海洋天然产物Essramycin类似物的合成及活性研究
发布时间：2018-10-05 12:48
【摘要】：1,2,4-三氮唑类化合物具有抗肿瘤、抗菌、止痛、除草等多方面的生物活性,在医药和农药领域都有广泛的应用,因而备受关注。Essramycin是含有1,2,4-三氮唑并嘧啶酮结构的海洋天然产物,具有抗菌、抗肿瘤等生物活性。本文以其为母体结构,设计并合成了系列1,2,4-三氮唑并嘧啶类杂环化合物,并进行了生物活性筛选,具体完成了以下工作:依据天然产物的母核结构,设计了两类化合物,即1,2,4-三氮唑嘧啶酮类化合物和1,2,4-三氮唑嘧啶胺类化合物。并以芳香酰氯和氨基胍为起始原料,经过酰胺化、环合、缩合环化等反应制备了1,2,4-三氮唑并嘧啶酮类化合物;通过对反应条件的优化,建立了收率良好的该类化合物通用合成方法。在此基础上,将该类化合物的羰基经氯化后胺解,制备了一系列具有全新结构的1,2,4-三氮唑并嘧啶胺类化合物。所有化合物结构均通过核磁、质谱、红外等谱学手段进行了确证。采用SRB法,在Hep G2、MCF-7、SKOV3和H1299这四种肿瘤细胞株上对所合成的46个化合物进行了抗肿瘤活性测试,发现1,2,4-三氮唑并嘧啶酮类化合物(Ⅴg)对Hep G2、MCF-7、SKOV3这三种肿瘤细胞株有一定的抑制作用,其IC50值分别为14.8μM、16.3μM、5.9μM;化合物(Ⅴa、Ⅴc)对Hep G2和SKOV3细胞株均有一定的抑制作用,其IC50值分别为21.7μM、33.1μM和15.5μM、23.1μM;1,2,4-三氮唑类嘧啶胺类化合物(ⅰp、ⅰo)对H1299细胞株有一定的抑制作用,其IC50值分别是12.2μM、25.4μM。初步的构效关系表明,化合物结构A中当R1和R2为供电子基团(甲基、甲氧基)时,R3为氢时,具有较好的抑制活性;化合物结构B中R4为供电基团(甲氧基)时,R6为取代苯环且取代基也为供电基团(甲基)时,有较好的抑制活性。将化合物用于原代大脑皮层神经元细胞胞内钙离子震荡模型,发现1,2,4-三氮唑嘧啶胺类化合物无任何抑制作用,1,2,4-三氮唑并嘧啶酮类化合物中有5个具有优良的抑制活性,并将其用于4-AP诱导的癫痫模型上,发现这五种化合物(Ⅴc、Ⅴf、Ⅴd、Ⅴe、Ⅴg)具有优异的抑制活性,其IC50分别为2.35μM、3.21μM、12.35μM、15.40μM、11.03μM,明显优于阳性对照药卡马西平(28μM)。初步的构效关系表明,嘧啶酮结构是抗癫痫活性的必须片段。抗癫痫活性结果为进一步研究开发具有抗癫痫活性的1,2,4-三氮唑并嘧啶酮类化合物提供重要的借鉴和指导。
[Abstract]:Due to their many biological activities, such as antitumor, antibacterial, analgesic and herbicide, they are widely used in the field of medicine and pesticide. Therefore, Essramycin is a marine natural product with the structure of 1C 2N 4 triazopyrimidine. Has antibacterial, anti-tumor and other biological activities. In this paper, a series of heterocyclic compounds of 1'2'2'- triazopyrimidine type have been designed and synthesized by using them as the parent structure, and their biological activities have been screened. The following works have been accomplished: according to the structure of the parent nucleus of natural products, two kinds of compounds have been designed. That is, 1, 2, 2, 4-triazolidone, and 1, 2, 2, 4-triazolidazole, 2, 2, 4-triazolidazolamine. Aromatic chlorides and aminoguanidine were used as starting materials to prepare 1'2'2 '4-triazole pyrimidine ketone by amidation, cyclization and condensation cyclization, and the reaction conditions were optimized. A general method for the synthesis of this kind of compounds in good yield was established. On the basis of these results, a series of novel compounds with a new structure, 1 / 2N / 4- triazopyrimidine amines, were prepared by the hydrolysis of carbonyl groups of these compounds with post-chlorinated amines. The structures of all compounds were confirmed by NMR, MS and IR. The antitumor activity of 46 compounds were tested by SRB method on four kinds of tumor cell lines, Hep G2CF-7, SKOV3 and H1299. It was found that the compounds (鈪，
本文编号：2253445
[Abstract]:Due to their many biological activities, such as antitumor, antibacterial, analgesic and herbicide, they are widely used in the field of medicine and pesticide. Therefore, Essramycin is a marine natural product with the structure of 1C 2N 4 triazopyrimidine. Has antibacterial, anti-tumor and other biological activities. In this paper, a series of heterocyclic compounds of 1'2'2'- triazopyrimidine type have been designed and synthesized by using them as the parent structure, and their biological activities have been screened. The following works have been accomplished: according to the structure of the parent nucleus of natural products, two kinds of compounds have been designed. That is, 1, 2, 2, 4-triazolidone, and 1, 2, 2, 4-triazolidazole, 2, 2, 4-triazolidazolamine. Aromatic chlorides and aminoguanidine were used as starting materials to prepare 1'2'2 '4-triazole pyrimidine ketone by amidation, cyclization and condensation cyclization, and the reaction conditions were optimized. A general method for the synthesis of this kind of compounds in good yield was established. On the basis of these results, a series of novel compounds with a new structure, 1 / 2N / 4- triazopyrimidine amines, were prepared by the hydrolysis of carbonyl groups of these compounds with post-chlorinated amines. The structures of all compounds were confirmed by NMR, MS and IR. The antitumor activity of 46 compounds were tested by SRB method on four kinds of tumor cell lines, Hep G2CF-7, SKOV3 and H1299. It was found that the compounds (鈪，
本文编号：2253445
本文链接：https://www.wllwen.com/kejilunwen/huaxue/2253445.html
教材专著
