Synthesis of electrophile-tethered preQ1 analogs for covalent attachment to preQ1 RNA.

Abstract

The preQ₁ cIass-I riboswitch aptamer can utilize 7-aminomethyl-7-deazaguanine (preQ₁) ligands that are equipped with an electrophilic handle for the covalent attachment of the ligand to the RNA. The simplicity of the underlying design of irreversibly bound ligand-RNA complexes has provided a new impetus in the fields of covalent RNA labeling and RNA drugging. Here, we present short and robust synthetic routes for such reactive preQ₁ and (2,6-diamino-7-aminomethyl-7-deazapurine) DPQ₁ ligands. The readily accessible key intermediates of preQ₀ and DPQ₀ (both bearing a nitrile moiety instead of the aminomethyl group) were reduced to the corresponding 7-formyl-7-deazapurine counterparts. These readily undergo reductive amination to form the hydroxyalkyl handles, which were further converted to the haloalkyl or mesyloxyalkyl-modified target compounds. In addition, we report hydrogenation conditions for preQ₀ and DPQ₀ that allow for cleaner and faster access to preQ₁ compared to existing routes and provide the novel compound DPQ₁.