TY - JOUR
T1 - Metal-free domino amination-Knoevenagel condensation approach to access new coumarins as potent nanomolar inhibitors of VEGFR-2 and EGFR
AU - Eliwa, Essam M.
AU - Frese, Marcel
AU - Halawa, Ahmed H.
AU - Soltan, Maha M.
AU - Ponomareva, Larissa V.
AU - Thorson, Jon S.
AU - Shaaban, Khaled A.
AU - Shaaban, Mohamed
AU - El-Agrody, Ahmed M.
AU - Sewald, Norbert
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Coumarin
KW - C–N coupling
KW - EGFR
KW - Knoevenagel condensation
KW - VEGFR-2
KW - metal-free domino reaction
UR - http://www.scopus.com/inward/record.url?scp=85115658538&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85115658538&partnerID=8YFLogxK
U2 - 10.1080/17518253.2021.1981462
DO - 10.1080/17518253.2021.1981462
M3 - Letter
AN - SCOPUS:85115658538
SN - 1751-8253
VL - 14
SP - 576
EP - 597
JO - Green Chemistry Letters and Reviews
JF - Green Chemistry Letters and Reviews
IS - 4
ER -
