Metathesis of Structurally Preorganized Bivalent Carbohydrates. Synthesis of Macrocyclic and Oligomeric Scaffolds

Bivalent carbohydrate substrates for metathesis were synthesized from glucuronic acid and phenylene-1,4-diamine. The substrate secondary structure depends on whether secondary or tertiary amides are present, and this influences the course of the metathesis reaction leading to novel multivalent scaffolding. Molecular modeling suggests that a very rigid macrocyclic scaffold has potential for the development of α-helix peptidomimetics

Metathesis of Structurally Preorganized Bivalent Carbohydrates. Synthesis of Macrocyclic and Oligomeric Scaffolds

Bivalent carbohydrate substrates for metathesis were synthesized from glucuronic acid and phenylene-1,4-diamine. The substrate secondary structure depends on whether secondary or tertiary amides are present, and this influences the course of the metathesis reaction leading to novel multivalent scaffolding. Molecular modeling suggests that a very rigid macrocyclic scaffold has potential for the development of α-helix peptidomimetics

Metathesis of Structurally Preorganized Bivalent Carbohydrates. Synthesis of Macrocyclic and Oligomeric Scaffolds

Bivalent carbohydrate substrates for metathesis were synthesized from glucuronic acid and phenylene-1,4-diamine. The substrate secondary structure depends on whether secondary or tertiary amides are present, and this influences the course of the metathesis reaction leading to novel multivalent scaffolding. Molecular modeling suggests that a very rigid macrocyclic scaffold has potential for the development of α-helix peptidomimetics

Metathesis of Structurally Preorganized Bivalent Carbohydrates. Synthesis of Macrocyclic and Oligomeric Scaffolds

Bivalent carbohydrate substrates for metathesis were synthesized from glucuronic acid and phenylene-1,4-diamine. The substrate secondary structure depends on whether secondary or tertiary amides are present, and this influences the course of the metathesis reaction leading to novel multivalent scaffolding. Molecular modeling suggests that a very rigid macrocyclic scaffold has potential for the development of α-helix peptidomimetics

Synthesis of Bivalent Lactosides Based on Terephthalamide, <i>N</i>,<i>N</i>′-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,N′-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 assay was 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 from plant toxin binding. The applied conjugation chemistry thus is compatible with the long-term aim to produce potent and selective lectin inhibitors

DataSheet1_Click Pt(IV)-Carbohydrates Pro-Drugs for Treatment of Osteosarcoma.pdf

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 described.</p

Synthesis of Bivalent Lactosides Based on Terephthalamide, <i>N</i>,<i>N</i>′-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,N′-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 assay was 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 from plant toxin binding. The applied conjugation chemistry thus is compatible with the long-term aim to produce potent and selective lectin inhibitors

DataSheet1_2D and 3D anticancer properties of C2-functionalised glucosamine-Pt (IV) prodrugs based on cisplatin scaffold.PDF

A series of C2-functionalied Pt (IV) glycoconjugates based on glucosamine have been synthesised, characterised and tested as anticancer agents on a series of different 2D and 3D cancer cell lines. The carbohydrate will act as a targeted delivery system to improve the selectivity, exploiting the Warburg Effect and the GLUTs receptors that are overexpressed in most of the cancer cells. The hydroxyl at C2 of the carbohydrates does not participate in hydrogen bonding with the GLUTs receptors, making C2 an attractive position for drug conjugation as seen in literature. In this study, we use the amino functionality at the C2 position in glucosamine and Copper-catalysed Azide-Alkyne Cycloaddition “click” (CuAAC) reaction to connect the prodrug Pt (IV) scaffold to the carbohydrate. We have investigated complexes with different linker lengths, as well as acetyl protected and free derivatives. To the best of our knowledge, this study represents the first series of Pt (IV) glucosamine-conjugates functionalised at C2.</p