The c-MYC oncogene is overactivated during Burkitt’s
lymphoma pathogenesis. Targeting c-MYC to inhibit
its transcriptional activity has emerged as an effective anticancer
strategy. We synthesized four series of disubstituted quindoline derivatives
by introducing the second cationic amino side chain and 5-N-methyl group based on a previous study of SYUIQ-5 (1) as c-MYC promoter G-quadruplex ligands.
The in vitro evaluations showed that
all new compounds exhibited higher stabilities and binding affinities,
and most of them had better selectivity (over duplex DNA) for the c-MYC G-quadruplex compared to 1. Moreover,
the new ligands prevented NM23-H2, a transcription factor, from effectively
binding to the c-MYC G-quadruplex. Further studies
showed that the selected ligand, 7a4, down-regulated c-MYC transcription by targeting promoter G-quadruplex and
disrupting the NM23-H2/c-MYC interaction in RAJI
cells. 7a4 could inhibit Burkitt’s lymphoma cell
proliferation through cell cycle arrest and apoptosis and suppress
tumor growth in a human Burkitt’s lymphoma xenograft.