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Design, Synthesis, and Evaluation of Isaindigotone Derivatives To Downregulate c-myc Transcription via Disrupting the Interaction of NM23-H2 with G-Quadruplex

Authors :
Chan Shan
Jin-wu Yan
Ding Li
Ai-Chun Chen
Jia-Heng Tan
Zhou-Li Huang
Zhi-Shu Huang
Tian-Miao Ou
Lian-Quan Gu
Tong Che
Pei-Fen Yao
Yu-Qing Wang
Source :
Journal of medicinal chemistry. 60(4)
Publication Year :
2017

Abstract

Transcriptional control of c-myc oncogene is an important strategy for antitumor drug design. G-quadruplexes in the promoter region have been proven to be the transcriptional down-regulator of this gene. The transcriptional factor NM23-H2 can reactivate c-myc transcription by unwinding the G-quadruplex structure. Thus, down-regulation of c-myc transcription via disrupting G-quadruplex-NM23-H2 interaction might be a potential approach for cancer therapy. Here, a series of new isaindigotone derivatives were designed and synthesized based on our previous study. The abilities of these derivatives on interacting with G-quadruplexes or NM23-H2, and disrupting G-quadruplex-NM23-H2 interaction were evaluated. Among these derivatives, 19d and 22d showed remarkable abilities on disrupting G-quadruplex-NM23-H2 interaction. They exhibited significant effects on c-myc-relating processes in SiHa cells, including inhibiting the transcription and translation, inhibiting cellular proliferation, inducing apoptosis, and regulating cell cycle. Our findings provided the basis for the anticancer strategy based on c-myc transcriptional regulation via small molecules disrupting G-quadruplex-protein interaction.

Details

ISSN :
15204804
Volume :
60
Issue :
4
Database :
OpenAIRE
Journal :
Journal of medicinal chemistry
Accession number :
edsair.doi.dedup.....88ca0f2ab785731bfc4367ea3f42e0ad