Target identification of a macrocyclic hexaoxazole G-quadruplex ligand using post-target-binding visualization.

Abstract

Macrocyclic hexaoxazoles (6OTDs) are G-quadruplex (G4) ligands, and some derivatives, such as L2H2-6OTD (1a) bearing two aminobutyl side chains, show cytotoxicity towards cancer cells. To identify the cellular target of 1a, we employed a post-target-binding strategy utilizing click reaction (Huisgen cyclization) between the azide-conjugated ligand L2H2-6OTD-Az (1b) and the cell-permeable dye CO-1 bearing a strained alkyne moiety and the BODIPY fluorophore under Cu-free conditions. We confirmed that introduction of the small azide group did not alter the physical or biological properties, including anti-cancer activity, of 1a, and we also demonstrated bias-free localization of CO-1. The post-binding visualization strategy suggested that L2H2-6OTD (1a) colocalized with RNA G4 in living cells.

• Authors: Mizuho Yasuda , Yue Ma , Sachiko Okabe , Yuki Wakabayashi , Dongdong Su , Young-Tae Chang , Hiroyuki Seimiya , Masayuki Tera , Kazuo Nagasawa
• Journal: Chemical communications (Cambridge, England) (Chem Commun (Camb)) Vol. 56 Issue 85 Pg. 12905-12908 (Nov 04 2020) ISSN: 1364-548X [Electronic] England
• PMID: 33030187 (Publication Type: Journal Article)

Chemical References

• Ligands
• Macrocyclic Compounds
• Oxazoles

Topics

• Binding Sites
• Cell Line, Tumor
• G-Quadruplexes
• Humans
• Ligands
• Macrocyclic Compounds (chemistry)
• Molecular Structure
• Oxazoles (chemistry)