Design, Synthesis, and Anticancer Activity of a Selenium-Containing Galectin-3 and Galectin-9N Inhibitor.

Sonia Di Gaetano,Michele Saviano,Francesco Luigi Gervasio,Ioannis Galdadas,Emilia Pedone,Alfonso Iadonisi,Domenica Capasso,Serena Traboni,Luciano Pirone

doi:10.3390/ijms23052581

Abstract

Galectins are soluble β-D-galactoside-binding proteins whose implication in cancer progression and disease outcome makes them prominent targets for therapeutic intervention. In this frame, the development of small inhibitors that block selectively the activity of galectins represents an important strategy for cancer therapy which is, however, still relatively underdeveloped. To this end, we designed here a rationally and efficiently novel diglycosylated compound, characterized by a selenoglycoside bond and the presence of a lipophilic benzyl group at both saccharide residues. The relatively high binding affinity of the new compound to the carbohydrate recognition domain of two galectins, galectin 3 and galectin 9, its good antiproliferative and anti-migration activity towards melanoma cells, as well as its anti-angiogenesis properties, pave the way for its further development as an anticancer agent.

Highlights

Galectins are a family of soluble β-D-galactoside-binding proteins characterized by a highly conserved carbohydrate recognition domain (CRD) [1] and are expressed in a broad range of animal species
CRD; (b) tandem repeat galectins with two distinct CRDs connected by a linker peptide; and (c) chimeric galectins represented by only one member, galectin 3, composed of a canonical domain connected to a long tail [5]
Derivatization at positions C4 and C6 is feasible, the hydrogen bond formed between the β-galactoside scaffold and galectins (Figure 1) indicate that these interactions stabilize the β-galactoside in the binding site but are expected to be necessary for substrate recognition

Summary

Introduction

Galectins are a family of soluble β-D-galactoside-binding proteins characterized by a highly conserved carbohydrate recognition domain (CRD) [1] and are expressed in a broad range of animal species. These proteins are present in various cell types, including epithelial and endothelial cells from the skin, lung, and gut, as well as immune cells and fibroblasts [2–4]. Based on their molecular structure, galectins have been classified into three groups: (a) proto-galectins (galectin 1, -2, -5, -7, -10, -11, -13, -14 and -15) with a single. The role of galectins in all these cellular pathways would imply lack of specificity, but this is far from being the case, as the structural complexity and variability of the carbohydrates that galectins recognize result in specific interactions that allow galectins to selectively activate different pathways

Methods

Results

Conclusion