1. Disubstituted 1,8-dipyrazolcarbazole derivatives as a new type of c-myc G-quadruplex binding ligands
- Author
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Chen, Wei-Jia, Zhou, Chen-Xi, Yao, Pei-Fen, Wang, Xiao-Xiao, Tan, Jia-Heng, Li, Ding, Ou, Tian-Miao, Gu, Lian-Quan, and Huang, Zhi-Shu
- Subjects
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CARBAZOLE derivatives , *QUADRUPLEX nucleic acids , *LIGAND binding (Biochemistry) , *POLYMERASE chain reaction , *CANCER cells , *CELL-mediated cytotoxicity , *GENE expression , *ONCOGENES , *CELL lines , *SPECTRUM analysis - Abstract
Abstract: 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. [Copyright &y& Elsevier]
- Published
- 2012
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