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ABSTRACT: Uropathogenic Escherichia coli (UPEC) are the major causative agents of urinary tract infections. During infection, UPEC adhere to mannosylated glycoreceptors on the urothelium via the FimH adhesin located at the tip of type 1 pili. Synthetic FimH antiadhesives such as alkyl and phenyl α-D-mannopyranosides are thus ideal candidates for the chemical interception of this crucial step in pathogenesis. The crystal structures of the FimH lectin domain in its ligand-free form and in complexes with eight medium- and high-affinity mannopyranoside inhibitors are presented. The thermodynamic profiles of the FimH-inhibitor interactions indicate that the binding of FimH to α-D-mannopyranose is enthalpy-driven and has a negative entropic change. Addition of a hydrophobic aglycon influences the binding enthalpy and can induce a favorable entropic change. The alleviation of the entropic cost is at least in part explained by increased dynamics in the tyrosine gate (Tyr48 and Tyr137) of the FimH receptor-binding site upon binding of the ligand. Ligands with a phenyl group directly linked to the anomeric oxygen of α-D-mannose introduce the largest dynamics into the Tyr48 side chain, because conjugation with the anomeric oxygen of α-D-mannose forces the aromatic aglycon into a conformation that comes into close contact (≈2.65 Å) with Tyr48. A propargyl group in this position predetermines the orientation of the aglycon and significantly decreases affinity. FimH has the highest affinity for α-D-mannopyranosides substituted with hydrophobic aglycons that are compatible in shape and electrostatic properties to the tyrosine gate, such as heptyl α-D-mannose.
Biochemistry 06/2012; 51(24):4790-9. · 3.42 Impact Factor
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ABSTRACT: 17alpha-substituted ethynylestradiols, derived from estrone, were converted to their corresponding 17 alpha-(bromo- or iodo-propargyl)estrone intermediates. Nucleophilic substitution onto these moieties with malonate diester followed by hydrolysis and complexation with cis-Pt(Me(2)en)I(2) (Me(2)en=N,N-dimethylethylenediamine) gave cis-Pt(Me(2)en)(2-(3-(17beta-estradiol-17 alpha-yl)-prop-2-ynyl)malonato) 7, thus demonstrating that these estrogen-derived compounds can be used to synthesize stable Pt(II) complexes. The 3-(17beta-estradiol-17 alpha-yl)-prop-2-ynyl-1-sulfanylethylthiol 23 was also prepared.
Steroids 03/2010; 75(7):489-98. · 2.83 Impact Factor
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ABSTRACT: A short and efficient strategy for the first synthesis of "Majoral-Type" multivalent glycodendrimers bearing covalently bound alpha-D-mannopyranosides onto a cyclotriphosphazene scaffold assembled using single-step Sonogashira and click chemistry is reported. New glycoclusters with valencies ranging from 6 to 18 and different epitope spatial arrangements were obtained. Cross-linking abilities of this series of glycodendrimers were evaluated with the model lectin from Canavalia ensiformis (Concanavalin A). The decameric mannoside 23, built around 19, was shown to be much faster in cross-linking the tetravalent lectin Concanavalin A than the positive control, which is the polysaccharide mannan from yeast. The new glycoconjugates reported may be promising tools as probes or effectors of biological processes involving multivalent carbohydrate-binding proteins.
The Journal of Organic Chemistry 12/2008; 73(23):9292-302. · 4.45 Impact Factor
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ABSTRACT: Mesenchymal stromal cells (MSC) mobilization and recruitment by experimental vascularizing tumors involves membrane type 1-matrix metalloproteinase (MT1-MMP) functions. Given that the mannose-specific lectin Concanavalin-A (ConA) induces MT1-MMP expression and mimics biological lectins/carbohydrate interactions, we synthesized and tested the potential of 11 mannoside clusters to block ConA activities on MSC. We found that tetra- and hexavalent mannosides reversed ConA-mediated changes in MSC morphology and antagonized ConA-induced caspase-3 activity and proMMP-2 activation. Tetra- and hexavalent mannosides also inhibited ConA- but not the cytoskeleton disrupting agent Cytochalasin-d-induced MT1-MMP cell surface proteolytic processing mechanisms, and effects on cell cycle phase progression. The antiproliferative and pro-apoptotic impact of ConA on the MT1-MMP/glucose-6-phosphate transporter signaling axis was also reversed by these mannosides. In conclusion, we designed and identified glycocluster constructions that efficiently interfered with carbohydrate-binding proteins (lectins) interaction with oligosaccharide moieties of glycoproteins at the cell surface of MSC. These glycoclusters may serve in carbohydrate-based anticancer strategies through their ability to specifically target MT1-MMP pleiotropic functions in cell survival, proliferation, and extracellular matrix degradation.
Glycobiology 03/2008; 18(2):195-204. · 3.58 Impact Factor
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ABSTRACT: Among the different PLA(2)s identified to date, the group IIA secretory PLA(2) (sPLA(2) GIIA) is implied in diverse pathological conditions. In this work we describe the synthesis, inhibitory activities, and structure-activity relationships (SAR) of a new class of substituted piperazine derivatives. The in vitro fluorimetric assay using two groups of enzymes, GIB and GIIA, revealed several compounds as highly potent inhibitors (IC(50)=0.1 microM). The in vivo activity assessed by ip or per os administration in a carrageenan-induced edema test in rats showed that two compounds proved to be as potent as indomethacin (10 mg/kg).
Bioorganic & medicinal chemistry 03/2008; 16(3):1242-53. · 2.82 Impact Factor
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ABSTRACT: Bacterial drug resistance against antimicrobial agents is a prevalent and central worldwide impasse. Infections with resistant organisms lead to adverse clinical outcomes, increased mortality, and are costly to healthcare systems. Several infectious diseases are initiated by the binding of pathogenic lectins to host cells glycoconjugates. The molecular understanding of these adhesion phenomena is crucial and presents promising new alternatives compared to traditional antibiotic therapies. Glycans or glycan mimetics could be used to inhibit the initial recognition events leading to adhesion and colonization of host tissues by pathogens. The bladder and urothelial lining are widely covered by cell surface glycoproteins bearing the required carbohydrate ligands responsible for the adhesion phenomena. However, when these interactions are measured on a per saccharide basis, they are generally too weak (mM) for the design of beneficial inhibition therapies. The interactions between microbial pathogens and host cells are often governed by polyvalent and overall strong avidities. To overcome this drawback, glycobiologists have design a new family of well-defined small macromolecules, called glycodendrimers that can successfully address this issue. This review will provide a brief introduction on glycodendrimers and detailed descriptions of design and applications of mannosylated inhibitors against fimbriated type 1 E. coli.
Mini Reviews in Medicinal Chemistry 01/2008; 7(12):1270-83. · 2.53 Impact Factor
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ABSTRACT: Pentaerythritol and bis-pentaerythritol scaffolds were used for the preparation of first generation glycodendrimers bearing aryl alpha-D-mannopyranoside residues assembled using single-step Sonogashira and click chemistry. The carbohydrate precursors were built with either para-iodophenyl, propargyl, or 2-azidoethyl aglycones whereas the pentaerythritol moieties were built with terminal azide or propargyl groups, respectively. Cross-linking abilities of this series of glycodendrimers were first evaluated with the lectin from Canavalia ensiformis (Concanavalin A). Surface plasmon resonance measurements showed these two families of mannosylated clusters as the best ligands known to date toward Escherichia coli K12 FimH with subnanomolar affinities. Tetramer 4 had a K(d) of 0.45 nM. These clusters were 1000 times more potent than mannose for their capacity to inhibit the binding of E. coli to erythrocytes in vitro.
ChemMedChem 09/2007; 2(8):1190-201. · 3.15 Impact Factor
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Mohamed Touaibia,
Atimé Djimdé,
Fei Cao,
Eric Boilard,
Sofiane Bezzine,
Gérard Lambeau,
Catherine Redeuilh,
Aazdine Lamouri,
France Massicot,
François Chau,
Chang-Zhi Dong,
Françoise Heymans
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ABSTRACT: Secreted phospholipases A2 (sPLA2s) have been reported to play an important role in various inflammatory conditions and thus represent an attractive therapeutic target. Previous SAR studies from our laboratory have revealed certain important features of our recently discovered specific hGIIA sPLA2 inhibitors, and we report here the synthesis and biological activities of glycerol-containing derivatives of our lead compound III (Figure 1). Efficient and selective synthesis methods have been developed to make glycerol trisubstituted by different groups on desired positions. In terms of biological activities, the best compounds (A3, A6, and A15) are more active than III (Figure 1), as potent as Me-Indoxam, an sPLA2s inhibitor of reference, against hGIIA, hGV, and hGX sPLA2s and at least 10 times less active toward the GIB enzymes in two in vitro assay systems. By synthesis of enantiopure (S)-A6, we demonstrated that no important improvement of the inhibitory potency could be achieved by this approach. Furthermore, the results show that the global lipophilicity is likely responsible for the anti-PLA2 activity and two oxadiazolone moieties seem too big to be accommodated by the active site of the hGIIA enzyme.
Journal of Medicinal Chemistry 05/2007; 50(7):1618-26. · 5.25 Impact Factor
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ABSTRACT: Several oligomannoside clusters having a hundred-fold increase in affinities toward E. coli were synthesized by Cu(I)-catalyzed [1,3]-dipolar cycloadditions using pentaerythritol scaffolds bearing either alkyne or azide functionalities.
Chemical Communications 02/2007; · 6.17 Impact Factor
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ABSTRACT: A wide variety of proteins can bind high-mannose oligosaccharides and are broadly neutralizing against HIV-1. However, success in eliciting broadly neutralizing antibodies against HIV-1 has been limited to date. The rational design of an HIV-1 vaccine is based on the information gained through the structural analysis of antibodies complexed with their epitopes. Of particular interest to this review are the binding of mannosides to human monoclonal antibody 2G12 recognizing Man(9)GlcNAc(2) from HIV-1 gp120. It is widely recognized that T-cell-independent antigens carbohydrates are poorly immunogenic, and fail to induce memory. To increase the immunogenicity, carbohydrate antigens have to be coupled to a highly immunogenic carrier. The design of peptide carbohydrate mimotopes (mimetics of carbohydrate antigens) is one approach that is currently explored to elicit neutralizing antibodies. This work is concerned with existing structural data on Man(9)GlcNAc(2) as the most promising epitope (or glycotope). Structural analysis of various torsion angles of Man(9)GlcNAc(2) is explored. The focus is made primarily on the third variable region (V3 loop) of gp120 due to its crucial relevance for coreceptor usage, as a principal neutralizing determinant (PND), and for its conserved glycosylation sites N295, N302 and N332. Valuable structural information from glycosylation effects is taken into account for the development of a V3 loop rational structure-based vaccine strategy using N295 and N302 as potential conformational epitope.
Current Medicinal Chemistry 02/2007; 14(30):3232-42. · 4.86 Impact Factor
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ABSTRACT: A furanocoumarin glycoside new named turbinatocoumarin (1) was isolated from the twigs of Dorstenia turbinata. The structure of turbinatocoumarin (1) was assigned as 5-methoxy-3-[3-(beta-glucopyranosyloxy)-2-hydroxy-3-methylbutyl]psoralen by means of spectroscopic analysis. Known compounds have also been isolated from this genus and identified as (2'S, 3'R)-3'-hydroxymarmesin (2), 5-methoxy-3-(3-methyl-2,3-dihydroxybutyl)psoralen (3), psoralen (4), kanzonol C (5) which was isolated for the first time from this genus, 4-hydroxylonchocarpin (6), umbelliferone, 4-hydroxy-3-methoxybenzaldehyde and 4-methoxyphenol. As part of our continuing search for potential naturally-occurring antitumor drug candidates, the inhibition of matrix metalloproteinase (MMP)-2 secretion from brain tumor-derived glioblastoma cells by the isolated compounds 1, 3, 5, and 6 was evaluated by zymography and compared to the documented naturally-occurring MMP secretion inhibitors chlorogenic acid (CHL) and epigallocatechin-3-gallate (EGCg). Among the compounds tested, the inhibiting MMP secretion concentrations ranged from 0.025 to 250 microM with up to 80% inhibition. The inhibitory activities of compounds 5 and 6 were found comparable to the common reference compounds CHL and EGCg. This suggests that alternate sources can be explored and exploited for the availability of chemopreventive molecules.
Phytochemistry 01/2007; 67(23):2573-9. · 3.35 Impact Factor
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Chang-Zhi Dong,
Azali Ahamada-Himidi,
Stéphanie Plocki,
Darina Aoun, Mohamed Touaibia,
Nadia Meddad-Bel Habich,
Jack Huet,
Catherine Redeuilh,
Jean-Edouard Ombetta,
Jean-Jacques Godfroid,
France Massicot,
Françoise Heymans
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ABSTRACT: We have recently reported the discovery of a series of specific inhibitors of human group IIA phospholipase A(2) (hGIIA PLA(2)) to display promising in vitro and in vivo properties. Here we describe the influence of different structural modifications on the specificity and potency against hGIIA PLA(2) versus porcine group IB PLA(2). The SAR results, as well as the logP and pK(a) values of oxadiazolone determined in this work, provide important information towards the comprehension of the mode of action of this kind of compounds.
Bioorganic & Medicinal Chemistry 04/2005; 13(6):1989-2007. · 2.92 Impact Factor
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ABSTRACT: 17α-substituted ethynylestradiols, derived from estrone, were converted to their corresponding 17α-(bromo- or iodo-propargyl)estrone intermediates. Nucleophilic substitution onto these moieties with malonate diester followed by hydrolysis and complexation with cis-Pt(Me2en)I2 (Me2en = N,N-dimethylethylenediamine) gave cis-Pt(Me2en)(2-(3-(17β-estradiol-17α-yl)-prop-2-ynyl)malonato) 7, thus demonstrating that these estrogen-derived compounds can be used to synthesize stable Pt(II) complexes. The 3-(17β-estradiol-17α-yl)-prop-2-ynyl-1-sulfanylethylthiol 23 was also prepared.
Steroids.
