New Selective Inhibitors of α-Glucosidase for the Treatment of Type 2 Diabetes Mellitus
Khanchouch, T.; Vallin, A.; Alali, U.; Benazza, M.; Abidi, R.; Bonnet, V.
Helv. Chim. Acta n/a, e202300222.
Abstract Type 2 diabetes mellitus is a metabolic dreadful disease caused by an uncontrolled glucose level in the bloodstream, particularly high after a meal. Inhibitors of glucosidases, involved in the digestion of carbohydrates, can regulate this post-prandial increase in glucose concentration. The traditional drugs act as competitive inhibitors of both pancreatic α-amylase and α-glucosidases and this unselective inhibition is behind severe gastrointestinal side effects related to the concomitant inhibition of α-amylase. We described herein some perglycosylated cyclodextrins as efficient and selective inhibitors of α-glucosidase with low micromolar IC50 (3.64-7.98 μM) compared to the acarbose (IC50 212 μM), clinically used for patients suffering from type 2 diabetes. On the other hand, they do not inhibit α-amylase (IC50>500 μM). Structure/activity relationship rationalization suggests multiple interactions between the described inhibitors and α-glucosidase, which support the existence of both active site and allosteric interactions.
https://dx.doi.org/10.1002/hlca.202300222

Synthesis, characterization and in vivo antitumor effect of new α,β-unsaturated-2,5-disubstituted-1,3,4-oxadiazoles
Fray, M.; Elbini-Dhouib, I.; Hamzi, I.; Doghri, R.; Srairi-Abid, N.; Lesur, D.; Benazza, M.; Abidi, R.; Barhoumi-Slimi, T.
Synth. Commun. 2022, 1-12.
AbstractNew α,?-unsaturated-2,5-disubstituted-1,3,4-Oxadiazoles (4a?j) and (10a?d) have been prepared in good to excellent yields starting from ?-chlorovinyl aldehydes and hydrazide. The synthesized oxadiazoles were fully characterized by (1H, 13C) NMR, IR and HRM Sspectroscopic techniques. The in vivo antitumor activity of 4b, 4c, 4g, 4d, and 10c was evaluated. Biochemical measurements of serum alanine aminotransferase, aspartate aminotransferase and creatinine levels of mice injected with a dose of 20?mg/kg, of each selected compound, showed no toxic effect, neither in liver nor in kidney organs. However, hepato/nephrotoxicities were observed in mice treated with a dose of 100?mg/kg. When tested on melanoma in a mice xenograft model, the pharmacodynamic study indicated that the two compounds 4c, bearing a trifluoromethyl group and 10c, bearing a triazole moiety, are potent antitumoral agents at the safe dose of 20?mg/kg against B16-F10-induced melanoma.
https://dx.doi.org/10.1080/00397911.2022.2053993

Heteroglycoclusters through Unprecedented Orthogonal Chemistry Based on N-Alkylation of N-Acylhydrazone
Fray, M.; Mathiron, D.; Pilard, S.; Lesur, D.; Abidi, R.; Barhoumi-Slimi, T.; Cragg, P. J.; BENAZZA, M.
Eur. J. Org. Chem. 2022
Orthogonal chemistry is a valuable tool in the preparation of complex molecules as heteroglycoclusters. Unfortunately, selective heteroconjugation of multifunctional starting materials remains a usually challenging problem to overcome. Herein, we report the first use of N -alkylation of N -acylhydrazone as a key step in the orthogonal synthesis. Sequentially associated with the azido-alkyne click chemistry, it stands out as a new and straightforward synthetic method of glycoconjugate small molecules, heterodisaccharides, and heteroglycoclusters based on cone p - t Bu-calix[4]arene and 1,3- alt p - t Bu-thiacalix[4]arene with
https://doi.org/10.1002/ejoc.202101537

Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN
Chakroun, K.; Taouai, M.; Porkolab, V.; Luczkowiak, J.; Sommer, R.; Cheneau, C.; Mathiron, D.; Ben Maaouia, M. A.; Pilard, S.; Abidi, R.; Mullie, C.; Fieschi, F.; Cragg, P. J.; Halary, F.; Delgado, R.; Benazza, M.
J. Med. Chem. 2021.
In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann-Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.
https://dx.doi.org/10.1021/acs.jmedchem.1c00818

Development of C-type lectin-oriented surfaces for high avidity glycoconjugates: towards mimicking multivalent interactions on the cell surface
Porkolab, V.; Pifferi, C.; Sutkeviciute, I.; Ordanini, S.; Taouai, M.; Thepaut, M.; Vivès, C.; Benazza, M.; Bernardi, A.; Renaudet, O.; Fieschi, F.
Org. Biomol. Chem. 2020.
Multivalent interactions between complex carbohydrates and oligomeric C-type lectins govern a wide range of immune responses. Up to date, standard SPR (surface plasmon resonance) competitive assays have largely been to evaluate binding properties from monosaccharide units (low affinity, mM) to multivalent elemental antagonists (moderate affinity, µM). Herein, we report typical case-studies of SPR competitive assays showing that they underestimate the potency of glycoclusters to inhibit the interaction between DC-SIGN and immobilized glycoconjugates. This paper describes the design and implementation of a SPR direct interaction over DC-SIGN oriented surfaces, extendable to other C-type lectin surfaces as such Langerin. This setup provides an overview of intrinsic avidity generation emanating simultaneously from multivalent glycoclusters and from DC-SIGN tetramers organized in nanoclusters at the cell membrane. To do so, covalent biospecific capture of DC-SIGN via StreptagII /StrepTactin interaction preserves tetrameric DC-SIGN, accessibility and topology of its active sites, that would have been dissociated using standard EDC-NHS procedure under acidic conditions. From the tested glycoclusters libraries, we demonstrated that the scaffold architecture, the valency and the glycomimetic-based ligand are crucial to reach nanomolar affinities for DC-SIGN. The glycocluster 3.D illustrates the tightest binding partner in this set for a DC-SIGN surface (KD= 18 nM). Moreover, the selectivity at monovalent scale of glycomimetic D can be easily analyzed at multivalent scale comparing its binding over different C-type lectin immobilized surfaces. This approach may give rise to novel insights into the multivalent binding mechanisms responsible for avidity and make a major contribution to the full characterization of the binding potency of promising specific and multivalent immodulators.
https://dx.doi.org/10.1039/D0OB00781A

Development Of C-Type Lectin Oriented Surfaces For High Avidity Glycoconjugates: Towards Mimicking Multivalent Interactions On The Cell Surface
Porkolab, V.; Pifferi, C.; Sutkeviciute, I.; Ordanini, S.; Taouai, M.; Thepaut, M.; Vives, C.; Benazza, M.; Bernardi, A.; Renaudet, O.; Fieschi, F.
bioRxiv 2019, 780452.
Multivalent interactions between complex carbohydrates and oligomeric C-type lectins govern a wide range of immune responses. Up to date, standard SPR (surface plasmon resonance) competitive assays have largely been to evaluate binding properties from monosaccharide units (low affinity, mM) to multivalent elemental antagonists (moderate affinity, μM). Herein, we report typical case-studies of SPR competitive assays showing that they underestimate the potency of glycoclusters to inhibit the interaction between DC-SIGN and immobilized glycoconjugates. This paper describes the design and implementation of a SPR direct interaction over DC-SIGN oriented surfaces, extendable to other C-type lectin surfaces as such Langerin. This setup provides a microscopic overview of intrinsic avidity generation emanating simultaneously from multivalent glycoclusters and from DC-SIGN tetramers that are organized in nanoclusters on the cell membrane. For this purpose, covalent biospecific capture of DC-SIGN via StreptagII /StrepTactin interaction offers the preservation of tetrameric DC-SIGN and the accessibility/functionality of all active sites. From the tested glycoclusters libraries, we demonstrated that the scaffold architecture, the valency and the glycomimetic-based ligand are crucial to reach nanomolar affinities for DC-SIGN. The glycocluster 3.D illustrates the tightest binding partner in this set for a DC-SIGN surface (Kd= 18 nM). Moreover, the selectivity at monovalent scale of glycomimetic D can be easily analyzed at multivalent scale comparing its binding over different C-type lectin immobilized surfaces. This approach may give rise to novel insights into the multivalent binding mechanisms responsible to avidity and make a major contribution to the full characterization of the binding potency of promising specific and multivalent immunomodulators.
https://dx.doi.org/10.1101/780452

Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms
Taouai, M.; Chakroun, K.; Sommer, R.; Michaud, G.; Giacalone, D.; Ben Maaouia, M. A.; Vallin-Butruille, A.; Mathiron, D.; Abidi, R.; Darbre, T.; Cragg, P. J.; Mullie, C.; Reymond, J. L.; O'Toole, G. A.; Benazza, M.
J. Med. Chem. 2019.
Opportunistic Gram-negative Pseudomonas aeruginosa uses adhesins (e.g., LecA and LecB lectins, type VI pili and flagella) and iron to invade host cells with the formation of a biofilm, a thick barrier that protects bacteria from drugs and host immune system. Hindering iron uptake and disrupting adhesins' function could be a relevant antipseudomonal strategy. To test this hypothesis, we designed an iron-chelating glycocluster incorporating a tetrahydroxamic acid and alpha-l-fucose bearing linker to interfere with both iron uptake and the glycan recognition process involving the LecB lectin. Iron depletion led to increased production of the siderophore pyoverdine by P. aeruginosa to counteract the loss of iron uptake, and strong biofilm inhibition was observed not only with the alpha-l-fucocluster (72%), but also with its alpha-d-manno (84%), and alpha-d-gluco (92%) counterparts used as negative controls. This unprecedented finding suggests that both LecB and biofilm inhibition are closely related to the presence of hydroxamic acid groups.
https://dx.doi.org/10.1021/acs.jmedchem.9b00481

Uncommon Strong Inhibition of α-Glucosidase by Multivalent Glycoclusters built on Cyclodextrins Scaffolds
Alali, U.; Vallin, A.; Bil, A.; Khanchouche, T.; Mathiron, D.; Przybylski, C.; Beaulieu, R. R.; Kovensky, J.; Benazza, M.; Bonnet, V.
Org. Biomol. Chem. 2019, 17, 7228-7237.
The homeostasis disruption of D-glucose causes diabetes, a dramatic world wide chronic disease. The type 1 diabetes is a succesfully treatable form, where the blood D-glucose is regulated by insulin treatement. In contrast the type 2 diabetes , the non Insulin dependent one, is problematic. The control of the D-glucose blood level via intestinal α-D-glucosidase inactivation can be achieved by using competitive inhibitors as iminosugars (e.g. acarbose) or sulfonium sugar derivatives (e.g. salacinol). Recently, an unprecedented result showed that multivalent diamond nanoparticules grafted with unmodified sugars displayed α-glucosidase inhibition at low micromolar concentrations. We describe herein the synthesis of multivalent glycoclusters using cyclodextrines (CDs) as scaffolds and their assessment as inhibithors of α-D-glucosidase. The glycoclusters were efficiently obtained from per-azido α, β and γ-CDs derivatives and propargyl glycosides using click-chemistry under microwave irradiation. The methodology was successfully applied to various protected and non-protected propargylated monosaccharides, including both O- and S- glycosides, giving clear evidences of its versatility. The targeted 6-per-glycosylated CDs were isolated in moderate to excellent yields (30-90 %) by silica gel chromatography. The results showed inhibition of α-glucosidase from Saccharomyces cerevisiae with IC50 values in a 32-132 µM range, lower than that of acarbose (IC50 ~250µM), a well knowm competitive inhibitor used in clinical treatment of type 2 diabetes. Preliminary experiments suggest a mixed-type non-competitive inhibition mode of these new glycoclusters.
https://dx.doi.org/10.1039/C9OB01344J

Unprecedented thiacalixarene fucoclusters strong inhibitors of Ebola cis-cell infection and HCMV-gB glycopro-tein/DC-SIGN C-type lectin interaction
Taouai, M.; Porkolab, V.; Chakroun, K.; Cheneau, C.; Luczkowiak, J.; Abidi, R.; Lesur, D.; Cragg, P. J.; Halary, F.; Delgado, R.; Fieschi, F.; Benazza, M.
Bioconjug Chem 2019, 30, 1114-1126.
Glycan-protein interactions control numerous biological events from cell-cell recognition and signaling to pathogen host cell attachment for infections. To infect cells, some viruses bind to immune cells thanks to DC-SIGN (dendritic cell [DC]-specific ICAM3-grabbing non-integrin) C-type lectin expressed on dendrit-ic and macrophage cell membrane, via their envelope protein. Prevention of this infectious interaction is a serious therapeutic option. Here, we describe the synthesis of first water-soluble tetravalent fucocluster pseudopeptide-based thiacalixarene 1,3-alternate as viral antigen mimics designed for the inhibition of DC-SIGN, to prevent viral particle uptake. Their preparation exploits straightforward convergent strate-gies involving one pot Ugi four-component (Ugi-4CR) and azido-alkyne click chemistry reactions as key steps. Surface plasmon resonance showed strong inhibition of DC-SIGN interaction properties by tetrava-lent ligands designed with high relative potencies and beta avidity factors. All ligands block DC-SIGN active sites at nanomolar IC50 preventing cis-cell infection by Ebola viral particles pseudotyped with EBOV gly-coprotein (Zaire species of Ebola virus) on Jurkat cells that express DC-SIGN. In addition, we observed strong inhibition of DC-SIGN/human cytomegalovirus (HCMV)-gB recombinant glycoprotein interaction. This finding opens the way to the simple development of new models of water-soluble glycocluster-based thiacalixarene with wide range antimicrobial activities.
https://dx.doi.org/10.1021/acs.bioconjchem.9b00066

Alditol thiacrowns via a ring-closing metathesis of carbohydrate-derived α,ω-dithioallylethers
Benazza, M.; Danquigny, A.; Novogrocki, G.; Valgimigli, L.; Amorati, R.; Ferroni, F.; Demailly-Mullie, C.; Siriwardena, A.; Lesur, D.; Aubry, F.; Demailly, G.
Tetrahedron 2015, 71, 5602-5609.
We report a newly developed synthesis of a no. of alditol thiacrowns using an eco-friendly and versatile two-step strategy: the regioselective thioallyletherification of a polyhydroxylated alditol followed by a ring closing metathesis using the Grubbs second generation catalyst. This approach allows a series of target thiacrown products to be obtained in acceptable to good yields, from the corresponding α,ω-dithioallylether alditol starting materials featuring either the xylo, ribo, threo, erythro, D-manno or D-gluco configurations. The per-O-acetylated D-mannitol dithioallyether 10, easily obtained on a large scale using this approach, was selected for evaluation as both an antibacterial and an antioxidant. Although no antibacterial activity was obsd. for the bacterial strains investigated, compd. 10 is shown to be an antioxidant, and able to quench hydrogen peroxide in a stoichiometric fashion.
http://dx.doi.org/10.1016/j.tet.2015.06.049

Concise synthesis of C-1-cyano-iminosugars via a new Staudinger/aza Wittig/Strecker multicomponent reaction strategy
Zoidl, M.; Müller, B.; Torvisco, A.; Tysoe, C.; Benazza, M.; Siriwardena, A.; Withers, S. G.; Wrodnigg, T. M.
Bioorg. Med. Chem. Lett. 2014, 24, 2777-2780.
A new Staudinger/aza Wittig/Strecker multicomponent reaction sequence to C-1-cyano iminoalditols has been developed. When applied to 5-azidodeoxy-d-xylose and -d-glucose as substrates the method leads smoothly in good yield and with excellent stereoselectivity to respectively, 1,5-dideoxy-1,5-imino-d-idurono nitrile and 2,6-didesoxy-2,6-imino-d-glycero-d-ido-heptononitrile.
http://dx.doi.org/10.1016/j.bmcl.2014.03.069

Synthesis of Unsymmetrical Thioethers Using an Uncommon Base-Triggered 1,5-Thiol Transfer Reaction of 1-Bromo-2-alkylthiolcarbonates
Taouai, M.; Abidi, R.; Garcia, J.; Siriwardena, A.; Benazza, M.
J. Org. Chem. 2014, 79, 10743-10751.
Described herein is a convenient, odorless, metal-free, one-pot strategy for the synthesis of unsym. thioethers. The key step in this new strategy is a base-catalyzed 1,5-thiol transfer reaction via a pseudointramol. mechanism of a 1-bromo-2-alkylthiolcarbonate, which is itself obtained through a straightforward microwave-assisted thioalkylation of a 1,2-cyclic-thionocarbonate precursor with an appropriate alkyl bromide. The starting 1,2-cyclic-thionocarbonates are easily obtained from the corresponding diols. When a propargylthiolcarbonate constitutes the key alkylthiolcarbonate 1,5-shift precursor, a copper-mediated dipolar cycloaddn. reaction ("click") with azide partners is rendered possible. This increases the versatility of the approach, as a very large variety of complex triazole-tethered substrates can potentially be integrated into the target unsym. thioether final products. As an example of the scope of the reaction, four 1,5-shift reactions have been triggered simultaneously from a sugar-derived tetrathiolcarbonate precursor using base catalysis, to allow four 6-thioglucose moieties to be installed (78% yield for each sugar unit) onto a 1,3-alternate thiacalix[4]arene scaffold in a one-pot transformation.
http://dx.doi.org/10.1021/jo5015504