article · RSC Advances
Researchers synthesized a series of novel pyrazolyl-chalcone hybrid derivatives using Claisen-Schmidt condensation, reacting 4-acetyl-5-thiophene-pyrazole with selected heteroaryl aldehydes to produce targeted compounds in good yields. All synthesized compounds were structurally characterised using elemental analysis, nuclear magnetic resonance, mass spectrometry, and infrared spectroscopy. In vitro evaluations assessed anticancer activity across three human cancer cell lines, namely MCF7 breast adenocarcinoma, PC3 prostate cancer, and PACA2 pancreatic carcinoma, alongside normal BJ1 skin fibroblasts. Compound 9e demonstrated superior potency against PACA2 cells compared to the standard drug doxorubicin, while compound 7d showed greater activity against MCF7 cells than the control. Subsequent investigations on breast and pancreatic lines confirmed their effects on DNA damage, DNA fragmentation, and gene expression. Molecular docking indicated favourable binding affinities for compound 9e towards the mutant tumour suppressor protein P53 Y220C, and compound 7d against Bcl2 and CDK4 targets.
Pancreatic and breast cancers remain difficult to treat, often requiring therapies with improved potency and selective mechanisms. By designing hybrid molecules that simultaneously target key biological pathways, this study identifies two candidate compounds that outperform standard doxorubicin in laboratory cell cultures. These findings offer valuable chemical starting points for developing alternative cancer therapies capable of inducing targeted cellular damage.
This research is at an early experimental stage, confined to chemical synthesis and preliminary in vitro laboratory testing. The findings could potentially serve pharmaceutical developers and oncology researchers seeking lead structures for future therapeutic drug candidates targeting pancreatic or breast cancers. Significant further preclinical development, including in vivo efficacy and safety testing, will be required before any commercial or clinical application can be considered.
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A unique series of pyrazolyl-chalcone derivatives was synthesized <i>via</i> the method of Claisen-Schmidt condensation. The desired chalcone derivatives 7a-d and 9a-f were obtained in good yields by reacting the 4-acetyl-5-thiophene-pyrazole with the appropriate heteroaryl aldehyde derivatives. The novel chalcones have undergone complete elemental analysis, <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, mass spectrometry, and IR characterization. The three human cancer cell lines MCF7 (human Caucasian breast adenocarcinoma), PC3 (prostatic cancer) and PACA2 (pancreatic carcinoma) as well as the normal cell line BJ1 (normal skin fibroblasts) were tested <i>in vitro</i> for the anti-cancer properties of the newly synthesized chalcone derivatives. When compared to the reference medicine doxorubicin (IC<sub>50</sub> = 52.1 μM), compound 9e showed the most promise derivative (IC<sub>50</sub> = 27.6 μM) against PACA2 cells, while compound 7d demonstrated anticancer efficacy (IC<sub>50</sub> = 42.6 μM against MCF7 cells compared to the reference drug doxorubicin (IC<sub>50</sub> = 48 μM). Using breast and pancreatic cell lines, the gene expression, DNA damage, and DNA fragmentation percentages for compounds 7d and 9e were evaluated. Moreover, the molecular docking study of compounds 7d and 9e was assessed. The binding affinities of compound 9e toward P53 mutant Y220C was -22 kcal per mole, while those of compound 7d towards Bcl2 and CDK4 were -27.81 and -26.9 kcal per mole, respectively, compared to the standard values (-15.82, -33.96 and -29.9 kcal per mole).
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DOI: 10.1039/d4ra03375b
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