TY - JOUR
T1 - Trisubstituted-imidazoles induce apoptosis in human breast cancer cells by targeting the oncogenic PI3K/Akt/mTOR signaling pathway
AU - Mohan, Chakrabhavi Dhananjaya
AU - Srinivasa, V.
AU - Rangappa, Shobith
AU - Mervin, Lewis
AU - Mohan, Surender
AU - Paricharak, Shardul
AU - Baday, Sefer
AU - Li, Feng
AU - Shanmugam, Muthu K.
AU - Chinnathambi, Arunachalam
AU - Zayed, M. E.
AU - Alharbi, Sulaiman Ali
AU - Bender, Andreas
AU - Sethi, Gautam
AU - Basappa,
AU - Rangappa, Kanchugarakoppal S.
N1 - Publisher Copyright:
© 2016 Mohan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted se, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/4
Y1 - 2016/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84978045141&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0153155
DO - 10.1371/journal.pone.0153155
M3 - Article
C2 - 27097161
AN - SCOPUS:84978045141
SN - 1932-6203
VL - 11
JO - PLoS ONE
JF - PLoS ONE
IS - 4
M1 - e0153155
ER -
