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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2014
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oai:doaj.org-article:ec334f3735274b5a85eba3c8c2d4fc772021-11-25T05:58:40ZSynthesis and characterization of novel 2-amino-chromene-nitriles that target Bcl-2 in acute myeloid leukemia cell lines.1932-620310.1371/journal.pone.0107118https://doaj.org/article/ec334f3735274b5a85eba3c8c2d4fc772014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0107118https://doaj.org/toc/1932-6203The 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 4 g was found to be the most bioactive, decreasing growth and increasing apoptosis of AML cells. Moreover, compound 4 g (at a concentration of 5 µM) increased the G2/M and sub-G1 (apoptosis) phases of AML cells. The AML cells treated with compound 4 g exhibited decreased levels of Bcl-2 and increased levels of caspase-9. In silico molecular interaction analysis showed that compound 4 g shared a similar global binding motif with navitoclax (another small molecule that binds Bcl-2), however compound 4 g 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 4 g in complex with Bcl-2 suggest a strong affinity of the complex, rendering 4 g as a promising Bcl-2 inhibitor for evaluation as a new anticancer agent.Hosadurga K KeerthyManoj GargChakrabhavi D MohanVikas MadanDeepika KanojiaRangappa ShobithShivananju NanjundaswamyDaniel J MasonAndreas BenderBasappaKanchugarakoppal S RangappaH Phillip KoefflerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 9, p e107118 (2014) |
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Medicine R Science Q Hosadurga K Keerthy Manoj Garg Chakrabhavi D Mohan Vikas Madan Deepika Kanojia Rangappa Shobith Shivananju Nanjundaswamy Daniel J Mason Andreas Bender Basappa Kanchugarakoppal S Rangappa H Phillip Koeffler Synthesis and characterization of novel 2-amino-chromene-nitriles that target Bcl-2 in acute myeloid leukemia cell lines. |
| 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 4 g was found to be the most bioactive, decreasing growth and increasing apoptosis of AML cells. Moreover, compound 4 g (at a concentration of 5 µM) increased the G2/M and sub-G1 (apoptosis) phases of AML cells. The AML cells treated with compound 4 g exhibited decreased levels of Bcl-2 and increased levels of caspase-9. In silico molecular interaction analysis showed that compound 4 g shared a similar global binding motif with navitoclax (another small molecule that binds Bcl-2), however compound 4 g 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 4 g in complex with Bcl-2 suggest a strong affinity of the complex, rendering 4 g as a promising Bcl-2 inhibitor for evaluation as a new anticancer agent. |
| format |
article |
| author |
Hosadurga K Keerthy Manoj Garg Chakrabhavi D Mohan Vikas Madan Deepika Kanojia Rangappa Shobith Shivananju Nanjundaswamy Daniel J Mason Andreas Bender Basappa Kanchugarakoppal S Rangappa H Phillip Koeffler |
| author_facet |
Hosadurga K Keerthy Manoj Garg Chakrabhavi D Mohan Vikas Madan Deepika Kanojia Rangappa Shobith Shivananju Nanjundaswamy Daniel J Mason Andreas Bender Basappa Kanchugarakoppal S Rangappa H Phillip Koeffler |
| author_sort |
Hosadurga K Keerthy |
| title |
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_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_sort |
synthesis and characterization of novel 2-amino-chromene-nitriles that target bcl-2 in acute myeloid leukemia cell lines. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/ec334f3735274b5a85eba3c8c2d4fc77 |
| work_keys_str_mv |
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