Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, I, -20133, Milan, Italy.
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via G. Venezian 21, 20133, Milan, Italy.
Chembiochem. 2024 Apr 16;25(8):e202400174. doi: 10.1002/cbic.202400174. Epub 2024 Mar 14.
Self-immolative (SI) spacers are degradable chemical connectors widely used in prodrugs and drug conjugates to release pharmaceutical ingredients in response to specific stimuli. Amine-carbamate SI spacers are particularly versatile, as they have been used to release different hydroxy cargos, ranging from 2° and 3° alcohols to phenols and oximes. In this work, we describe the ability of three amine-carbamate SI spacers to release three structurally similar imidazoquinoline payloads, bearing either a 1°, a 2° or a 3° alcohol as the leaving group. While the spacers showed comparable efficacy at releasing the 2° and 3° alcohols, the liberation of the 1° alcohol was much slower, unveiling a counterintuitive trend in nucleophilic acyl substitutions. The release of the 1° alcohol payload was only possible using a SI spacer bearing a pyrrolidine ring and a tertiary amine handle, which opens the way to future applications in drug delivery systems.
自毁（SI）间隔物是可降解的化学连接物，广泛应用于前药和药物偶联物中，以响应特定刺激释放药物成分。胺基碳酸酯 SI 间隔物特别多用途，因为它们已被用于释放不同的羟基负荷物，范围从 2°和 3°醇到酚和肟。在这项工作中，我们描述了三个胺基碳酸酯 SI 间隔物释放三个结构相似的咪唑并喹啉有效负载的能力，这些有效负载带有作为离去基团的 1°、2°或 3°醇。虽然间隔物在释放 2°和 3°醇方面表现出相当的功效，但 1°醇的释放要慢得多，揭示了亲核酰取代反应中的一种反直觉趋势。只有使用带有吡咯烷环和叔胺手柄的 SI 间隔物才能释放 1°醇有效负载，这为药物传递系统的未来应用开辟了道路。
