【摘要】：1,2,4-三氮唑類化合物具有抗腫瘤、抗菌、止痛、除草等多方面的生物活性,在醫(yī)藥和農(nóng)藥領(lǐng)域都有廣泛的應(yīng)用,因而備受關(guān)注。Essramycin是含有1,2,4-三氮唑并嘧啶酮結(jié)構(gòu)的海洋天然產(chǎn)物,具有抗菌、抗腫瘤等生物活性。本文以其為母體結(jié)構(gòu),設(shè)計(jì)并合成了系列1,2,4-三氮唑并嘧啶類雜環(huán)化合物,并進(jìn)行了生物活性篩選,具體完成了以下工作:依據(jù)天然產(chǎn)物的母核結(jié)構(gòu),設(shè)計(jì)了兩類化合物,即1,2,4-三氮唑嘧啶酮類化合物和1,2,4-三氮唑嘧啶胺類化合物。并以芳香酰氯和氨基胍為起始原料,經(jīng)過酰胺化、環(huán)合、縮合環(huán)化等反應(yīng)制備了1,2,4-三氮唑并嘧啶酮類化合物;通過對(duì)反應(yīng)條件的優(yōu)化,建立了收率良好的該類化合物通用合成方法。在此基礎(chǔ)上,將該類化合物的羰基經(jīng)氯化后胺解,制備了一系列具有全新結(jié)構(gòu)的1,2,4-三氮唑并嘧啶胺類化合物。所有化合物結(jié)構(gòu)均通過核磁、質(zhì)譜、紅外等譜學(xué)手段進(jìn)行了確證。采用SRB法,在Hep G2、MCF-7、SKOV3和H1299這四種腫瘤細(xì)胞株上對(duì)所合成的46個(gè)化合物進(jìn)行了抗腫瘤活性測(cè)試,發(fā)現(xiàn)1,2,4-三氮唑并嘧啶酮類化合物(Ⅴg)對(duì)Hep G2、MCF-7、SKOV3這三種腫瘤細(xì)胞株有一定的抑制作用,其IC50值分別為14.8μM、16.3μM、5.9μM;化合物(Ⅴa、Ⅴc)對(duì)Hep G2和SKOV3細(xì)胞株均有一定的抑制作用,其IC50值分別為21.7μM、33.1μM和15.5μM、23.1μM;1,2,4-三氮唑類嘧啶胺類化合物(ⅰp、ⅰo)對(duì)H1299細(xì)胞株有一定的抑制作用,其IC50值分別是12.2μM、25.4μM。初步的構(gòu)效關(guān)系表明,化合物結(jié)構(gòu)A中當(dāng)R1和R2為供電子基團(tuán)(甲基、甲氧基)時(shí),R3為氫時(shí),具有較好的抑制活性;化合物結(jié)構(gòu)B中R4為供電基團(tuán)(甲氧基)時(shí),R6為取代苯環(huán)且取代基也為供電基團(tuán)(甲基)時(shí),有較好的抑制活性。將化合物用于原代大腦皮層神經(jīng)元細(xì)胞胞內(nèi)鈣離子震蕩模型,發(fā)現(xiàn)1,2,4-三氮唑嘧啶胺類化合物無(wú)任何抑制作用,1,2,4-三氮唑并嘧啶酮類化合物中有5個(gè)具有優(yōu)良的抑制活性,并將其用于4-AP誘導(dǎo)的癲癇模型上,發(fā)現(xiàn)這五種化合物(Ⅴc、Ⅴf、Ⅴd、Ⅴe、Ⅴg)具有優(yōu)異的抑制活性,其IC50分別為2.35μM、3.21μM、12.35μM、15.40μM、11.03μM,明顯優(yōu)于陽(yáng)性對(duì)照藥卡馬西平(28μM)。初步的構(gòu)效關(guān)系表明,嘧啶酮結(jié)構(gòu)是抗癲癇活性的必須片段。抗癲癇活性結(jié)果為進(jìn)一步研究開發(fā)具有抗癲癇活性的1,2,4-三氮唑并嘧啶酮類化合物提供重要的借鑒和指導(dǎo)。
[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，

本文編號(hào)：2253445