Stabilization of G-Quadruplex DNA and Down-Regulation of Oncogene c-myc by Quindoline Derivatives

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• 作者：Tian-Miao Ou ; Yu-Jing Lu ; Chi Zhang ; Zhi-Shu Huang ; Xiao-Dong Wang ; Jia-Heng Tan ; Yuan Chen ; Dik-Lung Ma ; Kwok-Yin Wong ; Johnny Cheuk-On Tang ; Albert Sun-Chi Chan ; Lian-Quan Gu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：April 5, 2007
• 年：2007
• 卷：50
• 期：7
• 页码：1465 - 1474
• 全文大小：566K
• 年卷期：v.50,no.7(April 5, 2007)
• ISSN：1520-4804

文摘

Stabilization of G-quadruplex structures in the promoter region of certain oncogenes is an emerging fieldin anticancer drug design. Human c-myc gene is one of these oncogenes, and G-quadruplexes have beenproven to be the transcriptional controller of this gene. In the present study, the interaction of quindolinederivatives with G-quadruplexes in c-myc was investigated. The experimental results indicated that thesederivatives have the ability to induce/stabilize the G-quadruplexes in c-myc, which lead to down-regulationof the c-myc in the Hep G2 cell line. It was found that derivatives with terminal amino groups in their sidechains would selectively bind to the isomers with the double nucleotide loops in the absence of K⁺. Molecularmodeling studies revealed the binding mode between the derivatives and the G-quadruplexes is end-stackingat the 3'-position, and the positively charged side chain on the quindoline derivatives may contribute to theselectivity to certain loop isomers of topological quadruplexes as well as the improved stabilization action.