Abstract
Despite significant scientific advances and the wide variety of available treatments,
cancer remains a major cause of death worldwide. Chemotherapy, which is frequently
one of the first-line treatments, frequently suffers from low selectivity to cancer
cells, leading to the appearance of important side effects. Thus, it becomes imperative
to develop a new generation of targeted alternatives that spare the healthy tissues
by delivering the cytotoxic payloads safely and selectively to cancer cells. In this
respect, prodrugs that are activated by tumor-specific stimuli have attracted significant
attention. Despite being a hallmark of cancer and present in high concentrations in
cancer cells, reactive oxygen species (ROS) have been rather underexplored as a stimulus
for the preparation of targeted prodrugs, particularly when compared with an acidic
pH or glutathione. Despite their lower expression, ROS have recently been gaining
substantial consideration, with various ROS-responsive prodrugs already reported with
meaningful performances both in vitro and in vivo. This review aims to provide critical
insights into this strategy by discussing the various available functional groups
(with an important focus on boronic acids and their esters), their mechanisms of action,
examples of their applications, advantages, limitations, and future challenges.
1 Introduction
2 Boronic Acids and Boronate Esters
2.1 Histone Deacetylase Inhibitors
2.2 DNA Alkylating Agents
2.3 Selective Estrogen Receptor Modulators and Selective Estrogen Receptor Degraders
2.4 ROS Inducers
2.5 Prodrugs Based on Other Types of Anticancer Drugs
3 Other ROS-Responsive Moieties
3.1 Thiazolidinones
3.2 1,3-Oxathiolanes
3.3 Selenium Ethers
3.4 Sulfur-Containing ROS-Responsive Moieties
4 Summary and Future Perspectives
Key words
boronic acids - cancer therapy - medicinal chemistry - reactive oxygen species - prodrugs
- chemotherapy
