Abstract
The natural product-like carbamide (1) has been identified as a stabilizer of the c-myc G-quadruplex through high-throughput virtual screening. NMR and molecular modeling experiments revealed a groove-binding mode for 1. The biological activity of 1 against the c-myc G-quadruplex was confirmed by its ability to inhibit Taq polymerase-mediated DNA extension and c-myc expression in vitro, demonstrating that 1 is able to control c-myc gene expression at the transcriptional level presumably through the stabilization of the c-myc promoter G-quadruplex. Furthermore, the interaction between carbamide analogues and the c-myc G-quadruplex was also investigated by in vitro experiments in order to generate a brief structure-activity relationship (SAR) for the observed potency of carbamide 1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Biological Products / chemistry
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Biological Products / pharmacology*
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DNA Primers / genetics
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G-Quadruplexes / drug effects*
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Hep G2 Cells
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High-Throughput Screening Assays
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Humans
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Models, Molecular*
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Molecular Structure
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Nuclear Magnetic Resonance, Biomolecular
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Proto-Oncogene Proteins c-myc / metabolism*
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RNA Stability / drug effects*
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Reverse Transcriptase Polymerase Chain Reaction
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Structure-Activity Relationship
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Urea / chemistry
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Urea / pharmacology*
Substances
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Biological Products
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DNA Primers
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Proto-Oncogene Proteins c-myc
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Urea
Grants and funding
This work is supported by Hong Kong Baptist University (FRG2/10-11/008 and FRG2/11-12/009), Environment and Conservation Fund (ECF Project 3/2010), Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIR-SCM, HKBU), the Research Fund for the Control of Infectious Diseases (RFCID/11101212) and the Research Grants Council (HKBU/201811), the University of Macau (Start-up Research Grant to C.-H. Leung), MYRG091(Y1-L2)-ICMS12-LCH and MYRG121(Y1-L3)-ICMS12-LCH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.