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噻吩[2,3-d]嘧啶酮衍生物的合成及其生物活性研究
聂礼飞
学位类型博士
导师阿吉艾克拜尔·艾萨
2018-06-02
学位授予单位中国科学院大学
学位授予地点北京
学位专业有机化学
关键词抗肿瘤 噻吩[2 苯磺酰 3-d]嘧啶酮 黑素生成 抗菌
摘要

噻吩并嘧啶酮是一类含噻吩及嘧啶酮环的含氮稠杂环化合物。早在二十世纪七十年代就备受人们的关注,大量文献报道噻吩并嘧啶酮衍生物具有广泛的生物活性,己然成为医药化学品研究和开发的热点之一。从噻吩并嘧啶酮类衍生物的应用可以看出,探索这类化合物的合成方法对于寻找新型医药、农药等领域先导化合物具有极大的理论和应用价值。本文首先详细介绍了噻吩[2,3-d]嘧啶酮衍生物的合成方法及其应用。在此基础上,设计了一条原料易得、操作简单、合成路线较短且收率较高的合成路线:以草酸二乙酯、溴乙烷为原料,经四步反应合成氮杂环噻吩[2,3-d]嘧啶酮-3-甲酸化合物,然后,将脂肪胺和芳香胺引入到氮杂环噻吩[2,3-d]嘧啶酮-3-甲酸分子中,合成51个新型的氮杂环噻吩[2,3-d]嘧啶酮-3-甲酰胺类衍生物,并对所合成的化合物进行了结构表征,初步研究了所有化合物对小鼠B16细胞中黑素生成的作用、体外抗菌活性及抗肿瘤活性。促黑素生成活性结果表明:有22个化合物对黑素生成的促进作用优于阳性对照(8-MOP);抗菌活性结果表明:化合物8m、8q、9h、9m、9n、9q、和10q对白色念珠菌(Candida Albicans)有抑制作用;化合物8m、8q、9m、9q、10m和10q对金黄色葡萄球菌(Staphylococcus Aureus)也表现出了抑制作用;抗肿瘤活性结果表明:与阳性对照(喜树碱)相比,所有化合物均没有表现出明显的抗肿瘤活性。同时,以中间体氮杂环噻吩[2,3-d]嘧啶酮-3-甲酸类化合物为原料,通过两条不同的合成路线制备氮杂环噻吩[2,3-d]嘧啶酮-3-胺类化合物,并对两条路线的关键反应步骤进行了条件优化实验,确定最佳合成路线及反应条件。并在此基础上,将磺胺分子引入到氮杂环噻吩[2,3-d]嘧啶酮-3-胺分子中,合成72个新型的氮杂环噻吩[2,3-d]嘧啶酮苯磺酰胺类衍生物。并对所合成的化合物进行了结构表征,初步研究了所有化合物对小鼠B16细胞中黑素生成的作用、体外抗菌活性及抗肿瘤活性。促黑素生成活性结果表明:有25个化合物对黑素生成的促进作用优于阳性对照(8-MOP);抗菌活性结果表明:化合物14h和化合物14r对白色念珠菌(Candida albicans)有抑制作用,化合物14b对大肠杆菌(E. coli)也表现出了抑制作用;抗肿瘤活性结果表明:与阳性对照(喜树碱)相比,所有化合物没有表现出明显的抗肿瘤活性。此外,经培养得到化合物13o和13w的单晶结构。

其他摘要

Thienopyrimidinones are a class of nitrogen-containing heterocyclic compounds containing with fused thiophene and pyrimidinone rings. Since 1970s, it has attracted much attention and a large number of thienopyrimidone derivatives with wide range of biological activities have been reported, which led to the research of thienopyrimidone compounds one of the hot topics in the research and development of drug candidates. Therefore, it would be of great theoretical and practical value to explore the new synthesis methods of these compounds for finding new leads for drug and pesticides.The first chapter of the dissertation described the previous research works of the synthesis methods of thiophene [2,3-d] pyrimidinone derivatives. The second chapter documented a synthetic route with easy availability of raw materials, simple operation, and high yield to prepare thiophene [2,3-d]pyrimidinone-3-carboxamide derivatives. The synthesis of azacyclothiophene was carried out in four steps using diethyl oxalate and ethyl bromide as starting materials. Then, aliphatic amines and aromatic amines were introduced into the intermediate azacyclothiophene [2,3-d]pyrimidinone-3-carboxylic acid to afford 51 novel thiophene [2,3-d]pyrimidinone-3-carboxamide derivatives. The structures of the synthesized compounds were characterized, and the antitumor activity, melanogenesis in mouse B16 cells and antibacterial activity of all compounds were investigated. Melanogenesis test results showed that 22 compounds had better activity compared to the positive control compound 8-MOP. And antibacterial activity test results showed that compounds 8m, 8q, 9h, 9m, 9n, 9q, and 10q exhibited inhibitory effects on Candida Albicans, and compounds 8m, 8q, 9m, 9q, 10m, and 10q also showed against avtivity to Staphylococcus Aureus. Unfortunately, all compounds did not show any significant anti-tumor activity compared to the positive control camptothecin.Furthermore, the intermediate azaheterothiophene[2,3-d]pyrimidinone-3- carboxylic acid compounds were used as starting materials to synthesis azaheterothiophene[2,3-d]pyrimidinone-3-amine via two different synthetic routes. The optimized conditions for the key reaction steps of the two routes were tested to determine the best synthesis route. In addition, sulfonamide groups were introduced into the azacyclothiophene [2,3-d]pyrimidinone-3-amine to produce 72 novel azacyclic thiophene [2,3-d]pyrimidinone derivatives containing benzenesulfonamide. The structures of all synthesized compounds were characterized. The antitumor activity, melanogenesis in mouse B16 cellds and antibacterial activity of all compounds were also examined. The results showed that 25 compounds exhibited stronger activity of melanogenesis than positive control compound 8-MOP. And antibacterial test results showed that compounds 14h and 14r demonstrated certain inhibitory effects on Candida albicans and compound 14b displayed activity against E. coli. All compounds did not showed significant anti-tumor activity compared to the positive control Camptothecin. Single crystal structures of compounds 13w and 13o were obtained to further confirm their structures.

文献类型学位论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/5468
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聂礼飞. 噻吩[2,3-d]嘧啶酮衍生物的合成及其生物活性研究[D]. 北京. 中国科学院大学,2018.
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