School of Chemistry & Molecular Biosciences, The University of Queensland, Brisbane, Queensland, 4072, Australia.
Department of Chemistry and, Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada.
Chembiochem. 2023 Feb 14;24(4):e202200619. doi: 10.1002/cbic.202200619. Epub 2023 Jan 3.
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 intermediates. 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-氮杂糖类似物 L-艾杜糖醛酸（L-IdoA）和 D-葡萄糖醛酸（D-GlcA）及其相应的对映异构体已被合成，作为溶酶体贮积病 MPS I（由编码 α-艾杜糖苷酸酶（IDUA）的基因突变引起）的潜在药理学伴侣。这些化合物从 D-或 L-阿拉伯糖通过九或十个步骤高效合成，通过关键中间体的 X 射线晶体学分析确认了结构。所有化合物对 IDUA 均无活性，尽管 L-IdoA 构型的 8 适度抑制β-葡萄糖醛酸酶（β-GLU）。D-GlcA 构型的 9 是β-GLU 的有效抑制剂，也是内切-β-葡萄糖醛酸酶肝素酶的中度抑制剂。9 与肝素酶的共结晶揭示了 9 的内环氮与催化酸和催化亲核试剂形成紧密相互作用。
