Design, Synthesis, and Evaluation of Alkoxyamine Anticancer Prodrugs Bearing Galactoside as an Enzyme-Activated Trigger.
Enzyme-induced cytotoxicity can be considered the main challenge in modern cancer therapy that provides unique opportunities for targeted apoptosis. To address this challenge, we implemented enzyme-triggered activation of alkoxyamine-galactose conjugates with the formation of active carbon-centered radical species for the apoptosis of cancer cells. The comparative analysis of two alkoxyamine derivatives, bearing stable and self-immolative linkers between the radical precursor and galactose moiety, revealed the crucial role of molecular structure in anticancer activity. The study of cytotoxicity and induced oxidative stress of free amine and two galactosides revealed the enzyme-dependent nature of the activity of alkoxyamines having a self-immolative linker against distinct cancer cell lines such as PC-3 (prostate adenocarcinoma), SKOV-3 (ovarian adenocarcinoma), MCF-7 (breast adenocarcinoma), A-431 (epidermoid carcinoma), and Jurkat cells (human T-lymphoblastic leukemia). The collected data prove the applicability of enzyme-triggered glycosylated alkoxyamines as a new family of targeted prodrugs against cancer.