基于高尔基体 α-甘露糖苷酶 II (GMII) 抑制的新型抗癌疗法的开发因溶酶体 α-甘露糖苷酶的不良共抑制而受到严重阻碍，从而导致严重的副作用。在这篇文章中，我们描述了 (5S)-5-[4-(卤代)苄基]苦马豆素的完全立体选择性合成，作为 GMII 的高效选择性抑制剂。该合成从先前报道的可从 L-核糖中容易获得的醛开始，其关键特征包括具有底物控制的立体选择性的分子内还原胺化以及通过自身取代进行的苄基的后期衍生化。这些新型苦马豆素类似物被发现是高尔基体型 α-甘露糖苷酶 AMAN-2 (Ki = 23-75 nM) 的纳摩尔抑制剂，与溶酶体型刀豆 α-甘露糖苷酶相比具有优异的选择性（选择性指数 = 205-870） 。最后，进行分子对接和 pKa 计算，以更深入地了解抑制剂：酶复合物的结构，并进行配对相互作用能量分析 (FMO-PIEDA)，以合理化观察到的抑制剂的效力和选择性。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Development of novel anti-cancer therapeutics based on Golgi α-mannosidase II (GMII) inhibition is considerably impeded by an undesired co-inhibition of lysosomal α-mannosidase leading to severe side-effects. In this contribution, we describe a fully stereoselective synthesis of (5S)-5-[4-(halo)benzyl]swainsonines as highly potent and selective inhibitors of GMII. The synthesis starts from a previously reported aldehyde readily available from l-ribose, and the key features include an intramolecular reductive amination with substrate-controlled stereoselectivity and a late-stage derivatisation of the benzyl group via ipso-substitution. These novel swainsonine analogues were found to be nanomolar inhibitors of the Golgi-type α-mannosidase AMAN-2 (Ki = 23-75 nM) with excellent selectivity (selectivity index = 205-870) over the lysosomal-type Jack bean α-mannosidase. Finally, molecular docking and pKa calculations were performed to provide more insight into the structure of the inhibitor:enzyme complexes, and a pair interaction energy analysis (FMO-PIEDA) was carried out to rationalise the observed potency and selectivity of the inhibitors.Copyright © 2024 Elsevier Inc. All rights reserved.