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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838272/ https://www.ncbi.nlm.nih.gov/pubmed/27097161 http://dx.doi.org/10.1371/journal.pone.0153155 |
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author | Mohan, Chakrabhavi Dhananjaya Srinivasa, V. Rangappa, Shobith Mervin, Lewis Mohan, Surender Paricharak, Shardul Baday, Sefer Li, Feng Shanmugam, Muthu K. Chinnathambi, Arunachalam Zayed, M. E. Alharbi, Sulaiman Ali Bender, Andreas Sethi, Gautam Basappa, Rangappa, Kanchugarakoppal S. |
author_facet | Mohan, Chakrabhavi Dhananjaya Srinivasa, V. Rangappa, Shobith Mervin, Lewis Mohan, Surender Paricharak, Shardul Baday, Sefer Li, Feng Shanmugam, Muthu K. Chinnathambi, Arunachalam Zayed, M. E. Alharbi, Sulaiman Ali Bender, Andreas Sethi, Gautam Basappa, Rangappa, Kanchugarakoppal S. |
author_sort | Mohan, Chakrabhavi Dhananjaya |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4838272 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-48382722016-04-29 Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway Mohan, Chakrabhavi Dhananjaya Srinivasa, V. Rangappa, Shobith Mervin, Lewis Mohan, Surender Paricharak, Shardul Baday, Sefer Li, Feng Shanmugam, Muthu K. Chinnathambi, Arunachalam Zayed, M. E. Alharbi, Sulaiman Ali Bender, Andreas Sethi, Gautam Basappa, Rangappa, Kanchugarakoppal S. PLoS One Research Article 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. Public Library of Science 2016-04-20 /pmc/articles/PMC4838272/ /pubmed/27097161 http://dx.doi.org/10.1371/journal.pone.0153155 Text en © 2016 Mohan et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Mohan, Chakrabhavi Dhananjaya Srinivasa, V. Rangappa, Shobith Mervin, Lewis Mohan, Surender Paricharak, Shardul Baday, Sefer Li, Feng Shanmugam, Muthu K. Chinnathambi, Arunachalam Zayed, M. E. Alharbi, Sulaiman Ali Bender, Andreas Sethi, Gautam Basappa, Rangappa, Kanchugarakoppal S. Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway |
title | Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway |
title_full | Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway |
title_fullStr | Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway |
title_full_unstemmed | Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway |
title_short | Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway |
title_sort | trisubstituted-imidazoles induce apoptosis in human breast cancer cells by targeting the oncogenic pi3k/akt/mtor signaling pathway |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838272/ https://www.ncbi.nlm.nih.gov/pubmed/27097161 http://dx.doi.org/10.1371/journal.pone.0153155 |
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