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A Bioorthogonal Prodrug-Prodrug Strategy for Dual Activation Via Retro-Cope/Cope Elimination
Yan Huang1,2, Fushuang Xiang1,2, Miao Liu1,2
1College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215021, China.
Organic Letters
|May 15, 2026
Summary
This study introduces a novel prodrug-prodrug approach for dual-drug activation in combination therapy. It enables the simultaneous release of a covalent inhibitor and a chemotherapeutic agent for enhanced treatment efficacy.
Area of Science:
- Medicinal Chemistry
- Organic Chemistry
- Pharmacology
Background:
- Bioorthogonal prodrug strategies are crucial for effective combination therapy.
- Current strategies for dual payload activation are limited.
- Developing novel prodrug systems is essential for advancing cancer treatment.
Purpose of the Study:
- To develop a prodrug-prodrug strategy for simultaneous activation of two distinct therapeutic agents.
- To utilize a tandem retro-Cope and Cope elimination for controlled drug release.
- To demonstrate the coactivation of a covalent inhibitor with chemotherapeutics.
Main Methods:
- Design and synthesis of a novel prodrug-prodrug system.
- Employing a tandem retro-Cope and Cope elimination reaction mechanism.
- Investigating the kinetics of the retro-Cope elimination reaction.
- In vitro validation of dual drug coactivation using specific drug examples.
Main Results:
- Successfully developed a prodrug-prodrug strategy for dual payload activation.
- Demonstrated tunable rate constants for the retro-Cope elimination (up to 10^2 M^-1s^-1).
- Established proof of concept for coactivating osimertinib with doxorubicin or CA4.
- Validated the potential for combinational therapy through bioorthogonal chemistry.
Conclusions:
- The developed prodrug-prodrug strategy offers a promising platform for combination therapy.
- This approach allows for precise control over the release of multiple therapeutic agents.
- The strategy holds potential for enhancing the efficacy of cancer treatments by enabling dual-drug delivery.
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