Issue 12, 2023

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

Abstract

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 μM, respectively compared to staurosporine with IC50 values of 6.358 ± 0.24 and 4.849 ± 0.22 μM. 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 μM, compared to sunitinib with IC50 = 0.035 ± 0.012 μM. 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.

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

Supplementary files

Article information

Article type
Research Article
Submitted
08 Sep 2023
Accepted
23 Okt 2023
First published
07 Nov 2023

RSC Med. Chem., 2023,14, 2640-2657

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

A. M. Abdelhamed, R. A. Hassan, H. H. Kadry and A. A. Helwa, RSC Med. Chem., 2023, 14, 2640 DOI: 10.1039/D3MD00476G

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