Novel pyrazolo[3,4-d]pyrimidine derivatives: design, synthesis, anticancer evaluation, VEGFR-2 inhibition, and antiangiogenic activity

A novel series of 12 pyrazolo[3,4-d]pyrimidine derivatives were created and evaluated in vitro for their antiproliferative activity against the NCI 60 human tumor cell line panel. Compounds 12a-d displayed significant antitumor activity against MDA-MB-468 and T-47D (breast cancer cell lines), especially compound 12b, which exhibited the highest anticancer activity against MDA-MB-468 and T-47D cell lines with IC50 values of 3.343 +/- 0.13 and 4.792 +/- 0.21 mu M, respectively compared to staurosporine with IC50 values of 6.358 +/- 0.24 and 4.849 +/- 0.22 mu M. The most potent cytotoxic derivatives 12a-d were studied for their VEGFR-2 inhibitory activity to explore the mechanism of action of these substances. Compound 12b had potent activity against VEGFR-2 with an IC50 value of 0.063 +/- 0.003 mu M, compared to sunitinib with IC50 = 0.035 +/- 0.012 mu M. Moreover, there was an excellent reduction in HUVEC migratory potential that resulted in a significant disruption of wound healing patterns by 23% after 72 h of treatment with compound 12b. Cell cycle and apoptosis investigations showed that compound 12b could stop the cell cycle at the S phase and significantly increase total apoptosis in the MDA-MB-468 cell line by 18.98-fold compared to the control. Moreover, compound 12b increased the caspase-3 level in the MDA-MB-468 cell line by 7.32-fold as compared to the control.

Automated summary

A novel series of 12 pyrazolo[3,4-d]pyrimidine derivatives were evaluated for their antiproliferative activity against human tumor cell lines, showing that compound 12b exhibited the highest anticancer activity against breast cancer cell lines and had potent VEGFR-2 inhibitory activity and angiogenesis inhibition potential.