Inhibition of carbohydrate processing enzymes is a topic of great interest, as these enzymes are involved in a plethora of key biochemical events, such as digestion, lysosomal catabolism of glycoconjugates and post-translational glycoprotein processing. Among the most potent inhibitors of such enzymes, iminosugars have emerged as versatile tools for medicinal chemists, especially those in quest for new therapeutic agents. Supply of iminosugars from natural sources or by chemical synthesis has provided excellent targets for medical intervention, ranging from antidiabetics and antivirals to inhibitors of genetic disorders. Although a huge body of literature has been reported around iminosugars, most data have focused on D-series iminosugars, whereas relatively little attention has been devoted to the corresponding L-enantiomers, due to their supposed lack of biological activity profile, as well as their scarce availability from natural sources. Notwithstanding, recent insights into the molecular details of enzyme-inhibitor interactions have led to a reassessment of L-iminosugars for pharmaceutical purposes. On one hand, they have been used as tools for intensive SAR (structure-activity-relationship) studies, in order to gain new information on the enzymatic inhibition mechanisms. Likewise, early reports on biological activity of Liminosugars have led to reconsider their therapeutic skills. This review focuses on the most significant discoveries regarding medicinal chemistry of L-iminosugars. The important role L-iminosugars play in unravelling the inhibition mechanisms of specific enzymes is herein recognized; moreover, the high potential of this class of inhibitors as novel drug candidates is under discussion.

Last years have witnessed enormous progresses in glycomic field, mainly as a consequence of the crucial role carbohydrates have shown in biological systems. While up to a few years ago attention was mainly focused on the use of easily available D-sugars, a recent interest has emerged around their L-enantiomers, as they have been found to be key components of several bioactive compounds, whether in the form of oligosaccharides, glycopeptides, terpene glycosides or other clinically useful agents. However, L-sugars (L-hexoses especially) are rather rare in nature and not easily accessible from inexpensive sources. As demand for their synthesis in considerable amount and high purity is more and more pressing, intense efforts have been addressed to the development of new and general methodologies for their construction. This review covers the synthetic routes to L-hexoses, mainly those coming from the new century. Methodologies for monosaccharide assembly will comprise de novo approaches, based on carbon chain elongation, hetero Diels-Alder reaction, asymmetric dihydroxylation up to the most recent amino acid-catalyzed aldol addition – as well as D-sugar manipulation strategies, including epimerization by chemical or enzymatic methods. Application of such protocols for the construction of biologically relevant oligosaccharides and natural products will be also briefly mentioned.

Indole oxidation represents a real challenge for selectivity because it typically leads to complex mixtures of products even when highly selective enzymes are used. Here, we describe the catalytic potential of an artificial enzyme, Mn-Mimochrome VI*a (Mn-MC6*a), in promoting indole oxidation. This mini-enzyme contains a manganese–deuteroporphyrin active site within a scaffold of two synthetic small peptides covalently linked to porphyrin. Mn-MC6*a promotes the selective oxidation of indole at its C3 position, leading to a 3-oxindole derivative (2-TFE-3-oxindole) with unprecedented product selectivity (86% at pH 8.5) compared to native or artificial heme-enzymes. We also suggest a possible reaction mechanism based on the effect of pH, cosolvent, and indole substitution on the reaction outcome. These studies demonstrate that Mn-MC6*a is an excellent artificial peroxygenase for the production of 3-oxindole-containing compounds as key building blocks for the synthesis of fine chemicals.