n--(10h-indolo(3-2-b)quinolin-11-yl)-n-n-dimethylpropane-1-3-diamine and Burkitt-Lymphoma

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.

Topics: Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Burkitt Lymphoma; Cell Cycle Checkpoints; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; G-Quadruplexes; Humans; Indoles; Mice, Inbred NOD; Mice, SCID; Molecular Structure; Neoplasms, Experimental; Proto-Oncogene Proteins c-myc; Quinolines; Structure-Activity Relationship; Transcription, Genetic