Department of Chemistry
Structure-based design of flavone derivatives as c-myc oncogene down-regulators
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.
c-myc, Flavone derivatives, G-quadruplex DNA, Structure-based design
Source Publication Title
European Journal of Pharmaceutical Sciences
Link to Publisher's Edition
Yang, Hui, Hai-Jing Zhong, Ka-Ho Leung, Daniel Shiu-Hin Chan, Victor Pui-Yan Ma, Wai-Chung Fu, Rupesh Nanjunda, W. David Wilson, Dik-Lung Ma, and Chung-Hang Leung. "Structure-based design of flavone derivatives as c-myc oncogene down-regulators." European Journal of Pharmaceutical Sciences 48.2-1 (2013): 130-141.