期刊
NUCLEIC ACIDS RESEARCH
卷 50, 期 4, 页码 1829-1848出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkac090
关键词
-
资金
- National Natural Science Foundation of China [81473082, 22077020, 32050410289]
- Natural Science Foundation of Guangdong Province, China [2019A1515011799, 2017A030313078, 2017A030313071]
- Jiangmen Program for Innovative Research Team [2018630100180019806]
- Department of Education of Guangdong Province, China [2016KCXTD005, 2017KSYS010]
- Department of Agriculture and Rural Affairs of Guangdong Province, China [2018LM2175]
- Health and Medical Research Fund (HMRF) of the Food and Health Bureau, Hong Kong SAR [19200231]
- PolyU Startup Fund [P0035712]
This study reports a new approach of designing small molecules based on a non-selective thiazole orange scaffold to target G4 structures with improved selectivity. The ligands establish multi-site interactions with flanking residues and loops of the G4 motif, and demonstrate antitumor activity in cancer cells.
DNA G4-structures from human c-MYC promoter and telomere are considered as important drug targets; however, the developing of small-molecule-based fluorescent binding ligands that are highly selective in targeting these G4-structures over other types of nucleic acids is challenging. We herein report a new approach of designing small molecules based on a non-selective thiazole orange scaffold to provide two-directional and multi-site interactions with flanking residues and loops of the G4-motif for better selectivity. The ligands are designed to establish multi-site interactions in the G4-binding pocket. This structural feature may render the molecules higher selectivity toward c-MYC G4s than other structures. The ligand-G4 interaction studied with H-1 NMR may suggest a stacking interaction with the terminal G-tetrad. Moreover, the intracellular co-localization study with BG4 and cellular competition experiments with BRACO-19 may suggest that the binding targets of the ligands in cells are most probably G4-structures. Furthermore, the ligands that either preferentially bind to c-MYC promoter or telomeric G4s are able to downregulate markedly the c-MYC and hTERT gene expression in MCF-7 cells, and induce senescence and DNA damage to cancer cells. The in vivo antitumor activity of the ligands in MCF-7 tumor-bearing mice is also demonstrated.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据