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Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors
Potent and dual monocarboxylate transporter (MCT) 1 and 4 inhibitors have been developed for the first time as potential anticancer agents based on α-cyanocinnamic acid structural template. Candidate inhibitors 1–9 have been evaluated for in vitro cell proliferation against MCT1 and MCT4 expressing...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481325/ https://www.ncbi.nlm.nih.gov/pubmed/31040927 http://dx.doi.org/10.18632/oncotarget.26760 |
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author | Jonnalagadda, Shirisha Jonnalagadda, Sravan K. Ronayne, Conor T. Nelson, Grady L. Solano, Lucas N. Rumbley, Jon Holy, Jon Mereddy, Venkatram R. Drewes, Lester R. |
author_facet | Jonnalagadda, Shirisha Jonnalagadda, Sravan K. Ronayne, Conor T. Nelson, Grady L. Solano, Lucas N. Rumbley, Jon Holy, Jon Mereddy, Venkatram R. Drewes, Lester R. |
author_sort | Jonnalagadda, Shirisha |
collection | PubMed |
description | Potent and dual monocarboxylate transporter (MCT) 1 and 4 inhibitors have been developed for the first time as potential anticancer agents based on α-cyanocinnamic acid structural template. Candidate inhibitors 1–9 have been evaluated for in vitro cell proliferation against MCT1 and MCT4 expressing cancer cell lines. Potential MCT1 and MCT4 binding interactions of the lead compound 9 have been studied through homology modeling and molecular docking prediction. In vitro effects on extracellular flux via glycolysis and mitochondrial stress tests suggest that candidate compounds 3 and 9 disrupt glycolysis and OxPhos efficiently in MCT1 expressing colorectal adenocarcinoma WiDr and MCT4 expressing triple negative breast cancer MDA-MB-231 cells. Fluorescence microscopy analyses in these cells also indicate that compound 9 is internalized and concentrated near mitochondria. In vivo tumor growth inhibition studies in WiDr and MDA-MB-231 xenograft tumor models in mice indicate that the candidate compound 9 exhibits a significant single agent activity. |
format | Online Article Text |
id | pubmed-6481325 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-64813252019-04-30 Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors Jonnalagadda, Shirisha Jonnalagadda, Sravan K. Ronayne, Conor T. Nelson, Grady L. Solano, Lucas N. Rumbley, Jon Holy, Jon Mereddy, Venkatram R. Drewes, Lester R. Oncotarget Research Paper Potent and dual monocarboxylate transporter (MCT) 1 and 4 inhibitors have been developed for the first time as potential anticancer agents based on α-cyanocinnamic acid structural template. Candidate inhibitors 1–9 have been evaluated for in vitro cell proliferation against MCT1 and MCT4 expressing cancer cell lines. Potential MCT1 and MCT4 binding interactions of the lead compound 9 have been studied through homology modeling and molecular docking prediction. In vitro effects on extracellular flux via glycolysis and mitochondrial stress tests suggest that candidate compounds 3 and 9 disrupt glycolysis and OxPhos efficiently in MCT1 expressing colorectal adenocarcinoma WiDr and MCT4 expressing triple negative breast cancer MDA-MB-231 cells. Fluorescence microscopy analyses in these cells also indicate that compound 9 is internalized and concentrated near mitochondria. In vivo tumor growth inhibition studies in WiDr and MDA-MB-231 xenograft tumor models in mice indicate that the candidate compound 9 exhibits a significant single agent activity. Impact Journals LLC 2019-03-22 /pmc/articles/PMC6481325/ /pubmed/31040927 http://dx.doi.org/10.18632/oncotarget.26760 Text en Copyright: © 2019 Jonnalagadda et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Jonnalagadda, Shirisha Jonnalagadda, Sravan K. Ronayne, Conor T. Nelson, Grady L. Solano, Lucas N. Rumbley, Jon Holy, Jon Mereddy, Venkatram R. Drewes, Lester R. Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors |
title | Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors |
title_full | Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors |
title_fullStr | Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors |
title_full_unstemmed | Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors |
title_short | Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors |
title_sort | novel n,n-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481325/ https://www.ncbi.nlm.nih.gov/pubmed/31040927 http://dx.doi.org/10.18632/oncotarget.26760 |
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