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

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• 作者：Hui Yang^a ; ¹ ; Hai-Jing Zhong^b ; ¹ ; Ka-Ho Leung^a ; ¹ ; Daniel Shiu-Hin Chan^a ; Victor Pui-Yan Ma^a ; Wai-Chung Fu^a ; Rupesh Nanjunda^c ; W. David Wilson^c ; Dik-Lung Ma^a ; ^{edmondma@hkbu.edu.hk} ; Chung-Hang Leung^b ; ^{duncanleung@umac.mo}
• 关键词：G-quadruplex DNA ; c-myc ; Flavone derivatives ; Structure-based design
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2013
• 出版时间：23 January, 2013
• 年：2013
• 卷：48
• 期：1-2
• 页码：130-141
• 全文大小：3098 K

文摘

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.