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Updated: Mar 15, 2026
09:54
Synthesis and Characterization of 1,2-Dithiolane Modified Self-Assembling Peptides
Published on: August 20, 2018
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Insights into the activation patterns of 1,2-dithiolane unit in biofunctional molecules
Jintao Zhao1,2,3, Huimin Liu4, Tao Liu2,3
1School of Chemistry and Chemical Engineering, Nanjing University of Science & Technology, Nanjing, Jiangsu, China.
Nature Communications
|March 14, 2026
Summary
The 1,2-dithiolane scaffold shows promise in biofunctional molecule design. Amine-linked designs enhance selectivity for thioredoxin reductase (TrxR) activation, unlike hydroxyl-linked ones susceptible to glutathione (GSH).
Area of Science:
- Chemical biology
- Medicinal chemistry
- Drug discovery
Background:
- The 1,2-dithiolane moiety is a cyclic disulfide with potential in probe design and drug development.
- Challenges exist in achieving selective activation in biological settings due to reactions with abundant low-molecular-weight (LMW) thiols like glutathione (GSH), impacting thioredoxin reductase (TrxR) selectivity.
Purpose of the Study:
- To systematically evaluate the activation behavior of 1,2-dithiolane in biofunctional molecules.
- To determine how cargo linkage (amine vs. hydroxyl) affects TrxR-mediated activation and selectivity.
- To provide guidance for designing 1,2-dithiolane-based probes and drugs.
Main Methods:
- Synthesis of a panel of 1,2-dithiolane prodrugs and fluorescent probes.
- Incorporation of amine- or hydroxyl-linked cargoes.
- Evaluation of TrxR-mediated activation and selectivity in the presence of LMW thiols like GSH.
Main Results:
- TrxR-mediated selective activation of 1,2-dithiolane was achieved with amine-linked cargo frameworks.
- Hydroxyl-linked conjugates showed rapid cleavage by GSH, leading to significant loss of TrxR selectivity.
- The interplay between the 1,2-dithiolane recognition site, linker, and leaving group dictates TrxR activation selectivity.
Conclusions:
- Amine-based frameworks are crucial for achieving selective TrxR activation of 1,2-dithiolane-based biofunctional molecules.
- Hydroxyl-linked designs are less suitable for TrxR-targeted applications due to GSH interference.
- This study clarifies previous findings and offers a conceptual framework for optimizing 1,2-dithiolane scaffold utilization in drug and probe development.
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