Therapeutic Applications of Iminosugars: Current Perspectives and Future Opportunities

doi:10.1016/B978-0-12-381290-2.00004-5

Progress in Medicinal Chemistry

Volume 50, 2011, Pages 135-176

https://doi.org/10.1016/B978-0-12-381290-2.00004-5 Get rights and content

Publisher Summary

The understanding of the role of carbohydrates, their receptors, and their handling processes in the functioning of biological systems is an area in which major advances have been made during the past 20 years. The diverse structures displayed by carbohydrates provide a substantial opportunity for the identification of new chemotherapeutic targets and the development of new therapies. This has motivated both synthetic and medicinal chemists in the pursuit of new medicines although carbohydrates themselves can rarely be employed for this purpose owing to their metabolic instability and rapid degradation in vivo. As a consequence, researchers have focused on the design and synthesis of carbohydrate mimetics with greater stability, affinity, and efficacy. Iminosugars are the most attractive class of carbohydrate mimetics reported to date and are ideally positioned to take advantage of the increasing understanding of this area. The chapter summarizes the status of the iminosugar field providing an overview of the classification, occurrence, and synthesis of iminosugars, before discussing in detail the therapeutic potential of this class of molecule.

Section snippets

INTRODUCTION

Our understanding of the role of carbohydrates, their receptors and their handling processes in the functioning of biological systems is an area in which major advances have been made during the past 20 years. The diverse structures displayed by carbohydrates provide a substantial opportunity for the identification of new chemotherapeutic targets and the development of new therapies. This has motivated both synthetic and medicinal chemists, in the pursuit of new medicines although carbohydrates

IMINOSUGARS – CLASSIFICATION, OCCURRENCE AND HISTORICAL CONTEXT

Iminosugars are small organic compounds which mimic monosaccharides or their hydrolysis transition state equivalents but contain a nitrogen atom in place of the endocyclic oxygen, and as such fall under the definition of the polyhydroxylated alkaloids. The iminosugar motif can be recognized across many common compound classes including monocyclic and bicyclic templates. While the synthetic analogues may be represented by numerous ring forms, the naturally occurring iminosugars are classified

ADVANTAGEOUS PROPERTIES OF IMINOSUGARS

Iminosugars have a number of intrinsic properties which are positive attributes as potential drug candidates. The problem of the water solubility of lead molecules has occupied a prominent place in medicinal chemistry with many potent classical small molecules suffering from marginal water solubility. Enormous resources have been deployed to address this issue both in medicinal chemistry and in formulation. No such problem burdens the iminosugar field where adequate water solubility is a key

APPROACHES TO THE SYNTHESIS OF IMINOSUGARS

Despite the initial promise shown by these early compounds, to date, as a therapeutic class, iminosugars have failed to realize their full commercial potential. A number of chemical characteristics have impeded the rate of development and exploitation within the pharmaceutical and biotech sectors and this has undoubtedly restricted the level to which the iminosugar field has been explored by industry to date. The molecules are chirally complex, generally highly polar and generally lack a

THERAPEUTIC APPLICATIONS OF IMINOSUGARS

As would be expected for a series of polyhydroxylated glycomimetics, iminosugars have historically been of interest for their biological activity in modulating the action of carbohydrate processing enzymes and many therapeutic opportunities arise from targeting these processes [54], [55], [56], [57], [58]. The full impact of the pioneering work in exploring the importance of glycobiology is becoming increasingly apparent [59], [60], [61] with an array of new targets across different therapeutic

OUTLOOK AND FUTURE OPPORTUNITIES

The full impact of the pioneering work of Dwek, Varki and others in realizing the importance of glycobiology in health and disease is becoming increasingly apparent [59], [60], [61], [62], [63], [64], [65], [66]. The number of new druggable targets across different therapeutic areas is vast and current efforts have only just started to address what might be possible in the search for new therapeutics. Within each target class there are numerous individual targets encompassing a range of

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The glycoprocessing enzymes, glycosidases, and glycosyl transferases have been promising targets for drug discovery and therapeutic applications. Inspired by nojirimycin, a natural product isolated from Streptomyces roseochromogenes and Streptomyces lavendulae in 1967, great advances have been made in synthesizing several iminosugar analogs in search of potential inhibitors. Six-membered iminosugars represented by Miglitol, Miglustat, and Migalastat have emerged as successful inhibitors. Motivated by the success of six-membered iminosugars, efforts have been underway, parallelly, toward the synthesis of seven-membered analogs, assuming the conformational flexibility of seven-membered rings to provide additional assistance during the inhibition process. The seven-membered analogs of six-membered iminosugars are generally referred to as polyhydroxyazepanes and have attracted the attention of synthetic organic chemists. The presence of several stereocenters provides a rich diversity factor for synthesis and biological studies and for their implications in the inhibition process. Several successful synthetic schemes have been developed for their access. The effort in this area is now heading toward C-glycosides of seven-membered iminosugars as a valuable target for synthesis and biological studies. The chapter briefly reviews the work done in this area.
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Iminosugars represent the most important class of glycomimetics, as they offer the opportunity to mimic the biological action of carbohydrates while circumventing their drawbacks. For this reason, they are more and more investigated as potential new drugs. From the synthetic point of view, their obtainment is highly challenging. The use of carbohydrates as starting materials for their preparation still offers many advantages. This chapter aims to give an overview of selected important synthetic strategies developed for the synthesis of diverse classes of iminosugars, since 2015.
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We report the synthesis of iminosugar C,C-glycosides starting from 6-azidoketopyranoses. Their Staudinger-azaWittig-mediated cyclization provided bicyclic N,O-acetals, which were stereoselectively opened with AllMgBr to afford β-hydroxyazepanes with a quaternary carbon α to the nitrogen. Their ring contraction via a β-aminoalcohol rearrangement produced the six-membered l-iminosugars with two functional handles at the pseudoanomeric position. Inversion of the free OH at the azepane level furnished the d-iminosugars.
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Three new classes of nojirimycin analogues viz. N-alkyl with C1-substituent (4-phenylbutyl), N-substituted 1-deoxynojirimycin and its congener δ-lactam, and a 4-phenylbutyl-β-C-glycoside were designed and synthesized for immunological studies. The resulting diverse compound library exhibited proliferation of B Cells and T cells induced by LPS and Con A, respectively. The majority of the analogues augmented the secretion of IL-12 in dendritic cells and TNF-α secretion in murine peritoneal macrophages compared to LPS (10 μg/ml). A deoxynojirimycin-triazole conjugate of phytosphingosine analogue was superior in the responses mentioned above and exhibited nitric oxide response equal to LPS. In comparison to findings on its congeners with immunosuppressive action, early immunological tests show that the novel nojirimycin analogues have immunopotentiating effect. Hence, nojirimycin analogues offer tremendous potential in tuning the immunomodulatory activity of iminosugars by subtle to substantial structural variations.
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Therapeutic Applications of Iminosugars: Current Perspectives and Future Opportunities

Publisher Summary

Section snippets

INTRODUCTION

IMINOSUGARS – CLASSIFICATION, OCCURRENCE AND HISTORICAL CONTEXT

ADVANTAGEOUS PROPERTIES OF IMINOSUGARS

APPROACHES TO THE SYNTHESIS OF IMINOSUGARS

THERAPEUTIC APPLICATIONS OF IMINOSUGARS

OUTLOOK AND FUTURE OPPORTUNITIES

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Tetrahedron Lett.

Carbohydr. Res.

Phytochemistry

Anal. Biochem.

J. Pharm. Biomed. Anal.

Tetrahedron: Asymmetry

Tetrahedron Lett.

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Tetrahedron: Asymmetry

Tetrahedron: Asymmetry

Curr. Opin. Struct. Biol.

Cell

Mol. Oncol.

Phytomedicine

Immunopharmacology

Biochem. Pharmacol.

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Tetrahedron Lett.

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Curr. Med. Chem.

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