Synthesis of cNDI-Peptide-Dimer as a G4 Cluster-Selective Binder and its Interaction with G4 Dimer

The amino acid unit carrying cyclic naphthalene diimide (cNDI) was synthesized by linking the amino moiety of cNDI as a G4-specific ligand with the gamma-carboxylic acid moiety of Fmoc-Glu. cNDI-peptide-dimer, 1 was synthesized by peptide synthesizer using this unit. 1 exhibited an extremely strong binding constant of the order of 108 M-1 with telomeric G4 dimer, probably due to cooperative stacking of the its two G4 planes. It also showed an IC50 at the nM level by the TRAP assay. The results obtained here are expected to enable the design of peptide ligands with multiple cNDI sites targeting the G4 cluster by using the amino acid units of cNDI. Cyclic naphthalene diimide-peptide-dimer 1 showed strong telomerase inhibitory activity with a very strong binding constant on the order of 108 M-1 and an IC50 at the nM level in the TRAP assay. Comparison of the interaction with derivatives of 1 suggested that 1 result was probably due to cooperative stacking of the two G4 planes of telomere G4 dimer. 1 is expected to be a new type of telomerase activity inhibitor and ALT inhibitor. image