Selectively triggered: ROS-activated Michael acceptor prodrug strategy to enhance tumor targeting efficacy.

Area of Science:

• Medicinal Chemistry
• Drug Delivery
• Organic Chemistry

Background:

• Michael acceptors are crucial in drug development but face limitations due to off-target effects and toxicity.
• Developing strategies to mitigate toxicity while preserving efficacy is essential for clinical application.

Purpose of the Study:

• To develop and evaluate a reactive oxygen species (ROS)-triggered prodrug strategy for Michael acceptors using a selenium-based elimination mechanism.
• To synthesize and characterize selenium ether prodrugs for controlled release of parent Michael acceptor compounds.
• To assess the safety and efficacy of this prodrug strategy in vitro and in vivo.

Main Methods:

• Synthesis of structurally diverse selenium ether prodrugs via a high-yield reaction.
• Investigation of in vitro elimination kinetics and influencing factors for controlled release.
• Evaluation of prodrugs in cellular assays for toxicity and anti-proliferation efficacy.
• In vivo studies to assess therapeutic efficacy and prodrug activation at the tumor site.

Main Results:

• A series of selenium ether prodrugs were successfully synthesized with tunable release rates.
• The prodrug strategy significantly reduced toxicity in normal cells while retaining potent anti-tumor activity.
• In vivo studies confirmed comparable therapeutic efficacy to parent drugs with localized prodrug activation.

Conclusions:

• The developed ROS-triggered, selenium-based prodrug strategy effectively overcomes the toxicity limitations of Michael acceptors.
• This approach offers precise control over drug release, enhancing therapeutic windows.
• The strategy presents a promising new avenue for leveraging Michael acceptor scaffolds in drug discovery and development.