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Reactivity Modulation of Reactive OFF-ON Type G-Quadruplex Alkylating Agents
Yutong Chen1,2, Kazumitsu Onizuka1,2,3, Madoka E Hazemi1,2
1Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan.
Bioconjugate Chemistry
|October 31, 2022
Summary
Researchers developed novel OFF-ON alkylating agents for targeting G-quadruplex (G4) DNA and RNA. These agents offer tunable reactivity for applications in cancer chemotherapy and chemical biology, showing excellent storage stability.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Molecular Biology
Background:
- Alkylating agents are crucial in cancer chemotherapy and chemical biology.
- Modulating reactivity of alkylating agents towards specific nucleic acid structures like G-quadruplexes (G4) is challenging.
- Existing methods lack precise control over reactivity and stability.
Purpose of the Study:
- To develop novel OFF-ON type alkylating agents with tunable reactivity.
- To investigate the modulation of reactivity towards G-quadruplex (G4) DNA and RNA.
- To engineer agents with improved storage stability and controlled release.
Main Methods:
- Synthesis of vinyl quinazolinone (VQ) precursors with diverse amine leaving groups.
- Investigation of protonation-accelerated reaction mechanisms.
- Utilizing equilibrium elimination methods for reactivity control.
Main Results:
- A series of reactive OFF-ON alkylating agents were successfully synthesized.
- Demonstrated tunable reactivity modulation towards G-quadruplex (G4) DNA and RNA.
- Amine leaving groups exhibited high reactivity and excellent storage stability.
Conclusions:
- The developed VQ precursors represent a new class of tunable alkylating agents.
- These agents show significant potential for cancer chemotherapy and chemical biology applications.
- The protonation-accelerated and equilibrium elimination methods enable precise control over reactivity.
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