1073243-62-5

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• 1073243-50-1 1,3,2',2',6'-pentaazido-6,3',2,5,3',4'-hexa-O-benzyl-4',6'-O-benzylidene-1,3,2',2',6'-pentadeaminoparomomycin 

Relevant academic research and scientific papers

Synthesis of a Pseudodisaccharide Suitable for Synthesis of Ring i Modified 4,5-2-Deoxystreptamine Type Aminoglycoside Antibiotics

To facilitate the synthesis of paromomycin and/or neomycin analogues, we describe a cleavage of ring I from paromomycin that proceeds in the presence of azides and affords a glycosyl acceptor for the installation of a modified ring I. A paromomycin 4′,6′-diol is oxidized by the Dess-Martin periodinane followed by m-chloroperoxybenzoic acid. Base treatment then affords a protected pseudodisaccharide, which functions as a glycosyl acceptor. The method should also apply to the cleavage of pyranosyl 4,6-diols from oligosaccharides and glycoconjugates.

Structure-Based Design and Synthesis of Apramycin-Paromomycin Analogues: Importance of the Configuration at the 6′-Position and Differences between the 6′-Amino and Hydroxy Series

The preparation of a series of four analogues of the aminoglycoside antibiotics neomycin and paromomycin is described in which ring I, involved in critical binding interactions with the ribosomal target, is replaced by an apramycin-like dioxabicyclo[4.4.0]octane system. The effect of this modification is to lock the hydroxymethyl side chain of the neomycin or paromomycin ring I, as part of the dioxabicyclooctane ring, into either the gauche-gauche or the gauche-trans conformation (respectively, axial or equatorial to the bicyclic system). The antiribosomal activity of these compounds is investigated with cell-free translation assays using both bacterial ribosomes and recombinant hybrid ribosomes carrying eukaryotic decoding A site cassettes. Compounds substituted with an equatorial hydroxyl or amino group in the newly formed ring are considerably more active than their axial diastereomers, lending strong support to crystallographically derived models of aminoglycoside-ribosome interactions. One such bicyclic compound carrying an equatorial hydroxyl group has activity equal to that of the parent yet displays better ribosomal selectivity, predictive of an enhanced therapeutic index. A paromomycin analog lacking the hydroxymethyl ring I side chain is considerably less active than the parent. Antibacterial activity against model Gram negative and Gram positive bacteria is reported for selected compounds, as is activity against ESKAPE pathogens and recombinant bacteria carrying specific resistance determinants. Analogues with a bicyclic ring I carrying equatorial amino or hydroxyl groups mimicking the bound side chains of neomycin and paromomycin, respectively, show excellent activity and, by virtue of their novel structure, retain this activity in strains that are insensitive to the parent compounds.

Synthesis and evaluation of paromomycin derivatives modified at C(4′)

The 2-amino-2-deoxy-α-D-glucopyranosyl moiety (ring I) of paromomycin was replaced by a 2,4-diamino-2,4-dideoxy-α-D-glucopyranosyl, 2,4-diamino-2,4-dideoxy-α-D-galactopyranosyl, 2-amino-2-deoxy-α-D- galactopyranosyl, or 3,4,5-trideoxy-4-aza-α-D-erythro-heptoseptanosyl moiety to investigate the effect of the substituent at C(4′) on the interaction with ribosomal RNA. The triflate 6 was prepared from the key intermediate pentaazido 3′,6′-dibenzyl ether 5, and the hexosulose 10 was obtained by oxidation of 5 with Dess - Martin's periodinane. Stereoselective reduction of 10 with NaBH4 gave the alcohol 11 that was transformed into the triflate 12. The epimeric hexaazides 7 and 13 were obtained by treating the triflates 6 and 12, respectively, with tetrabutylammonium azide. Periodate cleavage of glycol 2 yielded the dialdehyde 24 that was reductively aminated with aniline and benzylamine to give the 3,4,5-trideoxy-4-aza-α-D-erythro-heptoseptanosides 25 and 26, respectively. Standard azide reduction and debenzylation yielded 9 (2,4-diamino-2,4-dideoxy-α-D-galactopyranosyl ring I), 13 (2-amino-2-deoxy-α-D-galactopyranosyl ring I), 17 (2,4-diamino-2,4- dideoxy-α-D-glucopyranosyl ring I), and 27 and 28 (3,4,5-trideoxy-4-aza- α-D-erythro-heptoseptanosyl ring I). The derivatives 9 and 13 possessing a D-galacto-configured ring I were less active than the corresponding D-gluco-analogues 17 and paromomycin (1), respectively. The C(4′)- aminodeoxy derivative 17 (D-gluco ring I) and the known 4′- deoxyparomomycin (23), prepared by a new route, displayed slightly lower antibacterial activities than paromomycin (1). Cell-wall permeability is not responsible for the unexpectedly low activity for 17, as shown by cell-free translation assays. The results evidence that the orientation of the substituent at C(4′) is more important than its nature for drug binding and activity.