Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway.
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.
Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India.
Chakrabhavi Dhananjaya
CD
Mohan
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.
V
V
Srinivasa
Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 060-0808, Japan.
Shobith
S
Rangappa
Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, United Kingdom.
Lewis
L
Mervin
Laboratory of Molecular Biology and Genetic Engineering, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
Surender
S
Mohan
Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, United Kingdom.|Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Shardul
S
Paricharak
Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, United Kingdom.|Applied Informatics Department, Informatics Institute, Istanbul Technical University, 34469, Istanbul, Turkey.
Sefer
S
Baday
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Feng
F
Li
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Muthu K
MK
Shanmugam
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh -11451, Kingdom of Saudi Arabia.
Arunachalam
A
Chinnathambi
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh -11451, Kingdom of Saudi Arabia.
M E
ME
Zayed
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh -11451, Kingdom of Saudi Arabia.
Sulaiman Ali
SA
Alharbi
Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, United Kingdom.
Andreas
A
Bender
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Department of Botany and Microbiology, College of Science, King Saud University, Riyadh -11451, Kingdom of Saudi Arabia.|School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Western Australia 6009, Australia.
Gautam
G
Sethi
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.
Basappa
Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India.
Kanchugarakoppal S
KS
Rangappa
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D020169:Caspases; D054377:Chemokine CXCL12; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases