2-(2-苯腙基)环己烷-1,3-二酮的杂环化合成噻吩、吡唑和 1,2,4-三嗪衍生物及其抗肿瘤和酪氨酸激酶抑制活性。
Heterocyclization of 2-(2-phenylhydrazono)cyclohexane-1,3-dione to Synthesis Thiophene, Pyrazole and 1,2,4-triazine Derivatives with Anti-Tumor and Tyrosine Kinase Inhibitions.
机构信息
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.
Department of Quality Assurance, Yemen Drug Company for Industry and Commerce, (YEDCO), Sana'a, Yemen.
出版信息
Anticancer Agents Med Chem. 2020;20(10):1209-1220. doi: 10.2174/1871520620666200310093911.
BACKGROUND
Recently tetrahydrobenzo[b]thiazole derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the thiazole nucleus were known.
OBJECTIVE
This work aimed to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from the arylhydrazonocyclohexan-1,3-dione followed by their heterocyclization reactions to produce anticancer target molecules.
METHODS
The arylhydrazone derivatives 3a-c underwent different heterocyclization reactions to produce thiophene, thiazole, pyrazole and 1,2,4-triazine derivatives. The anti-proliferative activity of twenty six compounds among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied.
RESULTS
Anti-proliferative evaluations, tyrosine and Pim-1 kinase inhibitions were perform for most of the synthesized compounds where the varieties of substituent through the aryl ring and the thiophene moiety afforded compounds with high activities.
CONCLUSION
The compounds with high anti-proliferative activity towards the cancer cell lines showed that compounds 3b, 3c, 5e, 5f, 8c, 9c, 11c, 12c, 14e, 14f and 16c were the most cytotoxic compounds. Further tests of the latter compounds toward the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 5e, 5f, 8c, 9c, 12c, 14e, 14f and 16c were the most potent of the tested compounds toward the five tyrosine kinases and compounds 6d, 11a, 20b and 21e were of the highest inhibitions towards Pim-1 kinase. Pan Assay Interference Compounds (PAINS) for the most cytotoxic compounds showed zero PAINS alert and can be used as lead compounds.
背景
最近，四氢苯并[b]噻唑衍生物因其广泛的药理活性，特别是治疗活性而受到特别关注。通过市场发现，许多含有噻唑核的药理学药物是已知的。
目的
本工作旨在合成不仅具有抗肿瘤活性而且具有激酶抑制剂活性的靶分子。靶分子是从芳基腙环已-1,3-二酮开始获得的，然后通过其杂环化反应产生抗癌靶分子。
方法
芳基腙衍生物 3a-c 经历不同的杂环化反应，生成噻吩、噻唑、吡唑和 1,2,4-三嗪衍生物。对 26 种合成化合物中的 26 种化合物对六种癌细胞系 A549、H460、HT-29、MKN-45、U87MG 和 SMMC-7721 的增殖活性进行了研究。
结果
对大多数合成化合物进行了增殖抑制评价、酪氨酸和 Pim-1 激酶抑制评价，其中芳基环和噻吩部分的取代基种类繁多，提供了具有高活性的化合物。
结论
对癌细胞系具有高增殖抑制活性的化合物表明，化合物 3b、3c、5e、5f、8c、9c、11c、12c、14e、14f 和 16c 是最具细胞毒性的化合物。对后 5 种酪氨酸激酶 c-Kit、Flt-3、VEGFR-2、EGFR 和 PDGFR 和 Pim-1 激酶的进一步测试表明，化合物 3c、5e、5f、8c、9c、12c、14e、14f 和 16c 是测试化合物中最有效的化合物对五种酪氨酸激酶和化合物 6d、11a、20b 和 21e 对 Pim-1 激酶的抑制作用最高。对最具细胞毒性的化合物进行泛分析干扰化合物 (PAINS) 检测，结果为零 PAINS 警报，可作为先导化合物。
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