1. Rational design of small-molecules to recognize G-quadruplexes of c-MYC promoter and telomere and the evaluation of their in vivo antitumor activity against breast cancer
- Author
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Wei Long, Bo-Xin Zheng, Ying Li, Xuan-He Huang, Dan-Min Lin, Cui-Cui Chen, Jin-Qiang Hou, Tian-Miao Ou, Wing-Leung Wong, Kun Zhang, and Yu-Jing Lu
- Subjects
Genes, myc ,Antineoplastic Agents ,Breast Neoplasms ,Telomere ,Ligands ,G-Quadruplexes ,Mice ,Drug Design ,MCF-7 Cells ,Genetics ,Animals ,Humans ,Female ,Promoter Regions, Genetic - Abstract
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 1H 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.
- Published
- 2022
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