Document Type

Journal Article

Department/Unit

Department of Chemistry

Title

Structure-based design of flavone derivatives as c-myc oncogene down-regulators

Language

English

Abstract

Based on molecular docking analysis of complexes between flavone and the c-myc G-quadruplex, we designed and screened 30 flavone derivatives containing various side chains that could potentially form interactions with the G-quadruplex grooves. As a proof-of-concept, the highest-scoring flavone derivatives containing cationic pyridinium side chains were synthesized and their interactions with the c-myc G-quadruplex were examined using a PCR-stop assay. The stabilizing effects of the flavone derivatives were found to be selective towards the c-myc G-quadruplex over other biologically relevant G-quadruplex structures, such as the human telomeric sequence (HTS). The interaction between the most potent compound of the series and the c-myc G-quadruplex was examined in depth using UV-Vis titration, molecular modeling and CD spectroscopy. Our results suggest that in addition to stabilizing the c-myc G-quadruplex, the flavone derivatives were capable of inducing the formation of the G-quadruplex structure even in the absence of monovalent cations. The flavone derivatives were found to be potent inhibitors of c-myc promoters within the cellular environment and displayed promising cytotoxic behavior against human cancer cell lines. © 2012 Elsevier B.V. All rights reserved.

Keywords

c-myc, Flavone derivatives, G-quadruplex DNA, Structure-based design

Publication Date

2013

Source Publication Title

European Journal of Pharmaceutical Sciences

Volume

48

Issue

2-1

Start Page

130

End Page

141

Publisher

Elsevier

DOI

10.1016/j.ejps.2012.10.010

Link to Publisher's Edition

http://dx.doi.org/10.1016/j.ejps.2012.10.010

ISSN (print)

09280987

ISSN (electronic)

18790720

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