Design and Synthesis of Novel Pyridine-Based Compounds as Potential PIM-1 Kinase Inhibitors, Apoptosis, and Autophagy Inducers Targeting MCF-7 Cell Lines: In Vitro and In Vivo Studies

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Abstract

2-((3-Cyano-4,6-dimethylpyridin-2-yl)oxy)acetohydrazide 1 was used as the precursor for the synthesis of 5-thioxo-1,3,4-oxadiazol-2-yl)methoxy)nicotinonitrile 2. The latter was alkylated with different alkylating agents to produce the S-alkylated products 3-6. Galactosylation of 5-thioxo-1,3,4-oxadiazol-2-yl)methoxy)nicotinonitrile 2 produces a mixture of S- and N-galactosides 8 and 9. The hydrazide 1 is converted to azide 10, coupled with glycine methyl ester hydrochloride and a set of amines to produce the target coupled amides 11-15. New compounds were assigned using NMR and elemental analysis. Compound 12 had potent cytotoxicity with IC50 values of 0.5 and 5.27 μM against MCF-7 and HepG2 cell lines compared with doxorubicin, which displayed the following IC50: 2.14 and 2.48 μM for the mentioned cell lines, respectively. Regarding the molecular target, compound 12 exhibited potent PIM-1 inhibition activity with 97.5% with an IC50 value of 14.3 nM compared to Staurosporine (96.8%, IC50 = 16.7 nM). Moreover, compound 12 significantly activated apoptotic cell death in MCF-7 cells, increasing the cell population by total apoptosis by 33.43% (23.18% for early apoptosis and 10.25% for late apoptosis) compared to the untreated control group (0.64%), and arresting the cell cycle at S-phase by 36.02% compared to control 29.12%. Besides, compound 12 caused tumor inhibition by 42.1% in solid tumors in the SEC-bearing mice. Results disclosed that compound 12 significantly impeded cell migration and cell proliferation by interfering with PIM-1 enzymatic activity via considerable apoptosis-induction, which made it an attractive lead compound for the development of chemotherapeutics to treat breast cancer.

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Shaban, S. M., Eltamany, E. H., Boraei, A. T. A., Nafie, M. S., & Gad, E. M. (2023). Design and Synthesis of Novel Pyridine-Based Compounds as Potential PIM-1 Kinase Inhibitors, Apoptosis, and Autophagy Inducers Targeting MCF-7 Cell Lines: In Vitro and In Vivo Studies. ACS Omega, 8(49), 46922–46933. https://doi.org/10.1021/acsomega.3c06700

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