CYCLIZING SELF-IMMOLATIVE SPACERS ENABLE FAST RELEASE OF HYDROXY GROUPS IN PRO-INFLAMMATORY DRUGS

Cancer therapy with conventional cytotoxic agents is often associated to dose-limiting toxicities and this stimulated an intense research activity aimed at improving the therapeutic window of these drugs through several drug-delivery strategies.[1] In particular, several drug release technologies include the so-called self-immolative (SI) spacers, i.e. synthetic devices designed to undergo spontaneous disassembly in response to specific stimuli.[2] Among the new pharmacologic approaches in oncology, the tumor-targeted delivery of small molecule agonists of Toll-like Receptors 7 and 8 (TLR7/8) is a promising strategy to activate immune cells to eradicate cancer. In this context, we synthesized two analogs of the TLR7/8 agonist Resiquimod[3] and connected their hydroxy groups to different amine-carbamate SI spacers. The cyclative release of the payloads was monitored through incubation of the prodrugs at 37 °C in a DMSO/phosphate buffer (pH 7.5): this analysis showed unveiled a high variability of drug release rates, not only influenced by the molecular structures of the spacers,[4] but also by the type of leaving group. References: 1. R.K. Jain, T. Stylianopoulos, Nat. Rev. Clin. Oncol. 2010, 7, 653. 2. a) A. Alouane, L. Jullien, et al. Angew. Chem. Int. Ed. 2015, 54, 7492; b) A. Dal Corso, C. Gennari et al. Angew. Chem. Int. Ed. 2020, 59, 4176 3. a) S. E. Ackerman et al., Nat. Cancer 2021, 2, 18; b) S. Fang et al., Mol. Pharmaceutics 2022, 19, 9, 3228. 4. A. Dal Corso, M. Frigoli, M. Prevosti, M. Mason, R. Bucci, L. Belvisi, L. Pignataro, C. Gennari, ChemMedChem 2022, 17, e202200279.