Current Topics in Medicinal Chemistry - Volume 3, Issue 5, 2003

Alkaloids mimicking sugars in size and shape are now believed to be widespread in plants and microorganisms. Iminosugars are monosaccharide analogs in which the ring oxygen has been replaced by an imino group. Such iminosugars inhibit the glycosidases involved in a wide range of important biological processes because of their structural resemblance to the sugar moiety of the natural substrate and the presence of the nitrogen atom mimicking the positive charge of the glycosyl cation intermediate in the enzyme-catalyzed glycoside hydrolysis. These iminosugars and their derivatives are arousing considerable attention as potential therapeutic agents. In this review, the distribution of naturally occurring iminosugars and their biological activities and therapeutic applications will be reviewed and the prospects of iminosugars and their derivatives for new therapeutic applications will also be described.

Recent iminosugar syntheses starting both from commercially available sugars and non-glycidic precursors, are reported in this article. Exploiting carbohydrate starting materials, different synthetic approaches are described, mainly based on the introduction of an amino function in the sugar skeleton and the subsequent aminocyclization in order to generate the piperidine or pyrrolidine ring. The aminocyclization has been performed in different ways: reductive amination of azidoketones, intramolecular amino group attack on leaving groups and activated double bonds. In some cases one-pot amination and cyclization have been performed using ammonia or a primary amine and a di-functionalised sugar. Bicyclic compounds have also been obtained through these procedures. Starting from non-carbohydrate precursors, the nitrogen containing cycle, already present or easily obtained by Diels-Alder reactions, has been variously functionalised and stereo-differentiated by asymmetric induction or by resolution of the racemate. The syntheses of a variety of innovative structures, such as 1-N-iminosugars, iminosugars with two nitrogen atoms in the ring, iminosugars incorporating a guanidine function, imidazole-, triazole- and tetrazolefused iminosugars, sugar-like aza-, oxa-, and thio-indolizidines, are reported. Finally the synthesis of glycoconjugate-related iminosugars, where the “pseudoanomeric” centre is linked to amino acid or peptide residues, and iminosugar phosphonates and nucleosides have been reviewed.

Iminosugars have emerged in the literature during mid-1960's as synthetic compounds. Around the same time, the first examples were found in Nature and their interesting enzyme inhibitory properties were recognised. Due to their powerful interference with glycohydrolases (glycosidases) as well as glycosyltransferases, quite a few representatives exhibit notable biological activities. These range from antidiabetic, insect antifeedant, nematicidal, plant growth regulating to immunomodulating, anti-cancer as well as - in selected cases - anti-infective properties. The latter will be the focus of the following survey.

Continued interest in imino-sugar nucleosides derives from the observations that N-ribosyltransferases are powerfully inhibited by imino-C-nucleoside analogues that mimic the ribooxacarbenium ion nature of their transition states. The synthesis of such compounds is challenging, and synthetic routes to imino- and imino-Cnucleosides are reviewed, together with the nature of the N-ribosyltransferases that are targets for these analogues. Examples are given to exemplify the promise these compounds hold for the treatments of biological disorders.

Due to their pivotal role in the biosynthesis of oligosaccharides and glycoconjugates, glycosyltransferases represent targets of choice for the development of potent inhibitors and therefore for drug discovery. Since glycosyltransferase reactions are thought to proceed through transition states similar to those of glycosidases, iminosugars and the related compounds have been recently used to design potential inhibitors of this major class of enzymes. The purpose of this review is to stimulate further research in this promising area by providing a description and a biological evaluation of the different types of inhibitors containing an iminosugar. These data in addition to the recent insights into the structural basis of glycosyltransferase catalysis may constitute the first steps toward a rational design of potent glycosyltransferases inhibitors.

The N-alkylated imino sugars have inhibitory activity against the first enzyme in the pathway for glucosylating sphingolipid in eukaryotic cells, ceramidespecific glucosyltransferase. A therapeutic approach termed ‘substrate deprivation’ or ‘substrate reduction therapy’ (SRT) aims to reduce biosynthetic capability in the cell to match the reduced lysosomal catalytic activity seen in lysosomal storage disorders. The use of N-alkylated imino sugars to establish this therapeutic strategy is described in cell culture and gene knockout mouse disease models. One imino sugar, N-butyl-DNJ (NB-DNJ) has been in clinical trials for type 1 Gaucher disease and has shown to be an effective therapy for this disorder.

Cancer metastasis is one of the major challenges in cancer research. Inhibitors of tumor metastasis are rapidly emerging as important new drug candidates for cancer therapy. Tumor metastasis formation occurs via a complex multistage process which involves a crucial step of tumor invasion through the basement membrane. Tumor cell invasion involves attachment of tumor cell to the basement membrane through laminin, degradation of the matrix by proteolytic enzymes from the tumor cell and cell migration through the basement membrane. New drugs aimed at the metabolism of tumor cell surface oligosaccharides and / or catabolism of glycoconjugates of extracellular matrix and basement membrane could inhibit tumor metastasis.In this article, current progress in the control of tumor metastasis by gem-diamine 1-N-iminosugars and related iminosugars (nojirimycin and D-glucaro-δ-lactam), which are potent and specific inhibitors of carbohydrate metabolism and catabolism, has been reviewed. gem-Diamine 1-N-iminosugars related to D-glucuronic acid and L-iduronic acid, nojirimycin and D-glucaro-δ-lactam suppress invasion of B16 melanoma variants and 3LL (lung carcinoma) cells through reconstituted basement membrane, and inhibit pulmonary metastasis of these tumor cells in mice and / or cKDH-8 / 11 (liver carcinoma) cells in rats. These results suggest that the metabolism of β-D-glucuronide and α-L-iduronide of glycoconjugates and / or the processing of carbohydrates of tumor cell surface may participate in tumor metastasis. That these gem-diamine 1-N-iminosugars and related iminosugars are potent inhibitors of tumor metastasis holds promise of new drug candidates for cancer chemotherapy.