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

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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.

Graphical abstract: Target identification of a macrocyclic hexaoxazole G-quadruplex ligand using post-target-binding visualization

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Article information


Submitted
21 Jul 2020
Accepted
25 Sep 2020
First published
26 Sep 2020

Chem. Commun., 2020, Advance Article
Article type
Communication

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

M. Yasuda, Y. Ma, S. Okabe, Y. Wakabayashi, D. Su, Y. Chang, H. Seimiya, M. Tera and K. Nagasawa, Chem. Commun., 2020, Advance Article , DOI: 10.1039/D0CC04957C

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