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

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 IC 50 values of 0.5 and 5.27 μM against MCF-7 and HepG2 cell lines compared with doxorubicin, which displayed the following IC 50 : 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 IC 50 value of 14.3 nM compared to Staurosporine (96.8%, IC 50 = 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.

Synthesis of novel bioactive pyrido[2,3-d]pyrimidine derivatives with potent cytotoxicity through apoptosis as PIM-1 kinase inhibitors

“…1 shows a number of pyridine and pyridopyrimidine (I-IV) compounds that have potent anticancer effects, and it also includes some of our earlier publications on cyanopyridinebased compounds that have been demonstrated to be effective PIM-1 kinase inhibitors that induce cell death. [18][19][20] Accordingly, new series of pyridines and pyridopyrimidines were rationally designed and synthesized, as highlighted Fig. 2, where the three pharmacophoric regions of lipophilic, hydrophilic moieties with the main scaffold of pyridopyrimidine were highlighted.…”