Metal-free domino amination-Knoevenagel condensation approach to access new coumarins as potent nanomolar inhibitors of VEGFR-2 and EGFR
| Autor: | Marcel Frese, Ahmed Halawa, Larissa V. Ponomareva, Mohamed Shaaban, Maha M. Soltan, Khaled A. Shaaban, Ahmed M. El-Agrody, Norbert Sewald, Essam M. Eliwa, Jon S. Thorson |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
biology
Chemistry VEGF receptors Science Condensation vegfr-2 General Chemistry Coumarin Combinatorial chemistry coumarin Domino chemistry.chemical_compound metal-free domino reaction Metal free knoevenagel condensation egfr biology.protein c–n coupling Environmental Chemistry Knoevenagel condensation QD1-999 Amination |
| Zdroj: | Green Chemistry Letters and Reviews, Vol 14, Iss 4, Pp 578-599 (2021) |
| ISSN: | 1751-8253 |
| Popis: | 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 ��M, respectively. Also, 4e showed the most promising cytotoxicity toward A549 with IC50 value of 12.94 �� 1.51 ��M. As well, 9d presented a more significant impact of potency against PC3 with IC50 7.31 �� 0.48 ��M. Moreover, 8d manifested selectivity against PC3 (IC50 = 20.16 �� 0.07 ��M), while 8e was selective toward KB-3-1 cell line (IC50 = 21 �� 4.24 ��M). 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|