A Selective Galactose–Coumarin-Derived Galectin-3 Inhibitor Demonstrates Involvement of Galectin-3-glycan Interactions in a Pulmonary Fibrosis Model

Abstract

Synthesis of doubly 3-O-coumarylmethyl-substituted thiodigalactosides from bis-3-O-propargyl-thiodigalactoside resulted in highly selective and high affinity galectin-3 inhibitors. Mutant studies, structural analysis, and molecular modeling revealed that the coumaryl substituents stack onto arginine side chains. One inhibitor displayed efficacy in a murine model of bleomycin-induced lung fibrosis similar to that of a known nonselective galectin-1/galectin-3 inhibitor, which strongly suggests that blocking galectin-3 glycan recognition is an important antifibrotic drug target.

3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3

“…De-acetylation of 16, regioselective 2-O-acetylation, 3-O-triflation, and treatment with sodium azide gave the 3-azido derivative 18. Acetate and benzylidene removal followed by Cu(I)-catalyzed cycloaddition [21,22] With the 4-fluoro-1-naphthamide 7 being identified as one of two naphthamide ligands showing the highest affinity, the hypothesis that combining this C1-naphthamido moiety with known affinity-enhancing 5,6-difluorocoumarin- [15,16] and 3,4,5-trifluorophenyltriazolyl moieties [17,18] in the same manner as described for the aldoxime derivatives [8] to give the doubly derivatized C-galactosyls 14 and 19 (Scheme 3) appeared plausible. Stannylidene-mediated propargylation at HO3 of 7 gave the propargyl ether 12.…”

“…Stannylidene-mediated propargylation at HO3 of 7 gave the propargyl ether 12. The remaining hydroxyl groups of 12 were acetylated to give 13 to be used as the alkyne source together with 5,6-difluorosalicylic aldehyde and tosyl azide for Cu(I)-mediated multicomponent coumarin synthesis [15,19] followed by de-acetylation to give the difluoro-coumarin 14.…”

Carbohydrate Recognition Mechanism of the Mushroom Galectin ACG

“…In fact, various galectin inhibitors have been developed, with the aim of developing galectin-targeted pharmaceutical drugs (39)(40)(41). As in the cases of galectin-3 and galectin-9 CRDs, affinity enhancement is evident in ACG for the repeating LacNAc unit (i.e., LacNAcβ1-3), while affinity increases for oligolactosamines, such as LacNAc 2 , LacNAc 3 , and LacnAc 5 , are rather modest in ACG.…”

Synthesis and biological evaluation of morpholines linked coumarin–triazole hybrids as anticancer agents

“…Recently, Rajput et al. have reported a selective galactose‐based coumarin derived galectin inhibitors and showed that the coumarin–arginine interactions are essential for galectin inhibition through molecular modelling studies (Rajput et al., ).…”

“…Coumarin (2H-chromen-2-one), a fused heterocyclic ring system consisting of benzene and 2-pyrone ring belongs to the family of neoflavonoids of plant secondary metabolites known for its wide variety of biological applications (Fylaktakidou, Hadjipavlou-Litina, Litinas, & Nicolaides, 2004;Gormley, Orphanides, Meyer, Cullis, & Maxwell, 1996;Hassan, Osman, Ali, & Ahsan, 2016;Kostova et al, 2011;Manvar et al, 2011;Sashidhara et al, 2011;Thakur, Singla, & Jaitak, 2015;Yuce et al, 2011). Recently, Rajput et al have reported a selective galactose-based coumarin derived galectin inhibitors and showed that the coumarin-arginine interactions are essential for galectin inhibition through molecular modelling studies (Rajput et al, 2016).…”