Parallel synthesis of a small library of novel aminoglycoside analogs based on 2-amino-2-deoxy-d-glucose and d-ribose scaffolds Christoph Rosenbohm, a,² Dirk Vanden Berghe, b Arnold Vlietinck b and Jesper Wengel a,p a Department of Chemistry, University of Southern Denmark, Odense, DK-5230 Odense M, Denmark b Department of Pharmaceutical Sciences, University of Antwerp, B-2610 Antwerp, Belgium Received 21 March 2001; revised 1 May 2001; accepted 17 May 2001 Abstract ÐThe synthesis of a small library of aminoglycoside analogues based on 2-amino-2-deoxy-d-glucose and d-ribose was achieved using reductive amination reactions as key transformations. q 2001 Elsevier Science Ltd. All rights reserved. 1. Introduction The vast majority of the drugs known today owe their pharmaceutical activity to interactions with proteins and only very few rely on interactions with RNA. In the last years the interest in RNA as a drug receptor has grown signi®cantly due to the discovery that RNA is involved in many catalytic processes 1 and to the approval of the ®rst antisense drug. 2 The increased awareness of the central role of RNA has led to research into small molecules that interact with RNA. The potency of aminoglycoside anti- biotics and the importance of circumventing the emerging problems of resistance has led to studies on the mechanism of action of these antibiotics focusing on understanding the molecular interactions leading to activity. 3 It was shown early that aminoglycosides interact with the bacterial ribo- some leading to miscoding and/or termination of growing peptide chains. 4 By using a foot-printing technique, Moazed and Noller were the ®rst to describe the secondary structure of the 16S rRNA 5 subunit of the ribosome and later the site of aminoglycoside binding to the A-site. 6 The A-site together with the P-site ensure the ®delity of tRNA selection and the binding of aminoglycosides interferes with the selection and proof-reading mechanism thereby lowering the accuracy of protein synthesis. Chemically, the natural aminoglycosides are a group of structurally related poly- amine oligosaccharides (Fig. 1). 7 Their common structural element is a meso-1,3-diaminocyclitol 2-deoxystreptamine unit. The 2-deoxystreptamine is glycosylated with a variety of saccharides both with and without amino groups at the 4-position as well as the 5-position as in the neomycin class, or at the 6-position as in the kanamycin±gentamicin class. Most of the information about the binding of aminoglyco- sides to the 16S rRNA subunit has been obtained from two NMR structures, one of the free As-wt oligonucleotide model for the 16S rRNA subunit 8 and one of a complex between paromomycin and the As-wt. 9 One of the striking features of these structures is that it is the paromamine part of paromomycin that is responsible for virtually all of the speci®c hydrogen bonding contacts to the RNA. The two other rings are apparently responsible for orienting the paromamine/neamine part in an optimal way. Aminoglyco- sides bind to a pocket in the bacterial 16S rRNA subunit created by a mismatched base pair and to a host of other RNA targets. Tok and Rando have furthermore shown that simple 1,3-hydroxylamine containing aminols are also able to bind the As-wt model with low micro molar af®nities which is comparable to the binding af®nities of some of the natural aminoglycosides. 10 Further investigations on the role of the different parts of the natural aminoglycosides on binding have been performed by Alper et al. 11 who have synthesized a series of neomycin B analogues in which the 2,6-dideoxy-2,6-diamino-l-idose unit was replaced by different groups. Further work by Wong and coworkers has shown that 2-amino-2-deoxy-d-glucose 12 and neamine 13 are effective scaffolds for the synthesis of libraries of amino- glycoside analogues with good RNA binding properties. A differently structured library based on neamine in which the 6 0 -amino group was functionalized by reductive aminations or Ugi type couplings has been prepared in order to further study RNA binding. 14 Tetrahedron 57 (2001) 6277±6287 Pergamon TETRAHEDRON 0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(01)00584-1 Keywords: carbohydrate libraries; aminoglycoside analogues; 2-amino-2- deoxy-d-glucose; reductive amination reactions. p Corresponding author. Tel.: 145-6550-2510; fax: 145-6615-8780; e-mail: jwe@chem.sdu.dk ² Present address: Cureon A/S, Fruebjergvej 3, DK-2100 Copenhagen, Denmark.