A New Series of Cytotoxic Pyrazoline Derivatives as Potential Anticancer Agents that Induce Cell Cycle Arrest and Apoptosis

Abstract

A new series of pyrazoline derivatives 1b–12b was designed, synthesized and evaluated for antiproliferative activity against three cancer cell lines (HepG-2, Hela and A549). Additionally, NIH/3T3 cell cytotoxicity were tested and the structure activity relationships (SARs) were also determined. Among these new derivatives, the compounds 3-(4-fluorophenyl)-5-(3,4,5-trimethoxythiophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (1b) and 3-(4-chlorophenyl)-5-(3,4,5-trimethoxythiphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (2b) showed the best activity against HepG-2 cells, with IC50 values of 6.78 μM and 16.02 μM, respectively. They also displayed potent activity against Hela cells; meanwhile, 3-(4-chlorophenyl)-5-(3-bromo-4-hydroxy-5-methoxythiophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (5b) and 3-(4-bromo-phenyl)-5-(3-bromo-4-hydroxy-5-methoxythiophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (6b) were also identified as promising anticancer agents against A549 cells owing to their notable inhibitory effect, compared with cisplatin (IC50 = 29.48 μM). Furthermore, it was also found that compounds 1b and 2b had low cytotoxicity against NIH/3T3 cells and further mechanistic studies revealed that 1b arrested HepG-2 cells cycle at the G2/M phase at high concentrations and induced apoptosis in HepG-2 cells. Moreover, 1b upregulated protein expression level of cleaved caspase-3, cleaved PARP, Bax and p53 and downregulated protein expression level of Bcl-2 in dose-dependent way in HepG-2 cells. Thus, this study indicates that compound 1b might be a promising antitumor drug candidate.

Design, synthesis, and pharmacology of some oxadiazole and hydroxypyrazoline hybrids bearing thiazoyl scaffold: antiproliferative activity, molecular docking and DNA binding studies

“…They exhibit a wide range of biological activities such as antidepressant, anti-inflammatory, antimicrobial, and anticancer effects etc. In accordance with literature, pyrazoline derivatives are not useful in treatment of various cancer types, including lung, breast, colon, rectum, brain, stomach, liver, bladder, pancreas, bone, mouth, esophagus, cervix and prostate cancers, and also some of them act as cancer chemopreventive agents [33, 34, 35, 36, 37, 38]. Numerous analysis shown, pyrazoline derivatives were reported as epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors [39], COX-2/B-Raf inhibitors [40], aurora kinase inhibitors [41], tubulin assembling inhibitors [42], telomerase inhibitors [43].…”

A novel series of pyrazole-platinum(II) complexes as potential anti-cancer agents that induce cell cycle arrest and apoptosis in breast cancer cells

“…and Wang et al. in their cell cycle disturbance studies 37 , 38 . An increase in the cell cycle of the G2/M phase may indicate that DNA strands have been damaged, which is compatible with one of the mechanisms of cisplatin 23 .…”

Synthesis, Docking, and Anticancer Activity of New Thiazole Clubbed Thiophene, Pyridine, or Chromene Scaffolds

“…Cytotoxicity determinations are based the transformation of the yellow 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) to a purple formazan derivative by mitochondrial succinate dehydrogenase in practical cells. The method of this MTT assay was performed as previously described in detail .…”