Cyclic
imides are known for their antitumor activity, especially the
naphthalimide derivatives, such as
Mitonafide and
Amonafide. Recently, we have demonstrated the cytotoxic effect of a series of
naphthalimide derivatives against B16F10
melanoma cells. On the basis of this fact, we have developed a study starting from the synthesis of different cyclic
imides and the evaluation of their cytotoxic properties on human acute
leukemia cells (K562 and Jurkat). Initially, a screening test was conducted to select the compound with the best cytotoxic effect, using the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. After this selection, structural modifications were performed in the most active compound to obtain five more derivatives. All compounds presented a good cytotoxic effect. The results of cell cycle analysis, fluorescence microscopy, and
Annexin V-FITC assay confirmed that the cells observed in the sub-G0/G1 phase were undergoing apoptosis. From this set of results, cyclic
imides 8, 10, and 12 were selected for the evaluation of the mechanisms involved in the apoptotic process. The results demonstrate the involvement of the intrinsic pathway of apoptosis, evidenced by the reduction in mitochondrial potential, an increase in the level of AIF
protein expression, a decreased level of expression of anti-apoptotic Bcl-2
protein, and an increased level of expression of
pro-apoptotic protein Bax in both K562 and Jurkat cells treated with cyclic
imides (8, 10, and 12). Furthermore, cyclic
imides 8 and 10 caused an increase in the level of Fas expression in Jurkat cells, indicating the additional involvement of the extrinsic apoptosis pathway. The compounds (8, 10, and 12) also caused a decreased level of expression of
anti-apoptotic protein survivin. The
biological effects observed with these cyclic
imide derivatives in this study suggest promising applications against acute
leukemia.