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

• DOI: 10.1371/journal.pone.0107118
• Publication Date: 2014-09-30T18:35:57Z
• Authors: Hosadurga K. Keerthy; Manoj Garg; Chakrabhavi D. Mohan; Vikas Madan; Deepika Kanojia; Rangappa Shobith; Shivananju Nanjun...; Daniel J. Mason; Andreas Bender; Basappa; Kanchugarakoppal ...; H. Phillip Koeffler
• Keywords: Myeloid; 0301 basic medicine; 570; Pediatric Cancer; Childhood Leukemia; General Science & Technology; Science; 610; Antineoplastic Agents; Acute; Drug Screening Assays; Cell Line; Inhibitory Concentration 50; 03 medical and health sciences; Rare Diseases; Cell Line, Tumor; Nitriles; 2.1 Biological and endogenous factors; Humans; Benzopyrans; Molecular Targeted Therapy; Aetiology; Cancer; Cell Proliferation; Pediatric; Tumor; Leukemia; Q; R; Hematology; Antitumor; 3. Good health; Molecular Docking Simulation; Chemistry; Leukemia, Myeloid, Acute; Orphan Drug; Proto-Oncogene Proteins c-bcl-2; Medicine; Drug Screening Assays, Antitumor; 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 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.