Click Chemistry in Carbohydrate Based Drug Development and Glycobiology

Abstract

The 1,3-dipolar cycloaddition reaction (1,3-DCR) of a 1,3-dipole to a dipolarophile for the synthesis of heterocycles is a ubiquitous transformation in synthetic organic chemistry. Recently, the Sharpless and Melda! groups have reported the dramatic rate enhancement (up to 107 times) and improved regioselectivity of the Huisgen 1,3-DCR of an organic azide to a terminal acetylene to afford, specifically a l ,4-disubstituted-1,2,3- triazole in the presence of a Cu1 catalyst. This Cu1 catalysed 1,3-DCR has successfully fulfilled the requirements of "click chemistry" as prescribed by Sharpless and within the past few years has become a premier component of the click chemistry paradigm. Click chemistry has proven to be of remarkable utility and broad scope, not only in organic synthesis, but in chemical biology and drug discovery. Click chemistry is highly modular and simplifies difficult syntheses. The biocompatibility of the reaction, tolerance towards a broad range of pH and relative inertness of acetylenes and azides within highly functionalised biological milieus has allowed click chemistry to become a viable bioconjugation strategy both for labelling biomolecules and for in situ lead discovery applications. More recently, click chemistry has emerged as a powerful conjugation strategy for the preparation of structurally diverse neoglycoconjugates of biomedical interest. This chapter aims to highlight recent developments appearing within the literature concerning the use of click chemistry in carbohydrate based drug discovery and glycobiology. Topics range from small molecule probes and drug leads, multivalent neoglycoconjugates acting as Iectin inhibitors and potential vaccines, to bioconjugation strategies for labelling of engineered cell surface glycans. The chapter aims to be comprehensive with commentary on future perspective.