Site-Selective RNA Activation by Acridine-Modified Oligodeoxynucleotides in Metal-Ion Catalyzed Hydrolysis: A Comprehensive Study

Various types of acridine were conjugated to DNA and used for site-selective RNA scission together with another unmodified DNA and a Lu(III) ion. The target phosphodiester linkage in the substrate RNA was selectively and efficiently activated, and was hydrolyzed by the free Lu(III) ion. Among the investigated 14 conjugates, the conjugate bearing 9-amino-2-isopropoxy-6-nitroacridine was the best RNA-activator. Systematic evaluation of the RNA-activating ability of the acridines showed that (1) the acridines act as an acid catalyst within the RNA activation, (2) the amino-group at the 9-position of acridine is essential to modulate the acidity of acridine, (3) the electron-withdrawing group at the 3-position further enhances the acid catalysis, and (4) the substituent at the 2-position sterically modulates the orientation of acridine-intercalation favorably for the catalysis. Moreover, it is revealed that the opposite base of acridine does not inhibit direct interaction of acridine with the target phosphodiester linkage.