Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 4, Pages 2125-2138Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01656
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Funding
- National Natural Science Foundation of China [81473082, 22077020]
- Natural Science Foundation of Guangdong Province, China [2017A030313078, 2017A030313071, 2019A1515011799]
- 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]
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The series of fluorescent ligands constructed from thiazole orange scaffold were investigated for their interactions with G-quadruplex structures and antitumor activity. Compound 3 showed excellent specificity towards telomere G4-DNA, with higher affinity compared to other nucleic acids. The findings support that compound 3 may be telomere G4-DNA specific and offer insights for anticancer drug design.
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 mu M) was found to be generally higher than noncancer cells (IC50 = 52.3 mu M). The findings may support that the ligand is telomere G4-DNA specific and may provide meaningful insights for anticancer drug design.
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