グアニン四重鎖構造を安定化する大環状ポリオキサゾール化合物類の合成と機能評価

概要

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G-quadruplex (G4) is known to exist in telomeres at the ends of chromosomes, as well as in promoter regions of some oncogenes. These G4s form inherent topology, depending upon the presence of monovalent cations or the precise DNA sequence, and have characteristic biological activities. Since G4 structures have various biological functions and are expected to be a promising chemotherapeutic target, discovery of new G4 structures in genes and their ligands is of great importance. Herein, macrocyclic polyoxazole compounds based upon telomestatin, which is known as the most potent G4 stabilizing reagent, as novel G4 ligands were developed. First, macrocyclic hexa- and hepta-oxazoles namely 6OTD- and 7OTD-type G4 ligands of L2H2-6OTD, L2G2-6OTD and L1H1-7OTD were synthesized. These are selective for the telomeric oligonucleotide and strongly stabilize it in the anti-parallel G4. These compounds also showed potent telomerase-inhibitory activity. Next, fluorescence-labeled 7OTD of L1BOD-7OTD as a fluorescent G4 ligand was developed. L1BOD-7OTD selectively interacts with some G4 forming DNA by inducing and stabilizing G4 structure and can detect them as green fluorescence.