Nicotinonitrile-derived apoptotic inducers: Design, synthesis, X-ray crystal structure and Pim kinase inhibition

• DOI: 10.1016/j.bioorg.2022.106126
• Publication Date: 2022-09-07T15:21:00Z
• Authors: Shaimaa M. Aboukh...; Amera O. Ibrahim; Hiroshi Aoyama; Ahmed S. Al-Behery; Moataz A. Shaldam; Ghada El-Ashmawy; Haytham O. Tawfik
• Keywords: 0303 health sciences; Molecular Structure; X-Rays; Apoptosis; Antineoplastic Agents; 3. Good health; Structure-Activity Relationship; 03 medical and health sciences; HEK293 Cells; Proto-Oncogene Proteins c-pim-1; Drug Design; Humans; Drug Screening Assays, Antitumor; Protein Kinase Inhibitors; Cell Proliferation

Although a plethora of targeted anticancer small molecule drugs became available, the low response rate and drug resistance imply the continuous need for expanding the anticancer chemical space. In this study, a novel series of nicotinonitrile derivatives was designed, synthesized and evaluated for cytotoxic activities in HepG2 and MCF-7 cells. All derivatives showed high to moderate cytotoxic activity against both cell lines, with cell-type and chemotype-dependent cytotoxic potential. The normal HEK-293 T cells were ca. 50-fold less susceptible to the cytotoxic effect of the inhibitors. The in vitro enzyme inhibitory activity of selected active cytotoxic derivatives 8c, 8e, 9a, 9e and 12 showed that they have sub- to one digit micromolar 50 % inhibitory concentration (IC50) against the three Pim kinase isoforms, with 8e being the most potent (IC50 ≤ 0.28 μM against three Pim kinases), comparable to the pan kinase inhibitor, Staurosporine. In HepG2, 8e induced cell cycle arrest at the G2/M phase. Apoptotic mechanistic studies with 8c and 8e in HepG2 cells, indicated a significant upregulation in both P53 and caspase-3 relative gene expression, as well as increased Bax/Bcl-2 protein expression level. Further, docking studies combined with molecular dynamic simulation showed a stable complex with high binding affinity of 8e to Pim-1 kinase; exploiting a negative electrostatic potential surface interaction with the added dimethyl amino group in the new compounds. Moreover, in silico ADME profile prediction indicated that all compounds are orally bioavailable and most of them can penetrate the blood-brain barrier. This study presents novel nicotinonitrile derivatives as auspicious hits for further optimization as antiproliferative agents against liver cancer cells and promising pan Pim kinase inhibitors at submicromolar concentrations.