AIMS
To design, synthesize, and biologically evaluate novel bis-thiazole derivatives as potential PIM-1 kinase inhibitors for breast cancer therapy.
MATERIALS AND METHODS
A series of new bis-thiazole derivatives were synthesized and evaluated for their antiproliferative activity against MDA-MB-231 and MCF-7 breast cancer cell lines. The most active compound 15c was further investigated for PIM-1 kinase inhibition, selectivity toward normal WI38 cells, apoptosis induction, and molecular interactions with the PIM-1 active site.
RESULTS AND CONCLUSION
Among the synthesized compounds, derivative 15c exhibited the highest antiproliferative activity against MDA-MB-231 and MCF-7 cells, with IC50 values of 2.17 and 1.46 μM, respectively. It demonstrated potent PIM-1 inhibitory activity (IC50 = 0.74 μM), a favorable selectivity index, and low toxicity toward WI38 cells. Furthermore, 15c significantly increased p53 and Bax levels by 6.8- and 6.2-folds, respectively, while reducing Bcl-2 levels to 0.34-fold relative to the control, indicating apoptosis induction. Molecular docking studies revealed strong binding interactions with key amino acid residues within the PIM-1 active site. Hence, compound 15c represents a promising PIM-1 kinase inhibitor with potent antiproliferative and pro-apoptotic activities, supporting its potential as a candidate for breast cancer treatment.
Alaa M. Abu Alnjaa, Jihan Qurban, E. Abbas et al.· Future Medicinal Chemistry· 0 citations
This study reports a sustainable and environmentally friendly approach for the synthesis of novel pyrimidine Schiff base derivatives through a multicomponent grinding reaction conducted at room temperature under solvent-free conditions. The synthesis involved pyrimidine, various aldehydes, and p-toluenesulfonic acid as a catalyst. The obtained compounds (1–3) were evaluated for their potential anticancer activity against the breast cancer estrogen receptor alpha (ERα). Structural characterization was carried out using FT-IR, NMR spectroscopy, mass spectrometry, and elemental analysis. In addition, molecular docking studies were performed to investigate the binding interactions of the synthesized 1,4-dihydropyrimidine-5-carboxylate derivatives (1–3) with the ERα protein. Among the tested compounds, derivative (3) demonstrated the most promising biological activity, exhibiting an IC₅₀ value of 8.91 μg/L compared with cisplatin (cis-Pt) as the reference drug, along with the highest binding affinity toward ERα. These findings suggest that compound (3) may serve as a promising lead candidate for breast cancer therapy. Molecular modeling studies were conducted using the Molecular Operating Environment (MOE 2019) software, while toxicity prediction was performed using Osiris software.
Alaa M. Abu Alnjaa· Oriental Journal of Chemistr...· 0 citations
The epidermal growth factor receptor (EGFR) is a key regulator of malignant cell growth and survival, making it an attractive target for cancer therapy. In this study, a new series of thiazole derivatives was rationally designed and synthesized as potential EGFR inhibitors and evaluated for their antiproliferative activity against two human colon cancer cell lines (HCT-116 and HT29). Several compounds exhibited potent anticancer activity, with compound 4j showing the highest potency, displaying half-maximal inhibitory concentration (IC50) values of 2.10 and 1.91 µM against HCT-116 and HT29 cells, respectively. Owing to its superior antiproliferative activity, compound 4j was further evaluated for EGFR inhibitory activity and demonstrated remarkable potency with an IC50 value of 0.27 µM. In addition, 4j exhibited a favorable selectivity index toward normal WI38 cells and effectively induced apoptosis through modulation of Bax, Bcl-2, and p53 expression. Molecular docking demonstrated strong binding interactions of 4j within the EGFR active site, while its ADME predictions supported its favorable drug-like profile. Overall, compound 4j represents a promising lead candidate for the development of novel EGFR-targeted anticancer agents.
Amani M. R. Alsaedi, Alaa M. Abu Alnjaa, Amel S. Younes et al.· Future Medicinal Chemistry· 0 citations
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