Disubstituted 1,8-dipyrazolcarbazole derivatives as a new type of c-myc G-quadruplex binding ligands

作者：Chen, Wei-Jia; Zhou, Chen-Xi; Yao, Pei-Fen; Wang, Xiao-Xiao; Tan, Jia-Heng; Li, Ding; Ou, Tian-Miao; Gu, Lian-Quan; Huang, Zhi-Shu^*

来源：Bioorganic & Medicinal Chemistry, 2012, 20(9): 2829-2836.

DOI：10.1016/j.bmc.2012.03.031

• G-Quadruplex
• c-myc Oncogene
• 1,8-Dipyrazolcarbazole derivatives
• Binding ligand
• Selectivity

A series of 1,8-dipyrazolcarbazole (DPC) derivatives (6a-6d, 7a-7d) designed as G-quadruplex ligands have been synthesized and characterized. The FRET-melting and SPR results showed that the DPC derivatives could well recognize G-quadruplex with strong discrimination against the duplex DNA. In addition, the DPC derivatives showed much stronger stabilization activities and binding affinities for c-myc G-quadruplex rather than telomeric G-quadruplex. Therefore, their interactions with c-myc G-quadruplex were further explored by means of CD spectroscopy, PCR-stop assay, and molecular modeling. In cellular studies, all compounds showed strong cytotoxicity against cancer cells, while weak cytotoxicity towards normal cells. RT-PCR assay showed that compound 7b could down-regulate c-myc gene expression in Ramos cell line, while had no effect on c-myc expression in CA46 cell line with NHE III1 element removed, indicating its effective binding with G-quadruplex on c-myc oncogene in vivo.

• 出版日期2012-5-1
• 单位中山大学