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 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

Post-translational mechanisms of zinc signalling in cancer

Three groups of proteins are actively involved in the control of intracellular zinc, consisting of ZIP channels (SLC39A), ZnT transporters (SLC30A), and metallothioneins. Malfunctions of many zinc transport proteins, especially those belonging to the ZIP family which increase cytosolic zinc availability, have been associated with cancer. Importantly, post-translational modifications have been reported to play an increasing role in the functional control of ZIP channels. In this chapter, we therefore detail the established role of zinc signalling in cancer, with an emphasis on breast cancer, as well as demonstrate effects of post-translational modifications by phosphorylation and proteolytic cleavage