Design, synthesis, and docking studies of novel pyrazole-based scaffolds and their evaluation as VEGFR2 inhibitors in the treatment of prostate cancer

Dalia H Soliman; Mohamed S Nafie

doi:10.1039/d3ra02579a

Design, synthesis, and docking studies of novel pyrazole-based scaffolds and their evaluation as VEGFR2 inhibitors in the treatment of prostate cancer

RSC Adv. 2023 Jul 10;13(30):20443-20456. doi: 10.1039/d3ra02579a. eCollection 2023 Jul 7.

Authors

Dalia H Soliman^{1

2}, Mohamed S Nafie³

Affiliations

¹ Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University Badr City Cairo Egypt dalia-soliman@eru.edu.eg.
³ Department of Chemistry (Biochemistry Program), Faculty of Science, Suez Canal University Ismailia 41522 Egypt mohamed_nafie@science.suez.edu.eg.

Abstract

Since VEGFR-2 plays a crucial role in tumor growth, angiogenesis, and metastasis, it is a prospective target for cancer treatment. In this work, a series of 3-phenyl-4-(2-substituted phenylhydrazono)-1H-pyrazol-5(4H)-ones (3a-l) were synthesized and investigated for their cytotoxicity against the PC-3 human cancer cell line compared to Doxorubicin and Sorafenib as reference drugs. Two compounds 3a and 3i showed comparable cytotoxic activity with IC₅₀ values of 1.22 and 1.24 μM compared to the reference drugs (IC₅₀ = 0.932, 1.13 μM). Compound 3i was found to be the most effective VEGFR-2 inhibitor using in vitro testing of the synthesized compounds, with nearly 3-fold higher activity than Sorafenib (30 nM), with IC₅₀ 8.93 nM. Compound 3i significantly stimulated total apoptotic prostate cancer cell death 55.2-fold (34.26% compared to 0.62% for the control) arresting the cell cycle at the S-phase. The genes involved in apoptosis were also impacted, with proapoptotic genes being upregulated and antiapoptotic Bcl-2 being downregulated. These results were supported by docking studies of these two compounds within the active site of the VEGFR2 enzyme. Finally, in vivo, the study revealed the potentiality of compound 3i to inhibit tumor proliferation by 49.8% reducing the tumor weight from 234.6 mg in untreated mice to 83.2 mg. Therefore, 3i could be a promising anti-prostate cancer agent.