Approaches to the Sulfation of Small Molecules: Current Progress and Future Directions

Abstract

Sulfation is one of the most important modifications that occur to a wide range of bioactive small molecules including polysaccharides, proteins, flavonoids, and steroids. In turn, these sulfated molecules have significant biological and pharmacological roles in diverse processes including cell signalling, modulation of immune and inflammation response, anti-coagulation, anti-atherosclerosis, and anti-adhesive properties. This essay summarises the most encountered chemical sulfation methods of small molecules. Sulfation reactions using sulfur trioxide amine/amide complexes are the most used method for alcoholic or phenolic groups in carbohydrates, steroids, proteins, and aliphatic or alicyclic scaffolds. Despite the effectiveness of these methods, they suffer from some issues such as multiple-purification steps, toxicity issues (eg pyridine contamination), purification challenges, stoichiometric excess of reagents which leads to increase of a reaction cost, and intrinsic stability issues of both the reagent and product. Recent advances including SuFEx, the Malins in situ reagent approach and TBSAB show the widespread appeal of novel sulfating approaches that will enable a larger exploration of the field in the years to come by simplifying the purification and isolation to access bespoke sulfated small molecules.