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5-(2-Oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) is an atural productf ormedd uring bacterial synthesis of vitamin B2. It potently activates mucosal associated invariant T( MAIT) cells and has immunomodulatory,i nflammatory,a nd anticancer properties. This highly polar and unstable compound forms ar emarkablys table Schiff base with al ysine residuei nm ajor histocompatibility complex class Irelated protein (MR1) expressed in antigen-presentingc ells. Inspiredb yt he importance of the ribityl moiety of 5-OP-RU for binding to both MR1 and the Tc ell receptor (TCR) on MAIT cells, each OH was removed in silico. DFT calculations and MD simulations revealedavery stable hydrogen bond betweent he C3'ÀOH and uracil N1H, which profoundly restrictsf lexibility and positioning of each ribityl-OH, potentially impacting their interactionsw ith MR1 and TCR. By using deoxygenation strategies and kinetically controlled imine formation,f our monodeoxyribityl and four monohydroxyalkyl analogues of 5-OP-RU were synthesised as new tools for probingTcell activation mechanisms.[a] G.Scheme4.Synthesis of 4-deoxy-d-ribitylamine (32)b yB arton-McCombied eoxygenation of d-ribose (24).Scheme5.Synthesis of 5-deoxy-d-ribitylamine (40)b yC 5-tosylate reduction of d-ribose (24).

1-Azasugar analogues of l-iduronic acid (l-IdoA) and d-glucuronic acid (d-GlcA) and their corresponding enantiomers have been synthesized as potential pharmacological chaperones for mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by mutations in the gene encoding α-iduronidase (IDUA). The compounds were efficiently synthesized in nine or ten steps from d-or l-arabinose, and the structures were confirmed by X-ray crystallographic analysis of key intermedi-ates. All compounds were inactive against IDUA, although l-IdoA-configured 8 moderately inhibited β-glucuronidase (β-GLU). The d-GlcA-configured 9 was a potent inhibitor of β-GLU and a moderate inhibitor of the endo-β-glucuronidase heparanase. Co-crystallization of 9 with heparanase revealed that the endocyclic nitrogen of 9 forms close interactions with both the catalytic acid and catalytic nucleophile.

1-Azasugar analogues of L-iduronic acid (L-IdoA) and D-glucuronic acid (D-GlcA) and their corresponding enantiomers were synthesized as potential pharmacological chaperones for mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by mutations in the gene encoding a-iduronidase (IDUA). The compounds were efficiently synthesized in nine or ten steps from D- or L-arabinose and the structures were confirmed by X-ray crystallographic analysis of key intermediates. All compounds were inactive against IDUA, although L-IdoA-configured 8 moderately inhibited b-glucuronidase (b-GLU). The D-GlcA-configured 9 was a potent inhibitor of b-GLU and a moderate inhibitor of the endo-b-glucuronidase heparanase. Co-crystallization of 9 with heparanase revealed that the endocyclic nitrogen of 9 forms close interactions with both the catalytic acid and catalytic nucleophile.

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