Pingitore Valeria, Martínez-Bailén Macarena, Carmona Ana T, Mészáros Zuzana, Kulik Natalia, Slámová Kristýna, Křen Vladimír, Bojarová Pavla, Robina Inmaculada, Moreno-Vargas Antonio J
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012-Sevilla, Spain.
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012-Sevilla, Spain.
Bioorg Chem. 2022 Mar;120:105650. doi: 10.1016/j.bioorg.2022.105650. Epub 2022 Feb 2.
Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC and (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric and dimeric compounds were screened for inhibition of β-N-acetylglucosaminidase from Jack beans, the plant ortholog of human lysosomal hexosaminidases. A selection of the best inhibitors of these libraries was then evaluated against human lysosomal β-N-acetylhexosaminidase B (hHexB) and human nucleocytoplasmic β-N-acetylglucosaminidase (hOGA). This evaluation identified a potent (nM) and selective monomeric inhibitor of hOGA (compound 7A) that showed a 6770-fold higher affinity for this enzyme than for hHexB. The corresponding dimeric derivative (compound 9D) further remarkably improved the selectivity in the inhibition of hOGA (2.7 × 10 times more selective for hOGA over hHexB) and the inhibition potency (by one order of magnitude). Docking studies were performed to explain the selectivity of inhibition observed in compound 7A.
通过铜催化的叠氮化物-炔烃环加成反应（CuAAC）以及（硫）脲键形成反应，从各自的叠氮基/氨基己基吡咯烷亚氨基糖前体合成了单聚体和二聚体吡咯烷亚氨基糖文库。对所得的单体和二聚体化合物进行筛选，以检测其对刀豆中β-N-乙酰氨基葡萄糖苷酶的抑制作用，刀豆中的该酶是人类溶酶体己糖胺酶的植物同源物。然后，对这些文库中选出的最佳抑制剂针对人类溶酶体β-N-乙酰己糖胺酶B（hHexB）和人类核质β-N-乙酰氨基葡萄糖苷酶（hOGA）进行评估。该评估确定了一种对hOGA具有强效（纳摩尔级）和选择性的单体抑制剂（化合物7A），该抑制剂对该酶的亲和力比对hHexB高6770倍。相应的二聚体衍生物（化合物9D）进一步显著提高了对hOGA抑制的选择性（对hOGA的选择性比对hHexB高2.7×10倍）以及抑制效力（提高了一个数量级）。进行对接研究以解释在化合物7A中观察到的抑制选择性。
