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The highly stereocontrolled de novo synthesis of L-NBDNJ (the unnatural enantiomer of the iminosugar drug Miglustat) and a preliminary evaluation of its chaperoning potential are herein reported. L-NBDNJ is able to enhance lysosomal α-glucosidase levels in Pompe disease fibroblasts, either when administered singularly or when co-incubated with the recombinant human α-glucosidase. In addition, differently from its D-enantiomer, L-NBDNJ does not act as a glycosidase inhibitor.

The combined use of silanes (Et3SiH or PMHS) and I2 as novel N-glycosidation reagents for the synthesis of bioactive oxathiolane nucleosides 3TC and FTC is reported. Both systems (working as anhydrous HI sources) were devised to act as substrate activators and N-glycosidation promoters. Excellent results in terms of chemical efficiency and stereoselectivity of the reactions were obtained; surprisingly, the nature of the protective group at the N4 position of (fluoro)cytosine additionally influenced the stereochemical reaction outcome.

The development of a novel tumor-targeting photosensitizer delivery system, with potential ability to selectively transport the photosensitizer prodrug 5-aminolevulinic acid methyl ester (MAL) into the tumor site has been herein described. Conjugation of MAL to folic acid (FA) via an unnatural β-peptide linker has been carried out almost entirely by an efficient solid phase approach. This molecular system has been devised for possible applications in selective photodynamic diagnosis (PDD) and therapy (PDT).

Rational design provides an attractive strategy to tune and control the reactivity of bioinspired catalysts. While there has been considerable progress in the design of heme oxidase mimetics with active site environments of ever-growing complexity and catalytic efficiency, their stability during turnover is still an open challenge. Here we show that the simple incorporation of two 2-amino isobutyric acids into an artificial peptide-based peroxidase resulted in a new catalyst (FeIII-MC6*a), with higher resistance against oxidative damage, and higher catalytic efficiency. A two-fold enhancement of the turnover number, respect to its predecessor, was observed. These results point out the protective role exerted by the peptide matrix and pave the way to the synthesis of robust bioinspired catalysts.

The synthesis and a preliminary evaluation of the pairing properties of ribo-cyclohexanyl nucleic acids (r-CNA) is herein reported. Incorporation of a single r-CNA nucleotide into natural duplexes did not enhance their stability, while a very high pairing selectivity for RNA was found. As deduced by comparative analysis of Tm and NMR data, a relationship between pairing selectivity and conformational preferences of the "sugar" moiety of r-CNA (and more generally of six-membered nucleic acids) was suggested.

Lipid A is the lipophilic region of lipopolysaccharides and lipooligosaccharides, the major components of the outer leaflet of most part of Gram-negative bacteria. Some lipid As are very promising immunoadjuvants. They are obtained by extraction from bacterial cells or through total chemical synthesis. A novel, semisynthetic approach to lipid As is ongoing in our laboratories, relying upon the chemical modification of a natural lipid A scaffold for the fast obtainment of several other lipid As and derivatives thereof. The first requisite for this strategy is to have this scaffold available in large quantities through a scalable process. Here, we present an optimized fed-batch fermentation procedure for the gram-scale production of lipid A from Escherichia coli K4 and a suitable phenol-free protocol for its purification. A study for regioselective de-O-phosphorylation reaction was then performed to afford pure monophosphoryl lipid A with an attenuated endotoxic activity, as evaluated by cytokine production in human monocytic cell line THP-1 in vitro. The reported method for the large-scale obtainment of monophoshoryl lipid A from the fed-batch fermentation broth of a recombinant strain of E. coli may permit the access to novel semisynthetic lipid A immunoadjuvant candidates.

The study of the base-pairing properties of nucleic acids with sugar moieties in the backbone belonging to the l-series (b-l-DNA, b-l-RNA, and their analogs) are reviewed. The major structural factors underlying the formation of stable heterochiral complexes obtained by incorporation of modified nucleotides into natural duplexes, or by hybridization between homochiral strands of opposite sense of chirality are highlighted. In addition, the perspective use of l-nucleic acids as candidates for various therapeutic applications, or as tools for both synthetic biology and etiology-oriented investigations on the structure and stereochemistry of natural nucleic acids is discussed.

Inspired by natural heme-proteins, scientists have attempted for decades to design efficient and selective metalloporphyrin-based oxidation catalysts. Starting from the pioneering work on small molecule mimics in the late 1970s, we have assisted to a tremendous progress in designing cages of different nature and complexity, able to accommodate metalloporphyrins. With the intent of tuning and controlling their reactivity, more and more sophisticated and diverse environments are continuously exploited. In this review, we will survey the current state of art in oxidation catalysis using iron- and manganese-porphyrins housed within designed or engineered protein cages. We will also examine the innovative metal-organic framework (MOF) systems, exploited to achieving an enzyme-like environment around the metalloporphyrin cofactor.

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 accessi- ble 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 reac- tion, asymmetric dihydroxylation up to the most recent amino acid-catalyzed aldol addition - as well as D-sugar manipula- tion strategies, including epimerization by chemical or enzymatic methods. Application of such protocols for the construc- tion of biologically relevant oligosaccharides and natural products will be also briefly mentioned. In the last two decades a new key role of carbohydrates in living organisms has emerged, as they have shown to be major information carriers between cells and their surround- ings, both in their free form or as glycoconjugates with pro- teins or lipids. This finding has rapidly brought to an increas- ing interest towards several aspects of carbohydrate chemis- try, particularly owing to the potential use of sugars in bio- chemical and pharmaceutical field. The need for specific saccharides in significant amount, in order to thoroughly understand their biological functions, has inspired modern synthetic approaches. The demand for compounds able to mimic natural substances by way of similar structure and/or biological function has stimulated elaboration of innovative preparative procedures in carbohydrate synthesis. The search for analogues of mono- and oligosaccharides resistant to enzymatic degradation has been also carried out. With a re- evaluation of the importance of carbohydrates, analogously to Proteomics and Genomics the term "Glycomics" (1) (or "Glycobiology" (2) or "Glycoscience" (3)) has been coined to refer to the role of carbohydrates in biological events. In view of the various biochemical pathways and disease proc- esses in which carbohydrates are crucially engaged - angio- genesis (4), cancer (5), tissue repair, cardiovascular diseases (6), immune-system function (7), microbial and viral patho- genesis (8), just to name a few of them - the possibilities for their use as therapeutics and diagnostics are numerous and exciting.

To investigate what properties make tetramolecular G-quadruplex ODNs good anti-HIV aptamers, we studied the stoichiometry and the self-assembly kinetics of the highly active 5'-end modified G-quadruplexes based on the d(TGGGAG) sequence. Our results demonstrate that the 5'-end conjugation does not necessarily increase the folding rate of the G-quadruplex; indeed, it ascribes anti-HIV activity. Unexpectedly, the G4-folding kinetics of the inactive G4 is similar to that of the 5'-end modified sequences. ESI-MS studies also revealed the formation of higher order G4 structures identified as octameric complexes along with tetramolecular G-quadruplexes.

A semisynthetic approach to novel lipid A derivatives from Escherichia coli (E. coli) lipid A is reported. This methodology stands as an alternative to common approaches based exclusively on either total synthesis or extraction from bacterial sources. It relies upon the purification of the lipid A fraction from fed-batch fermentation of E. coli, followed by its structural modification through tailored, site-selective chemical reactions. In particular, modification of the lipid pattern and functionalization of the phosphate group as well as of the sole primary hydroxyl group were accomplished, highlighting the unusual reactivity of the molecule. Preliminary investigations of the immunostimulating activity of the new semisynthetic lipid A derivatives show that some of them stand out as promising, new immunoadjuvant candidates.

De novo synthesis of noncompetitive glycosidase inhibitors l -gulo-DNJ and l -talo-DNJ has been achieved in 9–10 steps starting from Garner’s aldehyde. Key to the success of this procedure was the construction of the 2,3-unsaturated piperidine 14 , which syn dihydroxylation under Kishi’s and Donohoe’s conditions led to the desired iminosugars.

A highly convergent multistep process incorporating an aza-Achmatowicz rearrangement has been described, selectively providing enantiomerically pure bicyclic (dihydro)furans 9 and 18 as well as the tricyclic dihydropyridinone 23 from acyclic starting materials after up to eight sequential synthetic transformations in one step.

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 L-iminosugars 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.

A stereoselective and scalable route to 1,5-anhydrohexitol nucleoside analogues belonging to l -series as building blocks for l -HNA oligonucleotide synthesis has been efficiently tuned. Key to the successful outcome of our approach is the development of a DDQ-mediated domino reaction, which leads to the formation of an unsaturated 1,6-anhydrosugar derivative. Sugar elaborations and base insertion then enable to synthesize six-membered nucleosides.

A stereoselective procedure for the preparation of non-naturally occurring deoxy iminosugars belonging to L-series has been developed. The synthesis involves the construction of the key intermediate bicycle pyperidine 8, available in few steps by the coupling of the heterocyclic synthon 3 and the readily available Garner aldehyde 4. © 2007 American Chemical Society.

A simple synthetic route for novel L- (as well as D-) six-membered nucleosides is described. Particularly, we have provided a general approach to the synthesis of azasugar-based nucleosides, which preparation has been easily achieved starting from the coupling of our three carbon homologating agent 1 with the well known Garner aldehyde 4. Further suitable and stereocontrolled functionalizations of the intermediate 9 will provide, after the base insertion, a wide class of six membered modified azanucleosides to be tested as NRTIs.

[reaction: see text] An efficient route for the synthesis of orthogonally protected l-sugars has been opened up, starting from the heterocyclic homologating agent 1 and 2,3-O-isopropylidene-l-glyceraldehyde (2). Our synthetic path enables the synthesis of a 2,3-unsaturated-l-pyranoside, which can be suitably functionalized to afford the desired l-hexoses. In this paper, we report the synthesis of l-manno- and l-altro-pyranosides. Moreover, this strategy may be used to prepare all eight sugars and their derivatives in either enantiomeric form.