Mutual prodrugs containing bio-cleavable and drug releasable disulfide linkers

• We have reported novel mutual prodrugs containing drug-releasable disulfide linkers.
• Drug release in simulated gastric fluid and human plasma was studied.
• Plausible mechanisms of drug release from these mutual prodrugs have been proposed.
• Mechanistic studies have been conducted to support the proposed release mechanism.

We report herein the design and synthesis of several representative examples of novel mutual prodrugs containing nine distinct types of self-immolative drug-releasable disulfide linkers with urethane, ester, carbonate, or imide linkages between the linker and any two amine/amide/urea (primary or secondary) or carboxyl or hydroxyl (including phenolic)-containing drugs. We also report drug release profiles of a few representative mutual prodrugs in biological fluids such as simulated gastric fluid and human plasma. We also propose plausible mechanisms of drug release from these mutual prodrugs. We have also conducted a few mechanistic studies based on suggested sulfhydryl-assisted cleavage of mutual prodrugs and characterized a few important metabolites to give support to the proposed mechanism of drug release from the reported mutual prodrugs.

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