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

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 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.

Development of a Novel Azaspirane That Targets the Janus Kinase-Signal Transducer and Activator of Transcription (STAT) Pathway in Hepatocellular Carcinoma in Vitro and in Vivo

“…MTT Assay-The antiproliferative effect of CIMO against HepG2 cells was determined by the MTT dye uptake method as described previously (24,25). Briefly, the cells (2.5 ϫ 10 4 /ml) were incubated in triplicate in a 96-well plate in the presence or absence of different concentrations of CIMO in a final volume of 0.2 ml for up to 72 h at 37°C.…”

Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice

“…28 We evaluated whether FDPB can effect cell cycle distribution as described earlier. 29 We found the built up of cells in subG1 phase in the time dependent manner (Fig. 1C).…”

Triazole‐Pyridine Dicarbonitrile Targets Phosphodiesterase 4 to Induce Cytotoxicity in Lung Carcinoma Cells

“…The newly synthesized triazolo‐pyrimidines were investigated for their cytotoxic potential towards lung carcinoma (A549) cells using in vitro cytotoxicity assay . Among the new compounds, 7′‐[4‐(methylsulfonyl)phenyl]‐5′‐oxo‐1′,5′‐dihydrospiro[cyclohexane‐1,2′‐[1,2,4]triazolo[1,5‐ a ]pyridine]‐6′,8′‐dicarbonitrile ( 5h ) and 7′‐(1‐methyl‐1 H ‐imidazol‐2‐yl)‐5′‐oxo‐1′,5′‐dihydrospiro[cyclohexane‐1,2′‐[1,2,4]triazolo[1,5‐ a ]pyridine]‐6′,8′‐dicarbonitrile ( 5j ) displayed good cytotoxic activity with the IC 50 values of 15.2 and 24.1 μ m, respectively.…”