Design of Pyrrolidine-Carbamate Self-Immolative Spacers and their Application in Tumour-Targeted Drug Conjugates

Self-immolative (SI) spacers are covalent constructs that remain stable and inactive until triggered by specific stimuli, upon which they undergo a spontaneous disassembly process. The increasing interest for stimuli-responsive platforms has significantly expanded the use of SI spacers across various fields. In particular, they have become key components in the design of prodrugs, antibody–drug conjugates, and numerous controlled drug-delivery and release systems.1 In 2020, our research group developed a pyrrolidine-derived SI spacer that releases a variety of anticancer agents containing either alcohol or phenol functionalities. The release process is driven by a rapid intramolecular cyclization that involves carbamate cleavage and the generation of a bicyclic urea. Owing to its high release efficiency, this spacer demonstrated to be beneficial for the pharmacological performances of protease-activated prodrugs when compared with a widely employed SI spacer belonging to the same category.2 Following these promising results, our research efforts focused on the design and characterization of improved derivatives of this SI spacer,3 as well as on their application in tumour-targeted drug conjugates for subsequent preclinical evaluation. Over the past few years, this class of SI spacers has also attracted the attention of other research groups, which have employed them in the design of efficient drug-release systems. These studies have further demonstrated the versatility of such SI spacers as platforms for the controlled activation and release of drugs containing alcohol functionalities.4 References: 1. A. Alouane, R. Labruère, T. Le Saux, F. Schmidt, L. Jullien, Angew. Chem. Int. Ed. 2015, 54, 7492-7509. 2. A. Dal Corso, V. Borlandelli, C. Corno, P. Perego, L. Belvisi, L. Pignataro, C. Gennari, Angew. Chem. Int. Ed. 2020, 59, 4176-4181. 3. a) A. Dal Corso, S. Arosio, N. Arrighetti, P. Perego, L. Belvisi, L. Pignataro, C. Gennari, Chem. Commun. 2021, 57, 7778-7781; b) A. Dal Corso, M. Frigoli, M. Prevosti, M. Mason, R. Bucci, L. Belvisi, L. Pignataro, C. Gennari, ChemMedChem 2022, 17, e202200279; c) M. Mason, L. Bisbal Lopez, F. Bashiri, A. Herrero, A. Baron, R. Bucci, L. Pignataro, C. Gennari, A. Dal Corso, ChemBioChem 2024, 25, e202400174. 4. a) D. C. Liotta et al. J. Med. Chem. 2023, 66, 5397-5414; b) M. Raj et al. Nat. Commun. 2025, 16, 3780.