Thiosugars,
sugars that have their endocyclic oxygen substituted
for a sulfur atom, have been used as stable bioisosteres of naturally
occurring glycans because the thiosugar glycosydic linkage is supposed
to be stabilized toward chemical and enzymatic hydrolysis. We have
performed an in-depth investigation into the stability and reactivity
of furanosyl thiacarbenium ions, by assessing all four diastereoisomeric
thiofuranosides experimentally and computationally. We show that all
furanosyl thiacarbenium ions react in a 1,2-cis-selective
manner with triethylsilane, reminiscent of their oxo counterparts.
The computed conformational space occupied by the thiacarbenium ions
is strikingly similar to that of the corresponding furanosyl oxycarbenium
ions, indicating that the stereoelectronic substituent effects governing
the stability of furanosyl oxocarbenium ions and thiacarbenium ions
are very similar. While the thio-ribo-furanose appears
to be less reactive than its oxo counterpart, the thio-ara-, lyxo-, and xylo-furanosides
appear to be more reactive than their oxygen equivalents. These differences
are accounted for using the conformational preference of the donors
and the carbocation intermediates. The lower reactivity of the thio-ribo furanosides in (Lewis) acid-mediated reactions and
the similarity of the thia- and oxocarbenium ions make thio-ribo-furanosides excellent stabilized analogues of the naturally
occurring ribo-furanose sugars.
The 3D shape of glycosyl oxocarbenium ions determines their stability and reactivity and the stereochemical course of S
N
1 reactions taking place on these reactive intermediates is dictated by the conformation of these species. The nature and configuration of functional groups on the carbohydrate ring affect the stability of glycosyl oxocarbenium ions and control the overall shape of the cations. We herein map the stereoelectronic substituent effects of the C2‐azide, C2‐fluoride and C4‐carboxylic acid ester on the stability and reactivity of the complete suite of diastereoisomeric furanoses by using a combined computational and experimental approach. Surprisingly, all furanosyl donors studied react in a highly stereoselective manner to provide the 1,2‐
cis
products, except for the reactions in the xylose series. The 1,2‐
cis
selectivity for the
ribo
‐,
arabino
‐ and
lyxo
‐configured furanosides can be traced back to the lowest‐energy
3
E
or
E
3
conformers of the intermediate oxocarbenium ions. The lack of selectivity for the xylosyl donors is related to the occurrence of oxocarbenium ions adopting other conformations.
Stable NAD + analogues carrying single atom substitutions in either the furanose ring or the nicotinamide part have proven their value as inhibitors for NAD +-consuming enzymes. To investigate the potential of such compounds to inhibit the adenosine diphosphate ribosyl (ADPr) transferase activity of the Legionella SdeC enzyme, we prepared three NAD + analogues, namely carbanicotinamide adenosine dinucleotide (c-NAD +), thionicotinamide adenosine dinucleotide (S-NAD +) and benzamide adenosine dinucleotide (BAD). We optimized the chemical synthesis of thionicotinamide riboside and for the first time used an enzymatic approach to convert all three ribosides into the corresponding NAD + mimics. We thus expanded the known scope of substrates for the NRK1/NMNAT1 enzyme combination by turning all three modified ribosides into NAD + analogues in a scalable manner. We then compared the three NAD + mimics side-by-side in a single assay for enzyme inhibition on Legionella effector enzyme SdeC. The class of SidE enzymes to which SdeC belongs was recently identified to be important in bacterial virulence, and we found SdeC to be inhibited by S-NAD + and BAD with IC 50 values of 28 and 39 μM, respectively.
Adenosine diphosphate (ADP) ribosylation is an important
post-translational
modification (PTM) that plays a role in a wide variety of cellular
processes. To study the enzymes responsible for the establishment,
recognition, and removal of this PTM, stable analogues are invaluable
tools. We describe the design and synthesis of a 4-thioribosyl APRr
peptide that has been assembled by solid phase synthesis. The key
4-thioribosyl serine building block was obtained in a stereoselective
glycosylation reaction using an alkynylbenzoate 4-thioribosyl donor.
Energy maps of the full conformational space of 5‐membered ring glycosyl oxocarbenium ions have been generated to probe the stereoelectronic effects of C‐2‐fluoride, C‐2‐azide and C‐4‐carboxylic acid ester substituents. The computational results describing the overall shape of the reactive intermediates were complemented by experiments to show that the vast majority of studied furanosides react in an 1,2‐cis selective manner in SN1‐type glycosylation reactions. More information can be found in the Full Paper by J. D. C. Codée et al. on page 7149.
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