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, H., Zhong, H., Leung, K., Chan, D., Ma, V., Fu, W., Nanjunda, R., Wilson, W., Ma, D., & Leung, C. (2013). Structure-based design of flavone derivatives as c-myc oncogene down-regulators. European Journal of Pharmaceutical Sciences, 48 (2-1), 130-141. https://doi.org/10.1016/j.ejps.2012.10.010