Regioselective synthesis and anticancer evaluation of H2O2-activable nucleosides
Ying-Jie Sun1, Li Liu1, Liang Cheng1
1Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. chengl@iccas.ac.cn and University of Chinese Academy of Sciences, Beijing 100049, China.
Chemical Communications (Cambridge, England)
|May 28, 2020
Summary
Researchers developed novel hydrogen peroxide (H2O2)-activatable nucleosides. A gemcitabine prodrug showed rapid activation, low toxicity, and improved anticancer effects in cell lines.
Area of Science:
- Medicinal Chemistry
- Drug Delivery
- Biochemistry
Background:
- Hydrogen peroxide (H2O2) is a key signaling molecule in biological systems.
- Developing targeted drug delivery systems that respond to specific biomarkers like H2O2 is crucial for enhancing therapeutic efficacy and reducing side effects.
- Nucleoside analogs are important in cancer chemotherapy, but their systemic administration can lead to significant toxicity.
Purpose of the Study:
- To design and synthesize novel H2O2-activatable nucleosides.
- To develop a regioselective functionalization method for unprotected nucleoside precursors.
- To evaluate the biological activity and anticancer potential of a H2O2-responsive gemcitabine prodrug.
Main Methods:
- Efficient and regioselective functionalization of unprotected nucleoside precursors.
- Synthesis of H2O2-activatable nucleoside analogs.
- Biological evaluation of a H2O2-specific responsive prodrug of gemcitabine in cancer cell lines.
- Assessment of activation kinetics, toxicity, and anticancer efficacy.
Main Results:
- Successful design and synthesis of H2O2-activatable nucleosides.
- Demonstration of an efficient and regioselective functionalization strategy.
- The gemcitabine prodrug exhibited extremely fast activation in the presence of H2O2.
- The prodrug showed low toxicity and enhanced anticancer effects in two tested cell lines.
Conclusions:
- H2O2-activatable nucleosides represent a promising strategy for targeted cancer therapy.
- The developed prodrug approach allows for rapid and specific drug release.
- This technology has the potential to improve the therapeutic index of nucleoside-based anticancer drugs.
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