Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway

Chakrabhavi Dhananjaya Mohan; V Srinivasa; Shobith Rangappa; Lewis Mervin; Surender Mohan; Shardul Paricharak; Sefer Baday; Feng Li; Muthu K Shanmugam; Arunachalam Chinnathambi; M E Zayed; Sulaiman Ali Alharbi; Andreas Bender; Gautam Sethi; Basappa; Kanchugarakoppal S Rangappa

doi:10.1371/journal.pone.0153155

Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway

PLoS One. 2016 Apr 20;11(4):e0153155. doi: 10.1371/journal.pone.0153155. eCollection 2016.

Authors

Chakrabhavi Dhananjaya Mohan¹, V Srinivasa², Shobith Rangappa³, Lewis Mervin⁴, Surender Mohan⁵, Shardul Paricharak^{4

6}, Sefer Baday^{4

7}, Feng Li⁸, Muthu K Shanmugam⁸, Arunachalam Chinnathambi⁹, M E Zayed⁹, Sulaiman Ali Alharbi⁹, Andreas Bender⁴, Gautam Sethi^{8

9

10}, Basappa², Kanchugarakoppal S Rangappa¹

Affiliations

¹ Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India.
² Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.
³ Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 060-0808, Japan.
⁴ Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, United Kingdom.
⁵ Laboratory of Molecular Biology and Genetic Engineering, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
⁶ Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
⁷ Applied Informatics Department, Informatics Institute, Istanbul Technical University, 34469, Istanbul, Turkey.
⁸ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁹ Department of Botany and Microbiology, College of Science, King Saud University, Riyadh -11451, Kingdom of Saudi Arabia.
¹⁰ School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Western Australia 6009, Australia.

Abstract

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. Naïve 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects*
Caspases / metabolism
Cell Line, Tumor
Chemokine CXCL12 / antagonists & inhibitors
Down-Regulation / drug effects
Enzyme Activation / drug effects
G1 Phase / drug effects
Humans
Imidazoles / chemistry*
Imidazoles / metabolism
Imidazoles / pharmacology*
Molecular Docking Simulation
Neoplasm Invasiveness
Phosphatidylinositol 3-Kinases / metabolism*
Phosphorylation / drug effects
Protein Structure, Tertiary
Proto-Oncogene Proteins c-akt / chemistry
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction / drug effects*
TOR Serine-Threonine Kinases / metabolism*

Substances

Chemokine CXCL12
Imidazoles
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Caspases

Grants and funding

This research was supported by University Grants Commission (41-257-2012-SR), Vision Group Science and Technology, and Department of Science and Technology (NO. SR/FT/LS-142/2012) to Basappa. KSR thanks Department of Science and Technology Indo-Korea [INT/Indo-Korea/122/2011-12] and Institution of Excellence, University of Mysore for financial support and instrumentation facility. CDM thanks the University of Mysore for Department of Science and Technology-Promotion of University Research and Scientific Excellence (DST-PURSE) Research Associate fellowship. This work was supported by NUHS Bench-to-Bedside-to-Product grant to GS. Deanship of Scientific Research, College of Science Research Centre, King Saud University, Kingdom of Saudi Arabia is also acknowledged. SP thanks the Netherlands Organisation for Scientific Research (NWO, grant number NWO-017.009-065) and the Prins Bernhard Cultuurfonds for funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.