解决成药性问题的关键。基于已有的抗肿瘤氟喹诺酮构-效关系,C-3位羧基并非是抗肿瘤活性所必需的药效团,可用其等排体替代。本论文为进一步发现氟喹诺酮新的修饰方法,结合查尔酮类化合物的结构特征及其广泛的抗肿瘤活性,通过对抗菌氟喹诺酮C-3羧基的修饰,发展了一类新型结构的氟喹诺酮类查尔酮衍生物,并经目标化合物的体外抗肿瘤活性筛选结果,评价了结构修饰的合理性,为未来新化合物的设计提供依据。 1.目标化合物的设计与合成本文以商业氟喹诺酮羧酸为原料,经亲核取代、硼氢化钠还原脱羧,得到中间体C-7二乙醇胺二氢氟喹诺酮,再与芳香醛发生Claisen-Schmidt反应,得到相应的查尔酮类似物,产物经IR,1HNMR光谱数据进行表征。 2.体外抗肿瘤活性评价采用MTT实验方法,测试了新合成的28个化合物对人Panc胰腺癌、T24膀胱癌、PU145前列腺癌、HGC27胃癌、Capan胰腺癌体外生长抑制活性。结果表明,大部分化合物对人Panc胰腺癌、T24膀胱癌、PU145前列腺癌、HGC27胃癌、Capan胰腺癌均具有较强的生长抑制作用。 3.结论本文设计合成了28个C-7二乙醇胺取代的氟喹诺类酮衍生物,经1H-NMR、IR、光谱数据确证为目标化合物。体外抗肿瘤活性测试结果显示,对人五种癌细胞均有不同程度的抑制作用。表明C-3羧基和C-7哌嗪基并非是抗肿瘤所必须的基团,分别可以用亚甲基和二乙醇胺基替代。
[Abstract]:Chalcone is a kind of compound, which is based on 1 ~ 3- diphenyl propylene ketone or contains 伪, 尾 -unsaturated ketone, and widely exists in many medicinal plants. It has attracted much attention because of its various pharmacological activities. The modification of its structure is mainly focused on the changes of the substituents of benzene rings. The substitution of heterocyclic or dense heterocycles for classical benzene rings can improve its pharmacodynamic or pharmacokinetic properties and promote its development towards the direction of drug formation. It has become the focus of the study of neocalcone compounds. Fluoroquinolones are novel antimicrobial agents characterized by 1-substituted-6-fluoro-7-heterocyclic-quinoline-4-ketone-3-carboxylic acid. Because topoisomerase (Topo) is also an important target of antitumor drugs, it has become a new challenge for the development of fluoroquinolones to transform its antibacterial activity to antitumor activity. However, most of the studies on antitumor fluoroquinolones are due to the changes of the N-and C-7 substituents and C-3 carboxyl isoforms of antibacterial fluoroquinolones. The candidate compounds have not been evaluated because of biological problems, such as in vivo availability, toxicity or stability. Therefore, finding new ways and methods of structural modification and obtaining leading compounds with new structures may be the key to solve the problem of drug properties. Based on the existing structure-activity relationship of antitumor fluoroquinolones, C-3 carboxyl groups are not the necessary pharmacophore for antitumor activity. In order to find out a new modification method of fluoroquinolones, combining with the structural characteristics of chalcone compounds and their extensive antitumor activities, the modification of C-3 carboxyl groups of fluoroquinolones was carried out in this paper. A new class of fluoroquinolones derivatives was developed, and the rationality of structural modification was evaluated by screening the antitumor activity of the target compounds in vitro, which provided the basis for the design of new compounds in the future. 1. In this paper, the intermediate C-7 diethanolamine dihydrofluoroquinolone was synthesized from commercial fluoroquinolone carboxylic acid by nucleophilic substitution, sodium borohydride reductive decarboxylation, and Claisen-Schmidt reaction with aromatic aldehydes. The corresponding chalcone analogue was obtained and characterized by IR ~ 1H NMR spectra. MTT assay was used to evaluate the antitumor activity in vitro. The growth inhibitory activity of 28 new compounds against human Panc pancreatic carcinoma, bladder cancer, human bladder cancer, HGC27, gastric cancer and Capan pancreatic carcinoma was tested in vitro. The results showed that most of the compounds had strong growth inhibitory effects on human Panc pancreatic carcinoma, bladder cancer, human bladder cancer, and HGC27, HGC27, gastric cancer and Capan pancreatic carcinoma. Conclusion 28 C-7 diethanolamine substituted fluoroquinolone derivatives were designed and synthesized. The results of in vitro anti-tumor activity test showed that all five kinds of cancer cells were inhibited to some extent. The results showed that C-3 carboxyl group and C-7 piperazine group were not necessary groups for antitumor and could be replaced by methylene group and diethanolamine group respectively.
【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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