Synthesis and characterization of novel 2-amino-chromene-nitriles that target Bcl-2 in acute myeloid leukemia cell lines

Keerthy, H. K. and Garg, Manoj and Mohan, C. D. and Madan, V. and Kanojia, D. and Shobith, R. and Nanjunda Swamy, S. and Mason, D. J. and Bender, A. and Basappa and Rangappa, K. S. and Koeffler, H. P. (2014) Synthesis and characterization of novel 2-amino-chromene-nitriles that target Bcl-2 in acute myeloid leukemia cell lines. PLoS ONE, 9 (9). ISSN 1932-6203

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Abstract

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 mM) 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 p-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.

Item Type:	Article
Uncontrolled Keywords:	antineoplastic agent, apoptosis, Article, concentration response, controlled study, drug cytotoxicity, drug synthesis, human, human cell, IC50, unclassified drug, Antineoplastic Agents, Antitumor, Cell Line, chemistry, drug screening, Drug Screening Assays, Humans, synthesis, Tumor, tumor cell line, antagonists and inhibitors, cancer inhibition, molecular docking, Molecular Docking Simulation, molecular interaction, computer model, molecularly targeted therapy, cell proliferation, phenol derivative, Cell Proliferation, unindexed drug, drug targeting, protein bcl 2, biological activity, drug effects, drug protein binding, Nitriles, nitrile, dimethyl sulfoxide, Leukemia, leukemia cell line, antileukemic agent, alcohol derivative, cell cycle G1 phase, Inhibitory Concentration 50, 2 amino 4 (1h indol 3 yl) 4h benzogchromene 3 carbonitrile, 2 amino 4 (1h indol 3 yl) 5 oxo 4, 2 amino 4 (2, 2 amino 4 (2 butyl 4 chloro 1h imidazol 5 yl) 4h benzogchromene 3 carbonitrile, 2 amino 4 (2 butyl 4 chloro 1h imidazol 5 yl) 5 oxo 4, 2 amino 4 (2 butyl 4 chloro 1h imidazol 5 yl) 7 hydroxy 4h chromene 3 carbonitrile, 2 amino 4 (2 methyl 1h indol 3 yl) 5 oxo 4, 2 amino 4 (2 nitrophenyl) 4h benzogchromene 3 carbonitrile, 2 amino 4 (3, 2 amino 4 (3 nitrophenyl) 4h benzogchromene 3 carbonitrile, 2 amino 4 (4 bromophenyl) 4h benzogchromene 3 carbonitrile, 2 amino 4 (4 bromophenyl) 5 oxo 4, 2 amino 4 (4 fluorophenyl) 4h benzogchromene 3 carbonitrile, 2 amino 4 (4 fluorophenyl) 7 hydroxy 4h chromene 3 carbonitrile, 2 amino 4 (4 oxo 4h chromen 3 yl) 4h benzogchromene 3 carbonitrile, 2 amino 5 oxo 4 (4 oxo 4h chromen 3 yl) 4, 2 amino 7 hydroxy 4 (1h indol 3 yl) 4h chromene 3 carbonitrile, 2 aminochromene 3 carbonitrile derivative, 2 aminochromenenitrile derivative, 2 cchromene 3 carbonitrile, 2' amino 7' hydroxy 4 oxo 4h 4' 3, 4 dimethoxyphenyl) 5 oxo 4, 4' bichromene 3' carbonitrile, 5 dihydropyrano3, 6 dichlorophenyl) 4h benzogchromene 3 carbonitrile, Acute, acute granulocytic leukemia, BCL2 protein, benzopyran derivative, Benzopyrans, caspase 9, cell cycle G2 phase, cell cycle M phase, malanonitrile, Molecular Targeted Therapy, Myeloid, navitoclax, Proto-Oncogene Proteins c-bcl-2
Subjects:	C Chemical Science > Chemistry
Divisions:	Department of > Chemistry
Depositing User:	Arshiya Kousar Library Assistant
Date Deposited:	26 Jun 2019 06:38
Last Modified:	20 Jul 2022 05:52
URI:	http://eprints.uni-mysore.ac.in/id/eprint/3678

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