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-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.

Anti-cancer activity of novel dibenzo[b,f]azepine tethered isoxazoline derivatives.

BACKGROUND: Dibenzoazepine (DB) derivatives are important and valuable compounds in medicinal chemistry. The synthesis and chemotherapeutic properties of naturally occurring DBs and different heterocyclic moiety tethered DBs are reported. Herein, we report the DB-fused hybrid structure that containing isoxazolines (DBIs) and their anti-cancer activity, which could throw light on the structural and functional features of new molecules. RESULTS AND CONCLUSION: The synthesis and characterization of novel ring DB tethered isoxazoline derivatives (DBIs) were carried out. After the detailed structural characterization using 2D-NMR experiments, the compounds were identified as 5-substituted isoxazolines. The effect of newly synthesized DBIs against the invasion of murine osteosarcoma (LM8G7) cells was studied. Among the tested molecules, compound 4g (5-[-3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f]azepine), was found to inhibit the invasion of LM8G7 cells strongly, when compared to other structurally related compounds. Cumulatively, the compound 4g inhibited the invasion MDA-MB-231 cells completely at 10 µM. In addition to anti-invasion property the compound 4g also inhibited the migration of LM8G7 and human ovarian cancer cells (OVSAHO) dose-dependently. Compound 4g inhibited the proliferation of LM8G7, OVSAHO, human breast cancer cells (MCF-7) and human melphalan-resistant multiple myeloma (RPMI8226-LR5) cells that are comparable to cisplatin and suramin.