Journal
PLOS ONE
Volume 11, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0153155
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Funding
- University Grants Commission [41-257-2012-SR]
- Vision Group Science and Technology
- Department of Science and Technology [SR/FT/LS-142/2012]
- Department of Science and Technology Indo-Korea [INT/Indo-Korea/122/2011-12]
- Institution of Excellence, University of Mysore
- University of Mysore for Department of Science and Technology-Promotion of University Research and Scientific Excellence (DST-PURSE) Research Associate fellowship
- NUHS Bench-to-Bedside-to-Product grant
- Netherlands Organisation for Scientific Research (NWO) [NWO-017.009-065]
- Prins Bernhard Cultuurfonds
- Biotechnology and Biological Sciences Research Council [1372344] Funding Source: researchfish
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Overactivation of PI3K/Akt/mTOR is linked with carcinogenesis and serves a potential molecular therapeutic target in treatment of various cancers. Herein, we report the synthesis of trisubstituted-imidazoles and identified 2-chloro-3-(4, 5-diphenyl-1H-imidazol-2-yl) pyridine (CIP) as lead cytotoxic agent. Naive Base classifier model of in silico target prediction revealed that CIP targets RAC-beta serine/threonine-protein kinase which comprises the Akt. Furthermore, CIP downregulated the phosphorylation of Akt, PDK and mTOR proteins and decreased expression of cyclin D1, Bcl-2, survivin, VEGF, procaspase-3 and increased cleavage of PARP. In addition, CIP significantly downregulated the CXCL12 induced motility of breast cancer cells and molecular docking calculations revealed that all compounds bind to Akt2 kinase with high docking scores compared to the library of previously reported Akt2 inhibitors. In summary, we report the synthesis and biological evaluation of imidazoles that induce apoptosis in breast cancer cells by negatively regulating PI3K/Akt/mTOR signaling pathway.
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