Genomics Research Centre, Academia Sinica, 128, Section 2, Academia Road, 11529, Taipei, Taiwan.
Department of Chemistry, National Cheng-Kung University, 1, University Road, 701, Tainan, Taiwan.
Chem Asian J. 2022 Jul 15;17(14):e202200172. doi: 10.1002/asia.202200172. Epub 2022 May 23.
A general and flexible approach toward the development of α-l-rhamnosidase (α-l-Rha-ase) inhibitors is described. Five enantiopure poly-substituted pyrrolidine-based scaffolds bearing the C1-aminomethyl moiety were designed and synthesized from five-membered cyclic nitrones. Each structurally diversified amide library of these scaffolds was rapidly generated via combinatorial parallel synthesis and applied for in-situ inhibition study against α-l-Rha-ase, allowing us to efficiently identify new inhibition hits. Surprisingly, all promising inhibitors are derived from the same scaffold 3. Among them, the most potent and selective inhibitor is pyrrolidine 19 with K =0.24 μM, approximately 24-fold more potent than the reference compound DAA (K =5.7 μM). It is the first study to comprehensively prepare pyrrolidine-based scaffolds and libraries for inhibition study against α-l-Rha-ase.
描述了一种开发α-l-鼠李糖苷酶（α-l-Rha-ase）抑制剂的通用且灵活的方法。从五元环状硝酮出发，设计并合成了 5 个具有 C1-氨甲基部分的对映体纯的多取代吡咯烷骨架。通过组合平行合成，这些支架的每个结构多样化的酰胺文库都可以快速生成，并应用于α-l-Rha-ase 的原位抑制研究，使我们能够有效地鉴定新的抑制物。令人惊讶的是，所有有前景的抑制剂都来自相同的支架 3。其中，最有效和选择性的抑制剂是吡咯烷 19，其 K =0.24 μM，比参考化合物 DAA（K =5.7 μM）约强 24 倍。这是首次全面制备吡咯烷骨架并对α-l-Rha-ase 进行抑制研究的文库。
