含氧杂环的噻唑—吡唑类衍生物设计、修饰与生物活性评价

发布时间：2018-11-26 11:29

【摘要】：癌症是一种多因素诱导的疾病,近年来,各种癌症的发病率越来越高,对人类健康的威胁也越来越大。因此,对新型抗肿瘤化合物的研究引起人们越来越多的关注。受体酪氨酸激酶(RTKs)和表皮生长因子受体(EGFR)在调节肿瘤细胞增殖,分化,存活和凋亡中扮演非常重要的角色。配体与EGFR结合后,受体发生二聚化而发挥作用。EGFR和HER-2是目前肿瘤研究中最热门的靶点,因为它们的过度表达或异常活化常引起细胞恶性增生。吉非替尼(Gefitinib)和厄洛替尼(Erlotinib)是这类药物的代表,可以抑制EGFR/HER-2的过度表达,已经被美国食品药品监督管理局批准用来治疗非小细胞肺癌。很多具有吡唑骨架的化合物具有抗肿瘤、抗菌、抗炎症等多种生物活性,它们在化学界、医学界及药学界引起了人们的广泛关注。噻唑环衍生物也具有广谱的生物活性,如抗结核、抗菌、抗肿瘤等活性。尤其在与某些特定的活性基团结合后,吡唑和噻唑环能表现出更强的生物活性,这些特定的结构基团包括苯环,含氧杂环或者一些单链结构,如酰胺、磺酰脲等等。本论文设计合成了一系列具有噻唑和吡唑骨架衍生物的新型化合物,并进行了系统的活性筛选和构效关系研究,其中多数化合物具有很好的EGFR和HER-2抑制活性。根据基于结构设计的原理,借助于分子模拟计算技术,共设计合成了20个新化合物,并测试了所有化合物的生物活性,简述如下：合成了20个含氧杂环的噻唑-吡唑衍生物(C1-C20),并测定了它们的EGFR和HER-2抑制活性。首先分四步进行化学合成。然后对所有化合物进行结构鉴定,包括1H NMR、ESI-MS以及元素分析。最后对本系列化合物进行活性测定,主要包括MCF-7和B16-F10增殖试验,Western blotting, HER-2抑制试验。分子模拟结果显示,HER-2的ATP作用位点的氨基酸残基与化合物C6之间结合的最好(形成2个氢键)。综合分子模拟和生物活性筛选的结果,我们发现化合物C6对HER-2的抑制活性最好,ICso值为0.18 μM,与阳性对照Erlotinib相当。
[Abstract]:Cancer is a multi-factor induced disease. In recent years, the incidence of various cancers is increasing, and the threat to human health is also increasing. Therefore, more and more attention has been paid to the study of new anti-tumor compounds. Receptor tyrosine kinase (RTKs) and epidermal growth factor receptor (EGFR) play important roles in regulating proliferation, differentiation, survival and apoptosis of tumor cells. EGFR and HER-2 are the most popular targets in tumor research at present because their overexpression or abnormal activation often cause malignant proliferation of cells. Gefitinib (Gefitinib) and erlotinib (Erlotinib) are such drugs that inhibit the overexpression of EGFR/HER-2 and have been approved by the Food and Drug Administration for the treatment of non-small cell lung cancer. Many compounds with pyrazole skeleton have many biological activities, such as antitumor, antimicrobial, anti-inflammatory and so on, which have attracted wide attention in chemical, medical and pharmaceutical fields. Thiazole ring derivatives also have broad-spectrum biological activities, such as anti-tuberculosis, anti-bacterial, anti-tumor activities. Especially after binding with certain active groups, pyrazole and thiazole can exhibit stronger biological activity. These specific structural groups include benzene ring, oxygen-containing heterocyclic or some single-stranded structures, such as amide, sulfonylurea and so on. In this paper, a series of novel compounds with thiazole and pyrazole derivatives were designed and synthesized, and their activity screening and structure-activity relationship were systematically studied. Most of the compounds had good EGFR and HER-2 inhibitory activities. Based on the principle of structural design, a total of 20 new compounds were designed and synthesized with the help of molecular simulation techniques, and the biological activities of all compounds were tested. Twenty thiazole-pyrazole derivatives (C1-C20) containing oxygen heterocyclic compounds were synthesized and their EGFR and HER-2 inhibitory activities were determined. First, chemical synthesis is carried out in four steps. Then all the compounds were identified, including 1H NMR,ESI-MS and elemental analysis. Finally, the activity of this series of compounds was determined, including MCF-7 and B16-F10 proliferation test, Western blotting, HER-2 inhibition test. The results of molecular simulation showed that the amino acid residues at the ATP interaction site of HER-2 had the best binding to compound C 6 (forming two hydrogen bonds). Based on the results of molecular simulation and bioactivity screening, we found that the inhibitory activity of compound C6 on HER-2 was the best, with a ICso value of 0.18 渭 m, which was comparable to that of the positive control Erlotinib.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R91

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