Synthesis of Nitrone‐derived Pyrrolidine Scaffolds and Their Combinatorial Libraries to Develop Selective α‐l‐Rhamnosidase Inhibitors

Abstract

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 Ki=0.24 μM, approximately 24‐fold more potent than the reference compound DAA (Ki=5.7 μM). It is the first study to comprehensively prepare pyrrolidine‐based scaffolds and libraries for inhibition study against α‐l‐Rha‐ase.

A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease

“…We herein planned to adopt the NPICC approach to design and synthesize two new IFG-based scaffolds incorporating a C5a-aminomethyl moiety of different configurations from IFG-typed cyclic nitrone 1, allowing us to rapidly increase chemical space via conjugation with a structurally diverse carboxylic acid library (Fig. 1d) [37][38][39] . The resulting IFG derivatives were assessed for their ability to stabilize GCase and rh-GCase.…”