Fine-tuning phenoxy silyl scaffolds for the development of glutathione-responsive prodrugs and antibody–drug conjugates

Abstract

Silyl ether is particularly attractive for application in drug development for its easy preparation, non-toxicity and remarkable biocompatibility. Earlier studies relied on the use of intracellular acidic conditions to induce the cleavage of alkoxy silyl ethers. However, acidic conditions are not suitable to trigger the release of phenoxy silyl ethers, since they are more stable under acidic conditions compared with neutral conditions. We explored the vulnerability of the phenoxy silyl ether towards biological nucleophilic reagents and found that glutathione (GSH) could effectively and selectively induce the cleavage of phenoxy silyl ether. We also demonstrated that the rate of cleavage was controllable by adjusting the substituents on the phenyl ring. Phenoxy silyl ether-based prodrugs and antibody–drug conjugates (ADCs) were designed and synthesized, which could be effectively activated in cells with high GSH levels and there was an obvious therapeutic window between cells with different GSH levels.