Novel pyrazolopyrimidine urea derivatives: Synthesis, antiproliferative activity, VEGFR‐2 inhibition, and effects on the cell cycle profile

Abstract

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 GI₅₀ 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 IC₅₀ 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.