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

  • J Med Chem. 2021 Feb 25;64(4):2125-2138. doi: 10.1021/acs.jmedchem.0c01656.
Wei Long  1 ,  Bo-Xin Zheng  1 ,  Xuan-He Huang  1 ,  Meng-Ting She  1 ,  Ao-Lu Liu  1 ,  Kun Zhang  1  2 ,  Wing-Leung Wong  2  3 ,  Yu-Jing Lu  1  4
Affiliations
  • 1. School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, P. R. China.
  • 2. School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, P. R. China.
  • 3. State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
  • 4. Engineering Research Academy of High Value Utilization of Green Plants, Meizhou 514779, P. R. China.
PMID: 33559473 DOI: 10.1021/acs.jmedchem.0c01656
Abstract

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.

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