RESUMEN
Phosphodiesterase 4 (PDE4) is a key enzyme involved in the hydrolysis of cyclic adenosine monophosphate (cAMP) and widely expressed in several types of cancers. The inhibition of PDE4 results in an increased concentration of intracellular cAMP levels that imparts the anti-inflammatory response in the target cells. In the present report, two series of triazolo-pyridine dicarbonitriles and substituted dihydropyridine dicarbonitriles were synthesized using green protocol (TBAB in refluxed water). We next evaluated the title compounds for their cytotoxicity towards lung cancer (A549) cells and identified 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-1H-imidazol-2-yl)-5'-oxo-1',5'-dihydrospiro[cyclohexane-1,2'-[1,2,4]triazolo[1,5-a]pyridine]-6',8'-dicarbonitrile (5j) as lead analogs with the IC50 values of 15.2 and 24.1â µm, respectively. Furthermore, all the new compounds were tested for PDE4 inhibitory activity and 5j showed relatively good inhibitory activity towards PDE4 with inhibition of 50.9 % at 10â µm. In silico analysis demonstrated the favorable interaction of the title compounds with the target enzyme. Taken together, the present study introduces a new scaffold for the development of novel PDE4 inhibitors to fight against inflammatory diseases.
Asunto(s)
Antineoplásicos/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Nitrilos/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Piridinas/farmacología , Triazoles/farmacología , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Estructura Molecular , Nitrilos/química , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Piridinas/química , Relación Estructura-Actividad , Triazoles/química , Células Tumorales CultivadasRESUMEN
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.