Molecular Recognition and Imaging of Human Telomeric G-Quadruplex DNA in Live Cells: A Systematic Advancement of Thiazole Orange Scaffold To Enhance Binding Specificity and Inhibition of Gene Expression
| Autor: | Ao Lu Liu, Meng Ting She, Wing-Leung Wong, Xuan He Huang, Wei Long, Yu Jing Lu, Bo Xin Zheng, Kun Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
Down-Regulation
Ligands G-quadruplex 01 natural sciences Styrenes HeLa 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor Lateral loop Drug Discovery Humans Benzothiazoles Telomerase Binding selectivity Fluorescent Dyes 030304 developmental biology 0303 health sciences Microscopy Confocal biology Chemistry DNA biology.organism_classification 0104 chemical sciences Cell biology Telomere G-Quadruplexes 010404 medicinal & biomolecular chemistry Microscopy Fluorescence Cell culture Cancer cell Quinolines RNA Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 64:2125-2138 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c01656 |
| Popis: | A series of fluorescent ligands, which were systematically constructed from thiazole orange scaffold, was investigated for their interactions with G-quadruplex structures and antitumor activity. Among the ligands, compound 3 was identified to exhibit excellent specificity toward telomere G4-DNA over other nucleic acids. The affinity of 3-Htg24 was almost 5 times higher than that of double-stranded DNA and promoter G4-DNA. Interaction studies showed that 3 may bind to both G-tetrad and the lateral loop near the 5'-end. The intracellular colocalization with BG4 and competition studies with BRACO19 reveal that 3 may interact with G4-structures. Moreover, 3 reduces the telomere length and downregulates hTERC and hTERT mRNA expression in HeLa cells. The cytotoxicity of 3 against cancer cells (IC50 = 12.7-16.2 μM) was found to be generally higher than noncancer cells (IC50 = 52.3 μM). The findings may support that the ligand is telomere G4-DNA specific and may provide meaningful insights for anticancer drug design. |
| Databáze: | OpenAIRE |
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