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

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.

GRAPHICAL ABSTRACT

KEYWORDS:

• Coumarin
• metal-free domino reaction
• C–N coupling
• Knoevenagel condensation
• VEGFR-2
• EGFR

Acknowledgements

The authors are grateful to the NMR and MS Departments at Bielefeld University for spectral measurements. We would like to thank Carmela Michalek for biological activity testing and Marco Wißbrock with Anke Nieß for technical assistance. The authors also would like to thank the National Research Centre, Egypt for the laboratory facilities during VEGFR-2 and EGFR inhibitory studies. This work was also 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).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by German Academic Exchange Service (DAAD): [Grant Number ID57166072].