57 research outputs found
A Concise Synthesis of Glycolipids Based on Aspartic Acid Building Blocks
L-Aspartic acid building blocks bearing galactosyl moieties were used to
synthesise glycolipid mimetics of variable hydrocarbon chain length. The glycolipids were
readily prepared through amide bond formation using the TBTU/HOBt coupling
methodology. It was observed that, under these conditions, activation of the α-carboxylic
acid of the intermediates led to near complete racemisation of the chiral centre if the reaction
was carried out in the presence of a base such as triethylamine. The enantiomerically pure
glycolipids were obtained after careful consideration of the synthetic sequence and by
performing the coupling reactions in the absence of base
A Concise Synthesis of Glycolipids Based on Aspartic Acid Building Blocks
L-Aspartic acid building blocks bearing galactosyl moieties were used to synthesise glycolipid mimetics of variable hydrocarbon chain length. The glycolipids were readily prepared through amide bond formation using the TBTU/HOBt coupling methodology. It was observed that, under these conditions, activation of the α-carboxylic acid of the intermediates led to near complete racemisation of the chiral centre if the reaction was carried out in the presence of a base such as triethylamine. The enantiomerically pure glycolipids were obtained after careful consideration of the synthetic sequence and by performing the coupling reactions in the absence of base
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Inhibition of Burkholderia Multivorans Adhesion to Lung Epithelial Cells by Bivalent Lactosides
Burkholderia cepacia complex (Bcc) is an opportunistic pathogen in cystic fibrosis patients which is inherently resistant to antimicrobial agents. The mechanisms of attachment and pathogenesis of Bcc, a group of 17 species, are poorly understood. The most commonly identified Bcc species in newly colonised patients, Burkholderia multivorans, continues to be acquired from the environment. Development of therapies which can prevent or reduce the risk of colonization on exposure to Bcc in the environment would be a better alternative to antimicrobial agents. Previously, it has been shown that Bcc strains bound to many glycolipid receptors on lung epithelia. Using a real-time PCR method to quantify the levels of binding of B. multivorans to the lung epithelial cells, we have examined glycoconjugate derivatives for their potential to inhibit host cell attachment. Bivalent lactosides previously shown to inhibit galectin binding significantly reduced the attachment of B. multivorans to CF lung epithelial cells at micromolar concentrations. This was in contrast to monosaccharides and lactose, which were only effective in the millimolar range. Development of glycoconjugate therapies such as these, which inhibit attachment to lung epithelial cells, represent an alternative means of preventing infection with inherently antimicrobially resistant pathogens such as B. multivorans
Inhibition of Burkholderia multivorans Adhesion to Lung Epithelial Cells by Bivalent Lactosides
Burkholderia cepacia complex (Bcc) is an opportunistic pathogen in cystic
fibrosis patients which is inherently resistant to antimicrobial agents. The mechanisms of
attachment and pathogenesis of Bcc, a group of 17 species, are poorly understood. The most
commonly identified Bcc species in newly colonised patients, Burkholderia multivorans,
continues to be acquired from the environment. Development of therapies which can
prevent or reduce the risk of colonization on exposure to Bcc in the environment would be
a better alternative to antimicrobial agents. Previously, it has been shown that Bcc strains
bound to many glycolipid receptors on lung epithelia. Using a real-time PCR method to
quantify the levels of binding of B. multivorans to the lung epithelial cells, we have
examined glycoconjugate derivatives for their potential to inhibit host cell attachment.
Bivalent lactosides previously shown to inhibit galectin binding significantly reduced the
attachment of B. multivorans to CF lung epithelial cells at micromolar concentrations. This
was in contrast to monosaccharides and lactose, which were only effective in the
millimolar range. Development of glycoconjugate therapies such as these, which inhibit
attachment to lung epithelial cells, represent an alternative means of preventing infection
with inherently antimicrobially resistant pathogens such as B. multivorans
Synthesis of Bivalent Lactosides Based on Terephthalamide, N,N0-Diglucosylterephthalamide, and Glycophane Scaffolds and Assessment of Their Inhibitory Capacity on Medically Relevant Lectins
Glycan recognition by lectins initiates clinically relevant processes such as toxin binding or tumor
spread. Thus, the development of potent inhibitors has a medical perspective. Toward this goal, we
report the synthesis of both rigid and flexible bivalent lactosides on scaffolds that include secondary and
tertiary terephthalamides and N,N0-diglucosylterephthalamides. Construction of these compounds
involved Schmidt-Michel glycosidation, and amide coupling or Ugi reactions of relevant glycosyl
amines in key steps. A glycocluster based on a rigid glycophane was also prepared from coupling of a
glucuronic acid derivative and p-xylylenediamine with subsequent ring-closing metathesis. Finally, a
more flexible bivalent lactoside was produced from lactosyl azide with use of the copper-catalyzed
azide-alkyne cycloaddition. Distances between lactose residues were analyzed computationally as
were their orientations for the relatively rigid subset of compounds. Distinct spacing properties were
revealed by varying the structure of the scaffold or by varying the location of the lactose residue on the
scaffold. To relate these features to bioactivity a plant toxin and human adhesion/growth-regulatory
galectins were used as sensors in three types of assay, i.e. measuring agglutination of erythrocytes,
binding to glycans of a surface-immobilized glycoprotein, or binding to human cells.Methodologically,
the common hemeagglutination assaywas found to be considerably less sensitive than both solid-phase
and cell assays. The bivalent compounds were less effective at interfering with glycoprotein binding to
the plant toxin than to human lectins. Significantly, a constrained compound was identified that
displayed selectivity in its inhibitory potency between galectin-3 and its proteolytically processed form.
Conversely, compounds with a high degree of flexibility showed notable ability to protect human cells
fromplant toxin binding. The applied conjugation chemistry thus is compatiblewith the long-termaim
to produce potent and selective lectin inhibitors
Phenylenediamine-based bivalent glycocyclophanes: synthesis and analysis of the influence of scaffold rigidity and ligand spacing on lectin binding in cell systems with different glycomic profiles
The conjugation of carbohydrates to synthetic scaffolds has the goal of preparing potent inhibitors of
lectin binding. We herein report the synthesis of a panel of bivalent compounds (cyclophane and
terephthalamide-derivatives) then used to establish the influence of scaffold flexibility on respective
inhibitory potency in a medically relevant test system. Synthetic routes to two phenylenediamine-based
glycocyclophanes involving Ugi reactions of glucuronic acid derivatives and subsequent ring closing
metathesis are described, as are improvements for producing terephthalamide-based carbohydrate
carriers. Assays were performed with human tumour cells measuring quantitatively the influence of the
test compounds on fluorescent surface staining by labelled lectins. Biological evaluation using two
different lines of cancer cells as well as cells with known alterations in the glycomic profile (cells treated
with an inhibitor of glycan processing and a glycosylation mutant) reduced the risk of generating
premature generalizations regarding inhibitor potency. Bioactivity relative to free mannose was
invariably determined for the synthetic compounds. A clear trend for enhanced inhibitory properties for
macrocyclic compounds compared to non-macrocyclic derivatives was discerned for one type of
glycocyclophane. Herein we also document the impact of altering the spacing between the mannose
residues, altering cell surface ligand density and cell-type reactivity. The applied strategy for the cell
assays is proposed to be of general importance in the quest to identify medically relevant lectin
inhibitors
Click Pt(IV)-Carbohydrates Pro-Drugs for Treatment of Osteosarcoma
The selectivity vs. cancer cells has always been a major challenge for chemotherapeutic agents and in particular for cisplatin, one of the most important anticancer drugs for the treatment of several types of tumors. One strategy to overtake this challenge is to modify the coordination sphere of the metallic center with specific vectors whose receptors are overexpressed in the tumoral cell membrane, such as monosaccharides. In this paper, we report the synthesis of four novel glyco-modified Pt(IV) pro-drugs, based on cisplatin scaffold, and their biological activity against osteosarcoma (OS), a malignant tumor affecting in particular adolescents and young adults. The sugar moiety and the Pt
scaffold are linked exploiting the Copper Azide Alkyne Cycloaddition (CUAAC) reaction, which has become the flagship of click chemistry due to its versatility and mild conditions. Cytotoxicity and drug uptake on three different OS cell lines as well as CSCs (Cancer Stem Cell) are describe
Glycosylated metal chelators as anti-parasitic agents with tunable selectivity
Trypanosoma cruzi and Leishmania amazonensis are the causative agents of Chagas’ disease and leishmaniasis, respectively. These conditions affect millions of people worldwide, especially in developing countries. As such, there is an urgent need for novel, efficient and cost-effective treatments for these diseases, given the growing resistance and side-effects of current therapies. This work details the synthesis and evaluation of the anti-parasitic activity of novel amino- and iminopyridyl metal chelators, their glycosylated derivatives and some of their metal complexes. Our results revealed the potent and metal-dependent activity for the aminopyridyl compounds: Cu(II) complexes were most effective against T. cruzi trypomastigotes, while Zn(II) complexes presented excellent activity against L. amazonensis promastigotes. In addition, the compounds showed excellent selectivity indexes and very low relative toxicity as judged by in vitro and in vivo studies, respectively, using RAW macrophages and Galleria mellonella larvae model
Multivalent glycoconjugates as anti-pathogenic agents
Multivalency plays a major role in biological processes and particularly in the relationship between pathogenic microorganisms and their host
that involves protein–glycan recognition. These interactions occur during the first steps of infection, for specific recognition between host and
bacteria, but also at different stages of the immune response. The search for high-affinity ligands for studying such interactions involves the
combination of carbohydrate head groups with different scaffolds and linkers generating multivalent glycocompounds with controlled spatial
and topology parameters. By interfering with pathogen adhesion, such glycocompounds including glycopolymers, glycoclusters,
glycodendrimers and glyconanoparticles have the potential to improve or replace antibiotic treatments that are now subverted by resistance.
Multivalent glycoconjugates have also been used for stimulating the innate and adaptive immune systems, for example with carbohydrate-based
vaccines. Bacteria present on their surfaces natural multivalent glycoconjugates such as lipopolysaccharides and S-layers that can also be
exploited or targeted in anti-infectious strategie
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