Synthesis and molecular docking study of new pyrazole derivatives as potent anti-breast cancer agents targeting VEGFR-2 kinase

Abstract

Based on the previous studies that revealed the valuable role of pyrazole scaffold in cancer management and VEGFR-2 inhibition, a new set of pyrazole conjugated with pyrazoline, triazolopyrimidine and pyrazolone moieties were synthesized and investigated for their anticancer efficiency against human breast cancer MCF-7. The anticancer screening revealed the significant sensitivity of breast carcinoma towards compounds 4b, 5c, 6c, 7b, 7c and 12c with IC₅₀ values ranging from 16.50 - 26.73 µM in comparison with tamoxifen (IC₅₀ = 23.31 µM). Moreover, the new analogues were further examined for their VEGFR-2 inhibitory activity, among the tested derivatives 5c, 6c, 7b, 7c and 12c displayed prominent inhibitory efficiency versus VEGFR-2 kinase with % inhibition ranging from 70 to 79%. Compounds 6c, 7c and 12c revealed inhibitory efficiency in nanomolar level with IC₅₀ (913.51, 225.17 and 828.23 nM, respectively) comparing to sorafenib (IC₅₀ = 186.54 nM). Flow cytometric analysis revealed that the promising compound 12c prompted pre-G1 apoptosis and cell growth cessation at G2/M phase and stimulated apoptosis via activation of caspase-3. Moreover, molecular docking study of the promising derivatives was performed to highlight their binding modes and interactions with the amino acid residues of VEGFR-2 enzyme.

Keywords: Apoptosis; Breast cancer; Caspase-3; Molecular docking; Pyrazole; VEGFR-2.