Stabilization of Human Telomeric G-Quadruplex and Inhibition of Telomerase Activity by Propeller-Shaped Trinuclear PtII Complexes

Two novel propeller-shaped, trigeminal-ligand-containing, flexible trinuclear Pt-II complexes, {[Pt(dien)](3)(ptp)}(NO3)(6) (1) and {[Pt(dpa)](3)(ptp)}(NO3)(6) (2) (dien: diethylenetriamine; dpa: bis-(2-pyridylmethyl) amine; ptp: 6'-(pyridin-3-yl)-3,2': 4', 3 ''-terpyridine), have been designed and synthesized, and their interactions with G-quadruplex (G4) sequences are characterized. A combination of biophysical and biochemical assays reveals that both PtII complexes exhibit higher affinity for human telomeric (hTel) and c-myc promoter G4 sequences than duplex DNA. Complex 1 binds and stabilizes hTel G4 sequence more effectively than complex 2. Both complexes are found to induce and stabilize either antiparallel or parallel conformation of G4 structures. Molecular docking studies indicate that complex 1 binds into the large groove of the antiparallel hTel G4 structure (PDB ID: 143D) and complex 2 stacks onto the exposed G-quartet of the parallel hTel G4 structure (PDB ID: 1KF1). Telomeric repeat amplification protocol assays demonstrate that both complexes are good telomerase inhibitors, with IC50 values of (16.0 +/- 0.4) mu m and (4.20 +/- 0.25) mu m for 1 and 2, respectively. Collectively, the results suggest that these propeller-shaped flexible trinuclear Pt-II complexes are effective and selective G4 binders and good telomerase inhibitors. This work provides valuable information for the interaction between multinuclear metal complexes with G4 DNA.