Novel acyclic deoxystreptamine mimetics targeting the ribosomal decoding site.

KEYWORDS: aminoglycosides ¥ antibiotics ¥ drug design ¥ medicinal chemistry ¥ RNA recognition Natural aminoglycoside antibiotics such as paromomycin and neomycin B [1] disrupt functional protein synthesis in bacteria by specifically binding to the decoding-site RNA in the 30S ribosomal subunit (Figure 1), [2] thereby interfering with mRNA decoding fidelity and ultimately leading to bacterial cell death. Binding of the aminoglycosides to the decoding site displaces two adenine residues (A1492 and A1493) from the deep groove of the internal-loop RNA. This displacement facilitates the utilization of noncognate tRNAs and leads to decreased trans-lational accuracy. [3, 4] While the efficacy of natural aminoglyco-sides as antibiotics is compromised by bacterial resistance and undesirable pharmacological profiles, [5] their capability to bind with high affinity to the bacterial decoding site and other distinct RNA targets, [6] such as ribozymes and viral regulatory domains, renders them a lead paradigm in RNA molecular recognition. Aminoglycosides thus provide starting points for the design of novel RNA binders. [9±15] The daunting challenge of selective derivatization of the highly functionalized natural products has encouraged efforts to discover novel antibacterial ligands directed at the decoding site by starting from smaller fragments of aminoglycosides (Figure 1). Previous approaches to the synthesis of simplified aminoglycosides have focused on deriva-tization of 2-deoxystreptamine (2-DOS), as an individual moi-ety [10, 11] or in the context of the neamine [12] and parom-amine [13, 14] scaffolds, and on derivatization of the glucosamine fragment. [15] The availability of three-dimensional structures for aminoglycoside complexes of the bacterial decoding-site RNA [16, 17] and whole 30S ribosomal subunits [4, 18] has prepared the ground for rational structure-based design of readily accessible aminoglycoside mimetics. These will provide lead compounds for the development of novel antibiotics that achieve RNA target binding affinity, specificity, and antibacterial potency comparable to those of the natural products, and whose efficacy may not be compromised by bacterial resistance mechanisms specific to the natural products. Herein and in the accompanying report, [19] we outline novel strategies for linking the 6'-aminoglucosamine moiety, conserved among many potent natural aminoglycosides, to alternative scaffolds that mimic the unique spatial arrangement of the functional groups in 2-DOS that are required for the recognition of the RNA target. The novel scaffolds were designed by molecular modeling [20] based on the crystal structure of paromomycin complexed with the bacterial decoding site (Figure 1). [4, 16±18] In this report, we describe the synthesis and testing of 37 …