This strategy enables the diversity-oriented synthesis of various glycosphingolipids (GSLs). GSLs are a family of glycolipids with a sphingoid or a ceramide as the hydrophobic moiety linked to the downstream end of a carbohydrate chain through a glycosidic bond. GSLs are an essential component of the cell membrane and play a key role in many biological and pathological processes. Aberrant GSL expression and metabolism are associated with diseases such as cancer, diabetes, sclerosis, bacterial and viral infections, and Alzheimer’s disease, so exploring GSLs and their derivatives is popular in medical research. For example, neuroblastoma tumors surround themselves with orders of magnitude higher concentrations of GSLs, providing a target for treatment with monoclonal antibodies. However, the isolation of GSLs from nature is challenging, and it is only possible to obtain them in minor quantities. Chemical or enzymatic synthesis of GSLs is a promising alternative pathway to GSLs. However, these strategies suffer from low yields, high economic cost, poor solubility in water solutions, compatibility problems, and only provide individual structures one by one.
Researchers at the University of Florida have developed a strategy for high-yield synthesis of glycosphingolipids. This strategy combines chemical transformations and stepwise enzymatic elongations, rapidly producing diverse natural and functionalized glycolipids. These functional products can help achieve breakthroughs in research targeting specific cancers and degenerative diseases.
Diversity-oriented synthesis of glycosphingolipids important for diagnostic and biological applications, combining chemical and enzymatic transformations
This three-stage series of chemoenzymatic reactions efficiently synthesizes glycosphingolipids (GSLs). The first step involves the synthesis of a common GSL precursor by binding a protected mono- or disaccharide donor to a short lipid head via glycosylation and deprotection of the donor. The second step assembles a glycan in aqueous media through enzymatic elongation of the sugar chain. The final step comprises chemoselective reactions to construct the ceramide moiety on site. These reactions include metathesis to install the main lipid chain and azide reduction and acylation to install the N-linked lipid chain. All syntheses start or go through the same intermediates, making the process simple and reproducible. Furthermore, the synthesized GSLs may incorporate different lipids or functional groups, enabling a wide range of resulting GSL derivatives that may have valuable applications in drug development and medical and biological research.