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Novel pyrazolopyrimidine urea derivatives: Synthesis, antiproliferative activity, VEGFR‐2 inhibition, and effects on the cell cycle profile
Author(s) -
Kassab Asmaa E.,
ElDash Yara,
Gedawy Ehab M.
Publication year - 2020
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.201900319
Subject(s) - chemistry , cytotoxicity , cell cycle , apoptosis , cell cycle checkpoint , dna fragmentation , cell growth , cytotoxic t cell , stereochemistry , programmed cell death , biochemistry , docking (animal) , pharmacology , in vitro , biology , medicine , nursing
A series of novel diaryl urea pyrazolopyrimidine derivatives was designed and synthesized. All the synthesized compounds were evaluated for cytotoxic activity by the National Cancer Institute. A significant antiproliferative activity at a 10‐µM dose was shown by four compounds ( 5c, 5e, 5g , and 5h ), and they were accordingly evaluated at five concentrations. They showed a potent and broad‐spectrum antiproliferative activity, with GI 50 values between 0.553 and 3.80 µM and TGI values in the range of 2.17–100 µM. These four compounds potently inhibited the vascular endothelial growth factor receptor‐2 (VEGFR‐2) with IC 50 values in the nanomolar range. Molecular docking attributed their potent VEGFR‐2 inhibitory activity to their interactions with key amino acids in the VEGFR‐2 active site. Their flow cytometric analysis showed that they exerted their cytotoxic activity by reduction of the cellular proliferation and by induction of cell cycle arrest at the G2/M phase. Additionally, they induced DNA degradation or fragmentation, confirming the role of apoptosis in the cancer cell death and cytotoxicity induced by these compounds.