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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
PubMed

Insights

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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