期刊
ARCHIV DER PHARMAZIE
卷 353, 期 4, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ardp.201900319
关键词
antiproliferative; cell cycle arrest profile; pyrazolopyrimidine; synthesis; VEGFR-2
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-mu M 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 mu M and TGI values in the range of 2.17-100 mu M. 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.
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