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无金属多米诺胺化-克诺文纳格尔缩合方法用于获取新型香豆素，作为VEGFR-2和EGFR的强效纳摩尔抑制剂。

Metal-free domino amination-Knoevenagel condensation approach to access new coumarins as potent nanomolar inhibitors of VEGFR-2 and EGFR.

作者信息

Eliwa Essam M, Frese Marcel, Halawa Ahmed H, Soltan Maha M, Ponomareva Larissa V, Thorson Jon S, Shaaban Khaled A, Shaaban Mohamed, El-Agrody Ahmed M, Sewald Norbert

机构信息

Organic and Bioorganic Chemistry, Faculty of Chemistry, Bielefeld University, Bielefeld, Germany.

Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City-Cairo, Egypt.

出版信息

Green Chem Lett Rev. 2021;14(4):578-599. doi: 10.1080/17518253.2021.1981462. Epub 2021 Sep 24.

DOI:10.1080/17518253.2021.1981462
PMID:35821884
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9273165/
Abstract

A metal-free, atom-economy and simple work-up domino amination-Knoevenagel condensation approach to construct new coumarin analogous ( and ) was described. Further, new formyl () and nitro () coumarin derivatives were synthesized via C-N coupling reaction of various cyclic secondary amines and 4-chloro-3-(formyl-/nitro)coumarins (), respectively. The confirmed compounds were screened for their anti-proliferative activity against KB-3-1, A549 and PC3 human cancer cell lines using resazurin cellular-based assay. Among them, coumarin derivatives and displayed the best anti-cervical cancer potency (KB-3-1) with IC values of 15.5 ± 3.54 and 21 ± 4.24 μM, respectively. Also, showed the most promising cytotoxicity toward A549 with IC value of 12.94 ± 1.51 μM. As well, presented a more significant impact of potency against PC3 with IC 7.31 ± 0.48 μM. Moreover, manifested selectivity against PC3 (IC = 20.16 ± 0.07 μM), while was selective toward KB-3-1 cell line (IC = 21 ± 4.24 μM). Matching with docking profile, the enzymatic assay divulged that is a dual potent single-digit nanomolar inhibitor of VEGFR-2 and EGFR with IC values of 24.67 nM and 31.6 nM that were almost equipotent to sorafenib (31.08 nM) and erlotinib (26.79 nM), respectively.

摘要

描述了一种无金属、原子经济且后处理简单的多米诺胺化-克诺文纳格尔缩合方法来构建新的香豆素类似物（和）。此外，分别通过各种环状仲胺与4-氯-3-（甲酰基/硝基）香豆素（）的C-N偶联反应合成了新的甲酰基（）和硝基（）香豆素衍生物。使用基于刃天青细胞的测定法对确认的化合物针对KB-3-1、A549和PC3人癌细胞系的抗增殖活性进行了筛选。其中，香豆素衍生物和对宫颈癌（KB-3-1）显示出最佳的效力，IC值分别为15.5±3.54和21±4.24μM。此外，对A549显示出最有前景的细胞毒性，IC值为12.94±1.51μM。同样，对PC3的效力影响更显著，IC为7.31±0.48μM。此外，对PC3表现出选择性（IC = 20.16±0.07μM），而对KB-3-1细胞系具有选择性（IC = 21±4.24μM）。与对接图谱相匹配，酶活性测定表明是VEGFR-2和EGFR的双效单位数纳摩尔抑制剂，IC值分别为24.67 nM和31.6 nM，几乎分别与索拉非尼（31.08 nM）和厄洛替尼（26.79 nM）等效。

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