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.
Document Type
Article
Publication Date
9-24-2021
Digital Object Identifier (DOI)
https://doi.org/10.1080/17518253.2021.1981462
Funding Information
This work was supported by National Institutes of Health grant R01 GM115261 (JST), the Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Research and Innovation (CPRI, NIH P20 GM130456), the University of Kentucky College of Pharmacy, the University of Kentucky Markey Cancer Center, and the National Center for Advancing Translational Sciences (UL1TR000117 and UL1TR001998).
Repository Citation
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.; and Sewald, Norbert, "Metal-Free Domino Amination-Knoevenagel Condensation Approach to Access New Coumarins as Potent Nanomolar Inhibitors of VEGFR-2 and EGFR" (2021). Center for Pharmaceutical Research and Innovation Faculty Publications. 7.
https://uknowledge.uky.edu/cpri_facpub/7
Graphical abstract
Notes/Citation Information
Published in Green Chemistry Letters and Reviews, v. 14, issue 4.
© 2021 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.