H2Nl0H2rNH2 nh2

16 Hygromycin B 13 Apramycin

Figure 4 Structures of some aminoglycoside antibiotics.

Extending their work to search for small molecules that recognize RNA, Wong et al., considered the 1,3-hydroxyamine motif as a core for such molecules [162,165]. 1,3-Hydroxyamines can be effective motifs for molecular recognition of phospho-diesters because an interesting and common feature of almost all aminoglycoside antibiotics is the presence of a frans-1,3-hydroxyamine or c;'s-1,3-diamine motif. In fact, a model study by NMR spectroscopy [165] showed that the glyco-type 1,3-hydroxyamines interact via multiple hydrogen bonds, with phosphodiesters and the Hougsteen face of guanine, which is typically stronger than the cyclic guanidine group (Fig. 5).

To test these findings, new aminoglycoside derivatives were synthesized in a series bearing either one or both of these recognition motifs for RNA interaction

Figure 5 Strong interactions of ;6-1,3-hydroxyamine motif found in aminoglycoside antibiotics with (a) phosphodiesters and (b) Hougsteen face of guanine, compared to that of standard cyclic guanidine (c).

[162]. Some of the new compounds showed strong antibiotic activities and were effective in binding to the A-site RNA sequence (Fig. 3b) and to a drug-resistant mutant RNA in the micromolar range. For instance, compound 128 (Fig. 3a) with the neamine moiety as the recognition motif showed a value of 0.26 ^M [162], and the pyranoside derivative compound 131 bearing the 1,3-hydroxyamine motif as the core exhibited a value in the range of 10 ^M in binding to the A-site RNA model [162,166]. Application of this strategy in designing small molecules that target RNA could lead to development of potent sequence-specific RNA binders and potential discovery of new aminoglycoside antibiotics with less toxicity.

In a recent communication by Rando and colleagues [167], simple aminols were reported to be effective A-site RNA binders with a potency similar to or greater than the potent RNA binder aminoglycoside paromomycin (25). Discovery of these simple 1,3-(2)-aminol-containing molecules (e.g., 132 and 133), which act as potent substituents for the structurally complicated aminoglycosides in binding to the bacterial A-site decoding region, would pave the way for the design and synthesis of a new class of potent antibiotics.

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