ABSTRACT

A metal-free, atom-economy and simple work-up domino amination-Knoevenagel condensation approach to construct new coumarin analogous (4a-f and 8a-e) was described. Further, new formyl (5a,d-f) and nitro (9a,d-f) coumarin derivatives were synthesized via C-N coupling reaction of various cyclic secondary amines and 4-chloro-3-(formyl-/nitro)coumarins (1a,c), respectively. The confirmed compounds were screened for their in vitro anti-proliferative activity against KB-3-1, A549 and PC3 human cancer cell lines using resazurin cellular-based assay. Among them, coumarin derivatives 4e and 8e displayed the best anti-cervical cancer potency (KB-3-1) with IC₅₀ values of 15.5 ± 3.54 and 21 ± 4.24 µM, respectively. Also, 4e showed the most promising cytotoxicity toward A549 with IC₅₀ value of 12.94 ± 1.51 µM. As well, 9d presented a more significant impact of potency against PC3 with IC₅₀ 7.31 ± 0.48 µM. Moreover, 8d manifested selectivity against PC3 (IC₅₀ = 20.16 ± 0.07 µM), while 8e was selective toward KB-3-1 cell line (IC₅₀ = 21 ± 4.24 µM). Matching with docking profile, the enzymatic assay divulged that 8e is a dual potent single-digit nanomolar inhibitor of VEGFR-2 and EGFR with IC₅₀ 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、原子经济和简单的后处理多米诺胺化-Knoevenagel 缩合方法来构建新的香豆素类似物（4a-f和8a-e）。此外，通过各种环状仲胺和4-氯-3-(甲酰基-/硝基)香豆素( 1a , c )的CN偶联反应分别合成了新的甲酰基( 5a,df )和硝基( 9a,df )香豆素衍生物。 . 使用基于刃天青细胞的测定法筛选确认的化合物对 KB-3-1、A549 和 PC3 人癌细胞系的体外抗增殖活性。其中香豆素衍生物4e和8e显示出最好的抗宫颈癌效力 (KB-3-1)，IC ₅₀值分别为 15.5 ± 3.54 和 21 ± 4.24 µM。此外，4e对 A549 显示出最有希望的细胞毒性，IC ₅₀值为 12.94 ± 1.51 µM。同样，9d对 PC3 的效力具有更显着的影响，IC _{50 为}7.31 ± 0.48 µM。此外，8d对 PC3 具有选择性（IC ₅₀ = 20.16 ± 0.07 µM），而8e对 KB-3-1 细胞系具有选择性（IC ₅₀ = 21 ± 4.24 µM）。与对接剖面相匹配，酶法分析揭示了8e是一种双有效的单位数纳摩尔 VEGFR-2 和 EGFR 抑制剂，IC ₅₀值为 24.67 nM 和 31.6 nM，分别与索拉非尼 (31.08 nM) 和厄洛替尼 (26.79 nM) 几乎等效。