Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / chemical synthesis
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Alkaloids / chemistry
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Alkaloids / pharmacology*
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Burkitt Lymphoma / drug therapy*
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Burkitt Lymphoma / genetics
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Burkitt Lymphoma / pathology
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Cell Cycle Checkpoints / drug effects
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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G-Quadruplexes / drug effects
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry
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Indoles / pharmacology*
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Mice, Inbred NOD
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Mice, SCID
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / pathology
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
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Proto-Oncogene Proteins c-myc / genetics
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Quinolines / chemical synthesis
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Quinolines / chemistry
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Quinolines / pharmacology*
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Structure-Activity Relationship
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Transcription, Genetic / drug effects
Substances
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Alkaloids
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Antineoplastic Agents
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Indoles
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Proto-Oncogene Proteins c-myc
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Quinolines
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quindoline