Synthesis and biological characterization of natural and designed sugars

Carbohydrates represent a keystone among biological molecules. Well known as a source of energy, sugars also form the backbone of various biopolymers, act as markers and receptors for cellular communication and modulate lipid and protein functions. As such a powerful class, carbohydrates represent a useful pool from which both nature and man have drawn structures to produce biologically active compounds with a variety of modes of action. Beyond their importance to biology, sugars have represented attractive synthetic targets to chemists given their densely functionalized scaffolds. The work presented in this thesis aims to employ synthetic chemistry to provide both natural and designed carbohydrates in order to carry out biological studies to improve our understanding of these compounds' particular effects. In the first part, a synthesis is developed for the carboline disaccharide domain of the cytotoxic enediyne, shishijimicin A. The route employs a Reetz–Müller-Starke reaction to install the domain’s quaternary center, with addition of a carboline dianion to complete the target. Iminosugars represent the focus of the second portion of the thesis. These polyhydroxylated alkaloids have long been investigated for their ability to mimic single sugars, inhibiting various glycosidases and glycosyltransferases. The endocyclic nitrogen atom of members of this class can act as a functional handle for alkylation, with increased chain length increasing both potency of enzyme inhibition and toxicity in cellula. Specific iminopyranose structures with D-gluco stereochemistry have broad-spectrum antiviral activity, while those with D-galacto stereochemistry are antiviral with respect to hepatitis C, but not other genetically related viruses. Reported herein are syntheses of classes of iminosugars to determine the influence of both N-alkylation chain length and iminopyranose stereochemistry on the spectrum of antiviral activity. Complementing antiviral activity with isolated enzyme inhibition assays, the work aims to identify new targets for next generation antivirals. Finally, the prototypical iminosugar, D-deoxynojirimycin, is conjugated to a second natural product, D-α-tocopherol. By replacing the more common normal alkyl group with a lipid, the goal was to reduce cellular toxicity, while also taking advantage of the natural active transport for the lipid to increase uptake of the drug. Surprisingly, this change provided a marked shift in selectivity of enzyme inhibition and antiviral ability. In order to fully characterize the mechanism, the mentioned enzymatic and antiviral studies were supplemented with lipidomic, STED-microscopy and pharmacokinetic investigations.