Iminosugars: Therapeutic Applications and Synthetic Considerations

Abstract

Iminosugars, carbohydrate mimetics in which the endocyclic oxygen of the parent carbohydrate is replaced with nitrogen, are the most important class of carbohydrate mimetic reported to date with two marketed drugs and several in clinical development. Since their first isolation in the 1960s iminosugars have captured the imagination of both synthetic and medicinal chemists alike with recent therapeutic developments highlighting the need for improved routes of synthesis. The resurgence in the therapeutic application of iminosugars has arisen as a consequence of our growing understanding on the role that glycobiology plays in disease and development. There are myriad possible individual targets encompassing a range of therapeutic areas, all of which can potentially be addressed by iminosugars. This chapter presents the historcial development of this compound class before discussing some of the issues that iminosugars present as synthetic targets. The therapeutic potential of this class of compound with specific reference to the development of modulators of glucocerebrosidase activity is discussed.

Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

“…Consequently, modulation of their activity by using glycomimetics bears strong potential for the development of therapies against a broad range of conditions [ 1 ]. Polyhydroxylated alkaloids of the iminosugar family are by far the most intensely studied compounds in this regard, with some products being currently marketed as drugs [ 2 , 3 , 4 ]. Thus, the N -substituted 1-deoxynojirimycin (DNJ) derivative miglitol (Glyset ® , Pfizer, New York, NY, USA), an inhibitor of the intestinal α-glucosidases, is used for glycemic control in the management of type 2 diabetes mellitus [ 5 ], whereas N -butyl-DNJ (miglustat; Zavesca ® , Actelion Pharmaceuticals Ltd., Allschwil, Switzerland), which inhibits glucosylceramide synthase, is indicated in the treatment of Gaucher disease, a lysosomal storage disorder (LSD) resulting from the malfunctioning of the acid β-glucosidase (β-glucocerebrosidase, GCase) [ 6 ].…”

Amino Acid-Based Synthesis and Glycosidase Inhibition of Cyclopropane-Containing Iminosugars

“…Some of the most important natural piperidine iminosugars are nojirimycin (Figure , I ) and its epimers, which, together with their deoxy analogues have turned out to be the lead molecules for drug design. Thus, stereochemical changes and functional group variation have led to iminosugars that can modulate glycosidase enzymes, exhibiting immunosuppressive, antiviral, or anti-inflammatory activities . Bicyclic iminosugars, such as swainsonine ( II ), lentiginosine ( III ), castanospermine ( IV ), and their derivatives exhibit antitumor and immunosuppressive activities …”

Exploring endoperoxides as a new entry for the synthesis of branched azasugars

“…They are found in nature as pyrrolidines, piperidines, indolizidines, pyrrolizidines or nortropane alkaloids with a variety of ring substituents, typically hydroxy groups, carboxylic acids and amides [1]. The ability of azasugars, such as the natural product deoxynojirimycin, to inhibit the activity of a wide range of enzymes has attracted attention for their potential use as drug candidates [2–3]. Azasugars in clinical use today include Glyset, a licensed drug for treatment of diabetes type II, and Zavesca, which is used in treatment of type I Gaucher’s disease and Niemann Pick type C disease (Scheme 1).…”

“…However, a variety of alternative synthetic strategies have since been developed, including asymmetric and chemoenzymatic methods [2,6–8]. Substituted endoperoxides have been applied to the synthesis of substituted cyclopropanes, furans and carbohydrates [9–12].…”