Daniele D'Alonzo

Glycomimetics at the Mirror: Medicinal Chemistry of L-Iminosugars

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.

Exploring the Role of Chirality in Nucleic Acid Recognition

The study of the base‐pairing properties of nucleic acids with sugar moieties in the backbone belonging to the L‐series (β‐L‐DNA, β‐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.

Rapid Access to 1,6-Anhydro-β-l-hexopyranose Derivatives via Domino Reaction: Synthesis of l-Allose and l-Glucose

An expeditious and efficient synthesis of 1,6-anhydro-beta-L-hexopyranosyl derivatives 3 as valuable building blocks for the preparation of L-sugars is herein reported. This route relies upon the use of a domino reaction involving five synthetic steps from the 5,6-dihydro-1,4-dithiin 4. As 1,6-anhydro derivatives 3 are obtained, dithioethylene bridge removal and double-bond dihydroxylation give access to protected L-allose and L-glucose in stereoselective fashion and high yields.

Enantiomeric Selection Properties of β‐homoDNA: Enhanced Pairing for Heterochiral Complexes

The analysis of the physicochemical properties of sugarmodified nucleic acids is currently at the core of intense multidisciplinary investigations including chemistry, biology, biotechnology, and medicine. On one side, synthetic polymers acting as RNA/DNA mimics have extensively been devised for applications in therapy, diagnostics, and synthetic biology. On the other side, the construction of alternative pairing systems has been explored either to consider their use as orthogonal nucleic acid candidates or with the aim to potentially yield insights into the chemical evolution criteria ultimately leading to the current genetic system. In all cases, structural changes of natural (deoxy)ribose cores have been established to determine profound consequences in the pairing potential of the resulting artificial nucleic acids. In some noteworthy examples, oligonucleotide systems endowed with six-membered sugars in the backbone have been observed to hold the singular property (unique of its kind) of pairing with homochiral complements having opposite sense of chirality. Relevant to etiology-oriented investigations on nucleic acid structure, these findings could suggest the existence of a relationship between nature of the sugar backbone and chiral-selection properties of nucleic acids, thereby providing insights to enrich our understanding of the structural prerequisites for base pairing. From a comparative analysis of the pairing behavior of six-membered nucleic acids we perceived that, despite the large structural differences, oligonucleotide systems capable of isoand heterochiral hybridization (Figure 1) shared preorganized carbohydrate conformations with equatorially-oriented nucleobases. This observation took us to wonder if such an arrangement of the aglycon moiety, especially whereas inducing strong backbone-base inclination or even enabling formation of quasilinear oligomeric structures, could lead sugar chirality not to be crucial in hybridization processes. In view of systematic investigations aimed at addressing this question, we herein considered the chiral selection properties of the well-known pairing system composed of (6’!4’)-linked b-erythro-hexopyranosyl nucleotides (b-homoDNA; Figure 1). Based on above assumptions and early experimental data, we reasoned that the strongly inclined complexes provided by the “allequatorial” pyranose backbone of b-homoDNA could make the latter an interesting candidate displaying potential for heterochiral hybridization. An investigation into the enantioselectivity of the hybridization processes of b-homoDNA required access to oligomeric sequences in both enantiomeric forms (b-dand b-lhomoDNA). From a synthetic standpoint, while access to d-hexopyranosyl nucleosides was easily obtained by a carbohydrate-based route, the synthesis of the corresponding lenantiomers under the same reaction conditions was hampered by the limited commercial availability of almost all lhexoses. In an alternative path, our long studied de novo approach to l-monosaccharides and other structurallyrelated compounds was recently exploited for the preparation of the l-nucleosides 2a,b (T and A acting as model nucleobases) from the homologating agent 1 (Scheme 1). Figure 1. Sugar-modified nucleic acids displaying pairing aptitude for homochiral complements of opposite chirality.

Sulfur-assisted domino access to bicyclic dihydrofurans: case study and early synthetic applications.

A DDQ-mediated domino reaction (up to six steps in a single process) has been developed to selectively provide substituted dihydrofurans from a common starting material containing a cyclic bis-thioenol ether. Study of the reaction mechanism highlighted a role played by the sulfur-containing moiety in influencing reaction rate and stereoselectivity.

A Semisynthetic Approach to New Immunoadjuvant Candidates: Site‐Selective Chemical Manipulation of Escherichia coli Monophosphoryl Lipid A

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.

A De Novo Heterodimeric Due Ferri Protein Minimizes the Release of Reactive Intermediates in Dioxygen‐Dependent Oxidation

Metalloproteins utilize O2 as an oxidant, and they often achieve a 4-electron reduction without H2 O2 or oxygen radical release. Several proteins have been designed to catalyze one or two-electron oxidative chemistry, but the de novo design of a protein that catalyzes the net 4-electron reduction of O2 has not been reported yet. We report the construction of a diiron-binding four-helix bundle, made up of two different covalently linked α2 monomers, through click chemistry. Surprisingly, the prototype protein, DF-C1, showed a large divergence in its reactivity from earlier DFs (DF: due ferri, two iron). DFs release the quinone imine and free H2 O2 in the oxidation of 4-aminophenol in the presence of O2 , whereas FeIII -DF-C1 sequesters the quinone imine into the active site, and catalyzes inside the scaffold an oxidative coupling between oxidized and reduced 4-aminophenol. The asymmetry of the scaffold allowed a fine-engineering of the substrate binding pocket, that ensures selectivity.

Enhancement of Peroxidase Activity in Artificial Mimochrome VI Catalysts through Rational Design

Rational design provides an attractive strategy to tune and control the reactivity of bioinspired catalysts. Although 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. Herein, we show that the simple incorporation of two 2‐aminoisobutyric acids into an artificial peptide‐based peroxidase results in a new catalyst (FeIII‐MC6*a) with higher resistance against oxidative damage and higher catalytic efficiency. The turnover number of this catalyst is twice as high as that of its predecessor. These results point out the protective role exerted by the peptide matrix and pave the way to the synthesis of robust bioinspired catalysts.

Oxidation catalysis by iron and manganese porphyrins within enzyme-like cages

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.

A general route to D- and L-six-membered nucleoside analogues.

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.