Multivalent RNA‐Cleaving Agents on a Cubic Octameric Silsesquioxane Core

ABSTRACT

Selective RNA cleavage could provide versatile options in therapeutic applications. In this study, multivalent RNA‐cleaving agents, featuring 1,5,9‐triazacyclododecane or guanidine groups as catalytic centers, were synthesized on a cubic octameric silsesquioxane (COSS) core. Their catalytic efficiencies were first evaluated and compared in the presence and absence of metal ions Zn ²⁺ , Cu ²⁺ , and Pd ²⁺ using hexaribonucleotide models. COSS–lysine(N ₃ )–TACD–Zn ²⁺ ₈ exhibited base moiety selectivity for uracil bases, resulting in half‐lives of 2–11 h for the cleavage of the uracil‐containing hexaribonucleotides. Then, the cleavage of a biologically relevant HER2 mRNA model sequence was studied with the most effective catalysts. Surprisingly, an organocatalyst (COSS–lysine(N ₃ )–arginine) outperformed a metal–organic catalyst (COSS–lysine(N ₃ )–TACD–Zn ²⁺ ₈ ) in catalytic efficiency, the half‐lives being 14 and 31 h, respectively. In addition, the cleavage sites of the HER2 mRNA model were determined. While the COSS–lysine(N ₃ )–TACD–Zn ²⁺ ₈ produced high background cleavage, the organic catalysts COSS–lysine(N ₃ )–arginine and COSS–lysine(N ₃ )–guanidine exhibited clear site‐specificity in the HER2 mRNA cleavage. Additionally, a correlation between the reaction rates and the amount of the catalysts was verified by varying the catalyst concentrations. Fast reaction rates and site‐specificity of the cleavage indicate good potential for further development of these cleaving agents.