Short-chain fatty acid-hexosamine cancer prodrugs: The sugar matters!

This review describes short-chain fatty acid (SCFA)-sugar hybrids, exemplified by the lead compound But₄ManNAc where n-butyrate is linked to N-acetyl-D-mannosamine (ManNAc) in a single molecule, that merge two emerging modes of cancer therapy. First, n-butyrate is a histone deacetylase (HDAC) inhibitor that remodels chromatin, thereby influencing patterns of gene expression to 'make bad cells go good'. Second, ManNAc is the dedicated precursor for sialic acid biosynthesis, a sugar that is gaining increasing recognition as an important modulator of cell fate, including apoptosis, proliferation and differentiation. Herein we describe how, when combined with n-butyrate, ManNAc augments the epigenetic activity of the HDAC inhibitor to achieve sugar-dependent killing of cancer cells in vitro. Looking forward to the translation of this class of compounds into the clinic, we then discuss how the poor pharmacological properties of the individual n-butyrate and ManNAc moieties are dramatically improved by combination in a single molecule, where they function as mutual prodrugs. Finally, we conclude by outlining how But ₄ManNAc represents a versatile platform for future drug development efforts.