Precursors of Carboximidates Deriving from Thioamide-Trimethyl-Lock System: A General Method for Designing Stable Cascade Acid-Sensitive Prodrugs

We report a cascade acid-sensitive prodrug design strategy utilizing a thioamide-trimethyl-lock system. This approach successfully balances prodrug stability and high acid sensitivity, enabling precise drug release in acidic microenvironments. The thioamide system further acts as a hydrogen sulfide (H₂S) donor, providing organ-protective effects. In vivo studies in a mouse MCAO stroke model and a 4T1 breast tumor model confirmed significant therapeutic efficacy, including reduced toxicity, enhanced tumor inhibition, and improved safety. Histological analysis revealed minimized systemic toxicity, particularly cardiotoxicity, compared to conventional treatments. This robust and versatile cascade acid-sensitive design has broad applications in chemical biology and drug delivery.