1. Design, synthesis and cytotoxic evaluation of new thieno[2,3-d]pyrimidine analogues as VEGFR-2/AKT dual inhibitors, apoptosis and autophagy inducers.
- Author
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Abd El-Mawgoud HK, AboulMagd AM, Nemr MTM, Hemdan MM, Hassaballah AI, and Farag PS
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Molecular Docking Simulation, Cell Line, Tumor, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors, Vascular Endothelial Growth Factor Receptor-2 metabolism, Pyrimidines pharmacology, Pyrimidines chemical synthesis, Pyrimidines chemistry, Apoptosis drug effects, Drug Design, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Autophagy drug effects, Drug Screening Assays, Antitumor, Cell Proliferation drug effects, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Dose-Response Relationship, Drug
- Abstract
Novel thieno[2,3-d]pyrimidine analogues were designed, synthesized and evaluated for anti-proliferative activity against HepG-2, PC-3 and MCF-7 cancer cell lines. In addition, WI-38 normal cell line was used to explore the safety of all the tested compounds. Compounds 2 (IC
50 = 4.29 µM HePG-2, 10.84 µM MCF-7), 6 (IC50 = 14.86 μM HePG-2, 8.04 μM PC-3 and 12.90 μM MCF-7) and 17 (IC50 = 9.98 μM HePG-2, 33.66 μM PC-3 and 14.62 μM MCF-7) were the most promising candidates on the tested cancer cells with high selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where compound 2 inhibited VEGFR-2 and AKT at IC50 = 0.161 and 1.06 μM, respectively, Furthermore, derivative 6 inhibited VEGFR-2 and AKT at IC50 = 0.487 and 0.364 μM, respectively, while compound 17 showed IC50 = 0.164 and 0.452 μM, respectively. Moreover, compounds 2, 6 resulted in G1 phase cell cycle arrest while candidate 17 arrest cell cycle at G2/M phase. Similar to the apoptosis results, compound 17 showed the highest autophagic induction among the evaluated derivatives. Finally, docking studies were conducted to assess the binding patterns of these active derivatives. The results showed that the binding patterns inside the active sites of both the VEGFR-2 and AKT-1 (allosteric pocket) crystal structures were identical to the reference ligands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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