Graeme Horne

Iminosugars past, present and future: medicines for tomorrow.

Iminosugars comprise the most attractive class of carbohydrate mimetics reported to date and are ideally positioned to take advantage of our increasing understanding of glycobiology in the search for new medicines. First-generation iminosugar drugs suffered from lack of adequate selectivity, resulting in considerable side-effects in the clinic. Current efforts directed towards second-generation compounds, encompassing a much greater range of structures and addressing a wider selection of biochemical targets, are enabling the identification and development of suitable candidates that benefit from improved activity and selectivity. Furthermore, second-generation compounds can address a variety of established targets that have previously proved refractory to other compound classes. This review focuses on the breadth of opportunities provided by second-generation leads from iminosugars (Seglins™).

Therapeutic Applications of Iminosugars: Current Perspectives and Future Opportunities

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.

Synthesis of Eight Stereoisomers of Pochonicine: Nanomolar Inhibition of β-N-Acetylhexosaminidases

Pochonicine, the first naturally occurring polyhydroxylated pyrrolizidine containing an acetamidomethyl group, which was isolated from Pochonia suchlasporia var. suchlasporia TAMA 87, together with its enantiomer and their C-1 and/or C-3 epimers, have been synthesized from the sugar-derived cyclic nitrones 9D and 9L, respectively. An in-depth NMR study showed that both the (1)H and (13)C NMR spectra of the synthetic pochonicines (1D and 1L) matched very well with those of natural pochonicine in D2O, which unequivocally determined the relative configuration of the natural product as 1D or 1L. In addition, comparison of the optical rotations of the synthetic pochonicines and that of the natural product, but more convincingly their glycosidase inhibition profiles, confirmed the absolute configuration of natural pochonicine as 1R,3S,5R,6R,7S,7aR. Thereby, the structure of natural pochonicine was unequivocally determined as (+)-(1R,3S,5R,6R,7S,7aR)-pochonicine (1D). Glycosidase inhibition experiments showed that natural pochonicine 1D and its epimers 2D, 3D, and 4D all are powerful inhibitors of hexosaminidases (five β-N-acetylglucosaminidases and two β-N-acetylgalactosaminidases) while their enantiomers 1L, 2L, 3L, and 4L are much weaker inhibitors of the same enzymes. (-)-3-epi-Pochonicine (2L) was found to be a potent and selective inhibitor of α-l-rhamnosidase. None of the compounds showed any inhibition of α-GalNAcase.

Synthesis of fully substituted polyhydroxylated pyrrolizidines via Cope-House cyclization.

Total synthesis of the proposed structure of (-)-hyacinthacine C(5) and its epimers at C6 and C7 is described. A key step of the synthesis was the construction of the bicyclic pyrrolizidine system by means of a nucleophilic addition of a dithiane to a cyclic nitrone followed by a Cope-House cyclization.

(6S)-Methyl-l-swainsonine [(1R,2S,6S,8S,8aS)-6-methyl­octa­hydro­indolizine-1,2,8-triol]

(6S)-Methyl-l-swainsonine, C9H17NO3, together with the 6R-epimer, was formed in a synthetic sequence in which there was an ambiguity in configuration at position C-6. This ambiguity was resolved by establishing the relative stereochemistry of the title compound by X-ray crystallographic analysis. The absolute configuration was determined by the use of d-glycero-d-gulo-heptono-1,4-lactone as the starting material.