Leyden, Rosaria and Velasco-Torrijos, Trinidad and Andre, Sabine and Gouin, Sebastien and Gabius, Hans-Joachim and Murphy, Paul V.
Synthesis of Bivalent Lactosides Based on Terephthalamide,
N,N0-Diglucosylterephthalamide, and Glycophane Scaffolds and
Assessment of Their Inhibitory Capacity on Medically Relevant Lectins.
JOC - Journal of Organic Chemistry, 74 (23).
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.
||The definitive version of this article is available at JOC Journal of Organic Chemistry Vol.74(2009) pp.9010-9026. DOI: 10.1021/jo901667r
||Synthesis; Bivalent Lactosides; Terephthalamide; N0-Diglucosylterephthalamide; Glycophane Scaffolds; Inhibitory Capacity; Lectins;
||Science & Engineering > Chemistry
Dr. Trinidad Velasco-Torrijos
||28 Aug 2012 15:06
|Journal or Publication Title:
||JOC - Journal of Organic Chemistry
||American Chemical Society
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