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Synthesis and Characterization of Novel 2-Amino-Chromene-Nitriles that Target Bcl-2 in Acute Myeloid Leukemia Cell Lines

The anti-apoptotic protein Bcl-2 is a well-known and attractive therapeutic target for cancer. In the present study the solution-phase T3P-DMSO mediated efficient synthesis of 2-amino-chromene-3-carbonitriles from alcohols, malanonitrile and phenols is reported. These novel 2-amino-chromene-3-carbon...

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Autores principales: Keerthy, Hosadurga K., Garg, Manoj, Mohan, Chakrabhavi D., Madan, Vikas, Kanojia, Deepika, Shobith, Rangappa, Nanjundaswamy, Shivananju, Mason, Daniel J., Bender, Andreas, Basappa, Rangappa, Kanchugarakoppal S., Koeffler, H. Phillip
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182326/
https://www.ncbi.nlm.nih.gov/pubmed/25268519
http://dx.doi.org/10.1371/journal.pone.0107118
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author Keerthy, Hosadurga K.
Garg, Manoj
Mohan, Chakrabhavi D.
Madan, Vikas
Kanojia, Deepika
Shobith, Rangappa
Nanjundaswamy, Shivananju
Mason, Daniel J.
Bender, Andreas
Basappa,
Rangappa, Kanchugarakoppal S.
Koeffler, H. Phillip
author_facet Keerthy, Hosadurga K.
Garg, Manoj
Mohan, Chakrabhavi D.
Madan, Vikas
Kanojia, Deepika
Shobith, Rangappa
Nanjundaswamy, Shivananju
Mason, Daniel J.
Bender, Andreas
Basappa,
Rangappa, Kanchugarakoppal S.
Koeffler, H. Phillip
author_sort Keerthy, Hosadurga K.
collection PubMed
description The anti-apoptotic protein Bcl-2 is a well-known and attractive therapeutic target for cancer. In the present study the solution-phase T3P-DMSO mediated efficient synthesis of 2-amino-chromene-3-carbonitriles from alcohols, malanonitrile and phenols is reported. These novel 2-amino-chromene-3-carbonitriles showed cytotoxicity in human acute myeloid leukemia (AML) cell lines. Compound 4g was found to be the most bioactive, decreasing growth and increasing apoptosis of AML cells. Moreover, compound 4g (at a concentration of 5 µM) increased the G2/M and sub-G1 (apoptosis) phases of AML cells. The AML cells treated with compound 4g exhibited decreased levels of Bcl-2 and increased levels of caspase-9. In silico molecular interaction analysis showed that compound 4g shared a similar global binding motif with navitoclax (another small molecule that binds Bcl-2), however compound 4g occupies a smaller volume within the P2 hot spot of Bcl-2. The intermolecular π-stacking interaction, direct electrostatic interactions, and docking energy predicted for 4g in complex with Bcl-2 suggest a strong affinity of the complex, rendering 4g as a promising Bcl-2 inhibitor for evaluation as a new anticancer agent.
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spelling pubmed-41823262014-10-07 Synthesis and Characterization of Novel 2-Amino-Chromene-Nitriles that Target Bcl-2 in Acute Myeloid Leukemia Cell Lines Keerthy, Hosadurga K. Garg, Manoj Mohan, Chakrabhavi D. Madan, Vikas Kanojia, Deepika Shobith, Rangappa Nanjundaswamy, Shivananju Mason, Daniel J. Bender, Andreas Basappa, Rangappa, Kanchugarakoppal S. Koeffler, H. Phillip PLoS One Research Article The anti-apoptotic protein Bcl-2 is a well-known and attractive therapeutic target for cancer. In the present study the solution-phase T3P-DMSO mediated efficient synthesis of 2-amino-chromene-3-carbonitriles from alcohols, malanonitrile and phenols is reported. These novel 2-amino-chromene-3-carbonitriles showed cytotoxicity in human acute myeloid leukemia (AML) cell lines. Compound 4g was found to be the most bioactive, decreasing growth and increasing apoptosis of AML cells. Moreover, compound 4g (at a concentration of 5 µM) increased the G2/M and sub-G1 (apoptosis) phases of AML cells. The AML cells treated with compound 4g exhibited decreased levels of Bcl-2 and increased levels of caspase-9. In silico molecular interaction analysis showed that compound 4g shared a similar global binding motif with navitoclax (another small molecule that binds Bcl-2), however compound 4g occupies a smaller volume within the P2 hot spot of Bcl-2. The intermolecular π-stacking interaction, direct electrostatic interactions, and docking energy predicted for 4g in complex with Bcl-2 suggest a strong affinity of the complex, rendering 4g as a promising Bcl-2 inhibitor for evaluation as a new anticancer agent. Public Library of Science 2014-09-30 /pmc/articles/PMC4182326/ /pubmed/25268519 http://dx.doi.org/10.1371/journal.pone.0107118 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Keerthy, Hosadurga K.
Garg, Manoj
Mohan, Chakrabhavi D.
Madan, Vikas
Kanojia, Deepika
Shobith, Rangappa
Nanjundaswamy, Shivananju
Mason, Daniel J.
Bender, Andreas
Basappa,
Rangappa, Kanchugarakoppal S.
Koeffler, H. Phillip
Synthesis and Characterization of Novel 2-Amino-Chromene-Nitriles that Target Bcl-2 in Acute Myeloid Leukemia Cell Lines
title Synthesis and Characterization of Novel 2-Amino-Chromene-Nitriles that Target Bcl-2 in Acute Myeloid Leukemia Cell Lines
title_full Synthesis and Characterization of Novel 2-Amino-Chromene-Nitriles that Target Bcl-2 in Acute Myeloid Leukemia Cell Lines
title_fullStr Synthesis and Characterization of Novel 2-Amino-Chromene-Nitriles that Target Bcl-2 in Acute Myeloid Leukemia Cell Lines
title_full_unstemmed Synthesis and Characterization of Novel 2-Amino-Chromene-Nitriles that Target Bcl-2 in Acute Myeloid Leukemia Cell Lines
title_short Synthesis and Characterization of Novel 2-Amino-Chromene-Nitriles that Target Bcl-2 in Acute Myeloid Leukemia Cell Lines
title_sort synthesis and characterization of novel 2-amino-chromene-nitriles that target bcl-2 in acute myeloid leukemia cell lines
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182326/
https://www.ncbi.nlm.nih.gov/pubmed/25268519
http://dx.doi.org/10.1371/journal.pone.0107118
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