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Synthesis and characterization of novel 2-amino-chromene-nitriles that target Bcl-2 in acute myeloid leukemia cell lines.
- Source :
-
PloS one [PLoS One] 2014 Sep 30; Vol. 9 (9), pp. e107118. Date of Electronic Publication: 2014 Sep 30 (Print Publication: 2014). - Publication Year :
- 2014
-
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 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.
- Subjects :
- Antineoplastic Agents chemical synthesis
Benzopyrans chemical synthesis
Cell Line, Tumor
Cell Proliferation drug effects
Drug Screening Assays, Antitumor
Humans
Inhibitory Concentration 50
Leukemia, Myeloid, Acute drug therapy
Molecular Docking Simulation
Molecular Targeted Therapy
Nitriles chemical synthesis
Proto-Oncogene Proteins c-bcl-2 chemistry
Antineoplastic Agents pharmacology
Benzopyrans pharmacology
Nitriles pharmacology
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25268519
- Full Text :
- https://doi.org/10.1371/journal.pone.0107118