Organic & Biomolecular Chemistry Blog

Glycosidases are involved in a broad range of biological and pathological processes. The development of inhibitors of these enzymes that could potentially help with diseases such as type II diabetes mellitus, viral infections, cancer or hereditary enzyme deficiency diseases is one of the aims of Jose M Garcia Fernandez, Carmen Ortiz Mellet and their research groups in Spain.

In this paper, they prepare a library of sp₂-iminosugar-type glycomimetics and they evaluate their glycosidase inhibition properties against a panel of commercial glycosidases. They actually got very interesting results that show the potential of this molecular diversity-oriented approach to identify suitable hits for further in cell and in vivo studies.

Read this HOT article now that is free to access until the 5th May.

Bicyclic (galacto)nojirimycin analogues as glycosidase inhibitors: Effect of structural modifications in their pharmacological chaperone potential towards β-glucocerebrosidase
Matilde Aguilar-Moncayo, M. Isabel García-Moreno, Ana Trapero, Meritxell Egido-Gabás, Amadeu Llebaria, José M. García Fernández and Carmen Ortiz Mellet
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C1OB05234A

Researchers from the University of Alberta, Canada, have discovered an antagonist with impressive nanomolar inhibition of cholera toxin (CT) using a novel approach to design and synthesise a small, focused library of CT binding ligands.

David Bundle and co-workers aimed to design a ligand capable of binding to cholera toxin and that could be orally administered.  CT is the most important virulence factor in the disease and deactivating bacterial toxins may reduce the development of antibiotic resistance – a real problem in current cholera treatments.   Binding to CT occurs predominantly at GM₁ receptor, and a multiple binding strategy through weak ligand interactions has been demonstrated to be very effective.

Here, the authors have created a compound library of heterobifunctional ligands, with an invariable ligand, galactose – which is very effective at binding to GM₁ – conjugated to a polymer carrier.  The other, non-galactose ligand fragment was varied to probe a complimentary GM₁ binding site. The polymer scaffold, polyacrylamide or dextran,  provided a framework for the synthesis, purification and assay of the compounds as well as being necessary for the multivalent presentation of the ligands.  The library allowed the authors to identify weak ligands that are capable of complimenting the binding affinity of galactose for the cholera toxin protein.

Read how the authors obtained the nanomolar inhibition activities here – the article is free to access for four weeks!

Multifunctional multivalency: a focused library of polymeric cholera toxin antagonists
Huu-Anh Tran, Pavel I. Kitov, Eugenia Paszkiewicz, Joanna M. Sadowska and David R. Bundle
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C0OB01089H

Terpenes and other polycycles are very common in nature and as many are biologically active, have been a key target for synthetic organic chemists. Rama Heng and Samir Zard from Ecole Polytechnique in France have demonstrated a general approach to polycyclic structures featuring the direct formation of six-, seven-, and eight-membered rings. This very powerful, yet concise and highly flexible, approach to both fused and bridged polycyclic structures overcomes the limitations imposed by intrinsically slow radical transformations, opening numerous synthetic opportunities. Our referees were very enthusiastic about this paper and we think you will be too – expect to see more about this exciting new method!

This HOT article is available free until 21st April 2011! Read it today in OBC.

A flexible, unified radical-based approach to polycyclic structures
Rama Heng and Samir Z. Zard
Org. Biomol. Chem., 2011, Advance Article
DOI: 10.1039/C1OB00024A