新型查尔酮并杂环类衍生物的合成及活性研究

发布时间：2018-04-19 19:59

  本文选题：查尔酮 + 氨基二硫代甲酸酯　； 参考：《郑州大学》2017年硕士论文

【摘要】：氨基二硫代甲酸酯类化合物是一种天然小分子,能够有效地螯合重金属以及作为一种单功能性诱导物选择性增强二相酶活性,因此在临床药物研究中得到广泛应用。查尔酮化合物具有1,3-二苯基-丙烯酮结构,能够和不同的药物作用靶点结合从而发挥其药物活性。因而,对于这二类天然小分子的研究得到的药物学领域广泛的关注和研究。本论文根据文献报道,在充分研究具有氨基二硫代甲酸酯类、查尔酮结构化合物构效关系和药物活性的基础之上,保留了查尔酮活性片段的完整性,利用克莱森缩合反应和拼合原理分别将生物活性基团卤代烷基酰胺类、氨基二硫代甲酸酯、三氮唑等活性片段连分别连接到查尔酮的分子中,共合成的43个目标化合物。具体研究工作如下:第一部分是杂环类查尔酮衍生物的合成。主要通过克莱森缩合反应合成氨基查尔酮和叠氮查尔酮化合物。利用已合成的关键中间体,根据药物拼合原理,设计并合成了三个系列共43个新型查尔酮类衍生物,并且所有合成的化合物均经过核磁和质谱结构表征。第二部分是生物活性评价。对所合成的43个新型查尔酮衍生物,采用MTT法进行了抗肿瘤相关活性评价。主要选择性的是人前列腺细胞(PC-3)、胃癌细胞(MGC-803)、人食管癌细胞(EC-109)这三种癌细胞株。实验结果表明大部分卤代烷基酰胺类化合物和氨基二硫代甲酸酯并查尔酮类衍生物具有较好抗肿瘤活性,其中化合物Ⅰ-1、Ⅰ-2、Ⅰ-4、Ⅱ-4、Ⅱ-7、Ⅱ-10、Ⅱ-15表现出较好的抗肿瘤活性。其中活性最好的是Ⅱ-4。当引入卤代烷基酰胺类和氨基二硫代甲酸酯活性分子,发现其药物活性能够得到有效增加。但是,在此基础上引入三氮唑结构时,活性却降低。本论文的工作对于发现抗肿瘤活性更好,生物利用度更高的先导小分子提供一定基础。
[Abstract]:Aminodithiocarbamate is a kind of natural small molecule which can effectively chelate heavy metals and selectively enhance the activity of biphasic enzyme as a mono-functional inducer so it has been widely used in clinical drug research. Chalcone has the structure of 1: 3-diphenyl-propenone and can combine with different drug targets to exert its drug activity. Therefore, the study of these two kinds of natural small molecules has received extensive attention and research in the field of pharmacology. In this paper, based on the full study of the structure-activity relationship and drug activity of amino dithiocarbamate and chalcone, the integrity of the active fragment of chalcone was preserved. By using the Clayson condensation reaction and the splicing principle, the active fragments of bioactive groups, such as haloalkyl amides, amino dithiocarbamate and triazoles, were connected to the molecules of chalcone, respectively, and 43 target compounds were synthesized. The main work is as follows: the first part is the synthesis of heterocyclic chalcone derivatives. Aminocalcone and azacarone compounds were synthesized by Clayson condensation reaction. Three series of 43 new chalcone derivatives were designed and synthesized according to the principle of drug splicing using the key intermediates. All the synthesized compounds were characterized by NMR and MS. The second part is bioactivity evaluation. The anti-tumor activity of 43 new chalcone derivatives was evaluated by MTT method. Three kinds of cancer cell lines were mainly selected: human prostate cell line (PC-3H), gastric cancer cell line (MGC-803) and human esophageal carcinoma cell line (EC-109). The results showed that most of the halogenated amides and derivatives of aminodithiocarbamate and chalcone had good antitumor activity, and compounds 鈪，

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