2023
DOI: 10.1002/cbic.202200619
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Synthesis of Uronic Acid 1‐Azasugars as Putative Inhibitors of α‐Iduronidase, β‐Glucuronidase and Heparanase**

Abstract: 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 ag… Show more

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Cited by 2 publications
(5 citation statements)
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“…The costructure of 9 and HPSE has hydrogen bonds with the 4 eq -OH and Tyr391 and Asp62, as opposed to the hydrogen bond with water seen for 8 . The geminal diol 9 has the same hydrogen bonding network as the structure containing 11 , reported by Doherty et al, and additional H-bond between the 3 ax -OH with the nucleophile (Glu343), similar to what was observed in the active site of AcGH79. The 3 ax -OH in both structures is also within H-bonding distance of Asp62, an additional interaction that is not seen in the AcGH79-geminal diol structures.…”
Section: Resultssupporting
confidence: 68%
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“…The costructure of 9 and HPSE has hydrogen bonds with the 4 eq -OH and Tyr391 and Asp62, as opposed to the hydrogen bond with water seen for 8 . The geminal diol 9 has the same hydrogen bonding network as the structure containing 11 , reported by Doherty et al, and additional H-bond between the 3 ax -OH with the nucleophile (Glu343), similar to what was observed in the active site of AcGH79. The 3 ax -OH in both structures is also within H-bonding distance of Asp62, an additional interaction that is not seen in the AcGH79-geminal diol structures.…”
Section: Resultssupporting
confidence: 68%
“…As well, the hydroxyl on the β-face forms a hydrogen bond with Asp62 and the backbone nitrogen of Thr97, while the hydroxyl on the α-face is positioned to form hydrogen bonds with the catalytic nucleophile Glu343 and Asp62. The hydroxyl at the 4-position of inhibitor 3 lacks the hydrogen bond with Trp391 which is seen for gluco -configured inhibitors. , However, as in the costructure of 4 and BpHEP, the axial 4-hydroxyl forms a hydrogen bond with water present in the crystal structure.…”
Section: Resultsmentioning
confidence: 98%
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