Synthesis of nicotinamide derivatives having a hydroxy‐substituted benzene ring and the influence of their structures on the apoptosis‐inducing activity against leukemia cells

With the view of developing novel apoptosis‐inducing agents against malignant cells, nicotinamide derivatives containing substituted O‐benzoyl‐tyrosine, dopamine, and norepinephrine residues were synthesized. Antiproliferative activity measurements using leukemia U937 cells revealed that the benzoyl‐tyrosine derivative having two hydroxys at C‐2 and C‐3 on the benzoyl group, and the one having a hydroxy at C‐2 and a methoxy at C‐4 proved the most potent among the 9 nicotinamide derivatives. The IC₅₀ values of these compounds were 0.87 and 3.15 µM, which indicates their noteworthy activity compared with epigallocatechin gallate, a catechin component in green tea known for its noticeable activity. The cell death process was confirmed to be the result of apoptosis by agarose gel electrophoresis and dye staining, suggesting the high potential of these compounds as apoptosis‐inducing anticancer agents. Drug Dev Res 72: 289–297, 2011. © 2010 Wiley‐Liss, Inc.