Pharmacological, Physiochemical, and Drug-Relevant Biological Properties of Short Chain Fatty Acid Hexosamine Analogues Used in Metabolic Glycoengineering

In this study, we
catalog structure activity relationships (SAR)
of several short chain fatty acid (SCFA)-modified hexosamine analogues
used in metabolic glycoengineering (MGE) by comparing in silico and experimental measurements of physiochemical properties important
in drug design. We then describe the impact of these compounds on
selected biological parameters that influence the pharmacological
properties and safety of drug candidates by monitoring P-glycoprotein
(Pgp) efflux, inhibition of cytochrome P450 3A4 (CYP3A4), hERG channel
inhibition, and cardiomyocyte cytotoxicity. These parameters are influenced
by length of the SCFAs (e.g., acetate vs n-butyrate), which are added
to MGE analogues to increase the efficiency of cellular uptake, the
regioisomeric arrangement of the SCFAs on the core sugar, the structure
of the core sugar itself, and by the type of N-acyl
modification (e.g., N-acetyl vs N-azido). By cataloging the influence of these SAR on pharmacological
properties of MGE analogues, this study outlines design considerations
for tuning the pharmacological, physiochemical, and the toxicological
parameters of this emerging class of small molecule drug candidates.