The synthesis of tailored bioactive carbohydrates usually comprises challenging (de)protection steps, which lowers synthetic yields and increases time demands. We present here a regioselective single‐step introduction of benzylic substituents at 3‐hydroxy groups of β‐d‐galactopyranosyl‐(1→1)‐thio‐β‐d‐galactopyranoside (TDG) employing dibutyltin oxide in good yields. These glycomimetics act as inhibitors of galectins—human lectins, which are biomedically attractive targets for therapeutic inhibition in, for example, cancerogenesis. The affinity of the prepared glycomimetics to galectin‐1 and galectin‐3 was studied in enzyme‐linked immunosorbent (ELISA)‐type assays and their potential to inhibit galectin binding on the cell surface was shown. We used our original in vivo biotinylated galectin constructs for easy detection by flow cytometry. The results of the biological experiments were compared with data from molecular modeling with both galectins. The present work reveals a facile and elegant synthetic route for the preparation of TDG‐derived glycomimetics that exhibit differing selectivity and affinity to galectins depending on the choice of 3‐O‐substitution.
Galectin-3
(Gal-3) participates in many cancer-related metabolic
processes. The inhibition of overexpressed Gal-3 by, e.g., β-galactoside-derived
inhibitors is hence promising for cancer treatment. The multivalent
presentation of such inhibitors on a suitable biocompatible carrier
can enhance the overall affinity to Gal-3 and favorably modify the
interaction with Gal-3-overexpressing cells. We synthesized a library
of C-3 aryl-substituted thiodigalactoside inhibitors and their multivalent N-(2-hydroxypropyl)methacrylamide (HPMA)-based counterparts
with two different glycomimetic contents. Glycopolymers with a higher
content of glycomimetic exhibited a higher affinity to Gal-3 as assessed
by ELISA and biolayer interferometry. Among them, four candidates
(with 4-acetophenyl, 4-cyanophenyl, 4-fluorophenyl, and thiophen-3-yl
substitution) were selected for further evaluation in cancer-related
experiments in cell cultures. These glycopolymers inhibited Gal-3-induced
processes in cancer cells. The cyanophenyl-substituted glycopolymer
exhibited the strongest antiproliferative, antimigratory, antiangiogenic,
and immunoprotective properties. The prepared glycopolymers appear
to be prospective modulators of the tumor microenvironment applicable
in the therapy of Gal-3-associated cancers.
Telechelic poly(ethylene oxide) with glucose end-groups interacts with metallacarborane that leads to lamellar nanostructures in water. They can incorporate metallacarborane- and benzoxaborole-based probes via dynamic bonding.
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