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Natural aminoglycoside antibiotics recognize an internal loop of bacterial ribosomal-decoding-site RNA by binding to the deep groove of the RNA structure. We have designed, synthesized, and tested RNA-targeted paromamine derivatives that exploit additional interactions on the shallow groove face of the decoding-site RNA. An in vitro transcription-translation assay of a series of 6'-derivatives showed the 6'-position to be very sensitive to substitution. This result suggests that the group at the 6'-position plays a pivotal role in RNA target recognition.

Natural aminoglycoside antibiotics recognize an internal loop of bacterial ribosomal-decoding-site RNA by binding to the deep groove of the RNA structure. We have designed, synthesized, and tested RNA-targeted paromamine derivatives that exploit additional interactions on the shallow groove face of the decoding-site RNA. An in vitro transcription-translation assay of a series of 6'-derivatives showed the 6'-position to be very sensitive to substitution. This result suggests that the group at the 6'-position plays a pivotal role in RNA target recognition.

Based on the knowledge that certain bacterial strains can produce enzymes that are capable of phosphorylating the 3′-hydroxyl group of a series of aminoglycoside antibiotics, the pseudodisaccharide 3′-epiparomamine was prepared through a series of high yieldingsteps, starting from paromamine. Application of selective halogenation and subsequent animation reactions allowed the efficient transformation of 3′-epiparomamine to 3′-epineamine. The two compounds were not substrates for the inactivating enzymes, however, they are also much weaker antibiotics compared to the parent compounds paromamine and neamine. Model synthetic studies in the 2-amino-2-deoxy-D-ghicose series are also reported.