新型 N-烷基化苯并噻吩衍生物的合成方法及其抗增殖活性和分子对接研究。
New Approaches for the Synthesis N-alkylated Benzo[]thiophene Derivatives together with their Antiproliferative and Molecular Docking Studies.
机构信息
Pharmaceutical Chemistry Department, Pharmacy College, Jazan University, P.O. Box 114, Jazan, Saudi Arabia.
Department of Chemistry, Egyptian Drug Authority (EDA) 51 Wezaret El-Zeraa St, Dokki, Giza, A. R. Egypt.
出版信息
Anticancer Agents Med Chem. 2023;23(12):1429-1446. doi: 10.2174/1871520623666230316103419.
BACKGROUND
2-Amino thiophene derivatives are important compounds not only for their uses in many heterocyclic reactions but also due to their wide range of pharmaceutical and biological activities.
OBJECTIVE
The aim of this work was to explore a number of new heterocyclic derivatives, studying their inhibitions toward cancer cell lines and studying their structure activity relation ship.
METHODS
Alkylation of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was achieved through its reaction with chloroacetone and 2-bromo-1-(4-aryl)ethanone derivatives to give compounds 3 and 11a-c. The produced compoumds were subjected to further heterocylization reactions and cytotoxic evaluation against the three cancer cell lines MCF-7, NCI-H460 and SF-268, together with the normal cell line WI 38. Further evaluations were obtained through studying their inhibitions against cancer cell lines classified according to the disease. Anticancer screening against hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines for all compounds together with the molecular docking of 12c, 12d, 12e and 12f were studied.
RESULTS
Anti-proliferative evaluations and inhibitions for all of the synthesized compounds showed that many compounds exhibited high inhibitions.
CONCLUSION
Toward the three cancer cell lines, compounds 3, 5a, 7a, 9a, 9b, 11b, 12b, 12d, 12e, 12f, 14c, 14e, 14f, 15e, 15f, 16e, 16f, 17c, 18b, 22a and 22c were the most cytotoxic compounds. The high activities of some compounds were attributed to the presence of the electronegative CN and or Cl groups within the molecule. Most of the tested compounds exhibited inhibitions higher than the reference doxorubicin toward hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines. The score of binding energy of compounds 12c, 12d, 12e and 12f was close to the reference Foretinib which appeared through the molecular docking results of such compounds.
背景
2-氨基噻吩衍生物不仅因其在许多杂环反应中的用途而重要，而且因其广泛的药物和生物活性而重要。
目的
本工作旨在探索一些新的杂环衍生物，研究它们对癌细胞系的抑制作用，并研究它们的构效关系。
方法
通过与氯丙酮和 2-溴-1-(4-芳基)乙酮衍生物反应，对 2-氨基-4,5,6,7-四氢苯并[b]噻吩-3-甲腈进行烷基化，得到化合物 3 和 11a-c。所生成的化合物进一步进行杂环化反应，并对三种癌细胞系 MCF-7、NCI-H460 和 SF-268 以及正常细胞系 WI 38 进行细胞毒性评价。进一步的评价是通过研究它们对根据疾病分类的癌细胞系的抑制作用获得的。对所有化合物进行了针对肝癌 HepG2 和宫颈癌 HeLa 细胞系的抗癌筛选，以及对 12c、12d、12e 和 12f 的分子对接研究。
结果
所有合成化合物的抗增殖评价和抑制作用表明，许多化合物表现出高抑制作用。
结论
对三种癌细胞系，化合物 3、5a、7a、9a、9b、11b、12b、12d、12e、12f、14c、14e、14f、15e、15f、16e、16f、17c、18b、22a 和 22c 是最具细胞毒性的化合物。一些化合物的高活性归因于分子中存在的吸电子 CN 和或 Cl 基团。大多数测试化合物对肝癌 HepG2 和宫颈癌 HeLa 细胞系的抑制作用高于参考阿霉素。化合物 12c、12d、12e 和 12f 的结合能评分接近参考 Foretinib，这是通过这些化合物的分子对接结果得出的。
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