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Dual EGFR/VEGFR2 inhibitors and apoptosis inducers: Synthesis and antitumor activity of novel pyrazoline derivatives
Author(s) -
Alkamaly Omkulthom M.,
Altwaijry Najla,
Sabour Rehab,
Harras Marwa F.
Publication year - 2021
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202000351
Subject(s) - chemistry , apoptosis , cytotoxicity , ic50 , pyrazoline , downregulation and upregulation , pharmacology , in vitro , receptor tyrosine kinase , docking (animal) , kinase , cancer research , biochemistry , biology , medicine , nursing , organic chemistry , gene
Novel derivatives of the pyrazoline scaffold were synthesized and investigated for their cytotoxicity against prostate (PC‐3), hepatocellular (HepG2), and breast (MDA‐MB‐231) carcinoma cells. The most active compounds, 4a , 4b , 5b , and 7c , revealed significant and broad‐spectrum anticancer activities with IC 50 values of 1.30–7.18 μM in comparison with doxorubicin (IC 50 = 5.12–7.33 μM). Additionally, they exhibited lower cytotoxicity against normal WI‐38 cells, indicating their high safety profiles. Aiming to enlighten the inhibitory potential on receptor tyrosine kinases (RTKs), compounds 4a , 4b , 5b , and 7c were assessed for their activities against four different RTKs (EGFR, FGFR2, HER2, and VEGFR2) and their apoptotic potencies on PC‐3 cells. The results revealed that compounds 5b and 7c are potent dual EGFR and VEGFR2 inhibitors (IC 50 = 0.21 and 0.23 μM, respectively, against EGFR; 0.22 and 0.21 μM, respectively, against VEGFR2), whereas they displayed moderate inhibitory activities against HER2 and FGFR2. Besides, compounds 4a , 4b , 5b , and 7c prompted apoptosis via the upregulation of Bax, p53, and caspase‐3, together with the downregulation of the levels of Bcl‐2. Also, it was found that compounds 5b and 7c are more potent as apoptosis inducers than the other tested derivatives. Furthermore, molecular docking analyses of compounds 4a , 4b , 5b , and 7c in the EGFR and VEGFR ATP binding sites were performed, to confirm the in vitro assays.