Design and synthesis of dinuclear bismuth(III) complexes with potent ribonuclease-like activity

Several metal complexes with ribonuclease-like activity have been developed as chemical biology tools for RNA regulation. However, their RNA-cleavage activity is insufficient under physiological conditions. Here, we have identified novel dinuclear bismuth(III) complexes that contain dipyridine/dipicolinate-based ligands as artificial ribonucleases to induce efficient RNA cleavage. Our optimization studies of the ligand structure indicated that the dipyridine/dipicolinate scaffold of the ligands plays a key role in maintaining the dinuclear arrangement of the bismuth(III) centers and tuning the Lewis acidity of the bismuth(III) ions to achieve potent RNA-cleavage activity. The mechanistic analysis of the RNA-cleavage reaction suggested that cooperative activation of a phosphate group in RNAs and water molecules coordinated by two bismuth(III) centers results in a rapid nucleophilic attack of the 2′-hydroxy group of a ribose to the phosphate and facilitates the removal of a 5′-alkoxide by protonation to generate a 2′,3′-cyclic phosphate and a 5′-hydroxy product. Thus, the developed dinuclear bismuth(III) complexes represent promising tools for chemical biology studies.