Carbasugars in Drug Design: Novel Strategies for Mimicking Carbohydrate Properties

Abstract

Carbasugars are currently regarded as valuable scaffolds in drug design due to their structural similarity to carbohydrates and enhanced stability and enzymatic resistance. The ability to mimic oxocarbenium-ion-like transition states and to form covalent enzyme adducts make them potent glycoside hydrolase (GH) inhibitors. This literature review provides an overview and discussion of the various syntheses for carbasugars and the use in drug design. Recent studies unveil two main directions in carbasugar-based drug design – allylic carbasugar inhibitors and cyclic warhead-containing inactivators. Allylic carbasugar inhibitors, more specifically halogenated derivatives, have been found to exhibit selective and tuneable inhibition of GHs. Introducing fluorine or chlorine atoms into this moiety enhances intermediate stability, with improved control over enzyme reactivity. Mechanistic studies on vinyl halide-modified cyclitols have provided a glimpse into enzyme binding and covalent intermediate formation with possible inhibition based on the SN1/SN1' mechanism. Cyclic warhead-containing inactivators, such as epoxides, aziridines, and cyclosulphates, have, on the other hand, been shown to be potent irreversible GH enzyme inactivators. Cyclosulphates, specifically, have shown strong specificity through mimicking substrate-enzyme interactions and trapping Michaelis-like conformations, making them good candidates for therapeutic applications along with activity-based protein profiling. Also, developing multiple new avenues for isoform-specific inhibition could drive novel strategies for targeted therapies.