Bcl-2 gene is a kind of apoptosis-related oncogene, in which a G-quadruplex structure can be formed in its promoter P1 region. In this study, a new series of compounds (1a-3c), in the basis of 1, 8-naphthalimide as a core skeleton, aiming at G-quadruplex structure were designed and synthesized. By CCK-8 assay, it was found that the compound 2-(3-(piperazin-1-yl)propyl)-6-(1H-benzo[d][1,2,3]triazol- 1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (3a) had obvious activity against A549 cells. Through extracellular assays, including FRET melting, EMSA, CD, molecular simulation, results showed that 3a selectively interacted with bcl-2 G-quadruplex. While results by intracellular assays, including western blotting, immunofluorescence and flow cytometry, verified that 3a mediated death of A549 cells by two pathways: inhibition of the expression of bcl-2 gene causing tumor cell apoptosis and promotion of genetic instability giving rise to the occurrence of autophagy. This study suggests that the type of compounds, in particular, 3a, may be a potential molecule to be used in exploration of bcl-2 G-quadruplex-targeted drugs against A549 lung cancer cells.
1, 8-naphthalimide derivative;bcl-2;G-quadruplex;anti-tumor