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Updated: Aug 8, 2026
09:06
Preparation of DNA-crosslinked Polyacrylamide Hydrogels
Published on: August 27, 2014
Intercalation-enhanced "Click" Crosslinking of DNA
Masayuki Tera1,2, Zahra Harati Taji1, Nathan W Luedtke1
1Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
Angewandte Chemie (International Ed. in English)
|September 22, 2018
Summary
A novel DNA cross-linking agent, DiMOC, intercalates into DNA and rapidly forms interstrand crosslinks (ICLs) via a strain-promoted double click reaction. This method enhances bioorthogonal reactions within living cells, offering a new strategy for targeted therapies.
Area of Science:
- Chemical Biology
- Medicinal Chemistry
- Molecular Biology
Background:
- DNA-DNA cross-linking agents are vital chemotherapeutics but cause side effects due to non-specific reactions.
- Developing targeted DNA cross-linking agents with improved efficacy and reduced toxicity is crucial.
Purpose of the Study:
- To develop a novel cationic Sondheimer diyne derivative, DiMOC, for targeted DNA cross-linking.
- To investigate the mechanism of DiMOC-induced DNA interstrand crosslinks (ICLs).
- To demonstrate intercalation-enhanced bioorthogonal reactions within living cells.
Main Methods:
- Synthesis and characterization of the cationic Sondheimer diyne derivative (DiMOC).
- Investigation of DiMOC's interaction with DNA, including intercalation and cross-linking kinetics.
- Cellular studies involving metabolic incorporation of azide-containing nucleosides and subsequent DiMOC treatment.
Main Results:
- DiMOC exhibits weak, reversible intercalation into duplex DNA (Kd = 15 μm).
- DiMOC rapidly forms DNA-DNA interstrand crosslinks (ICLs) with azide-containing DNA (kapp = 2.1×10^5 M^-1 s^-1), a 21,000-fold enhancement over nucleoside reactions.
- Low cytotoxicity of single agents, but high toxicity observed upon metabolic incorporation of azide groups followed by DiMOC treatment, generating DNA-DNA ICLs.
Conclusions:
- DiMOC enables intercalation-enhanced bioorthogonal chemical reactions on DNA.
- The study presents the first strain-promoted double click (SPDC) reactions within living cells.
- This approach offers a promising strategy for developing targeted chemotherapeutics with enhanced efficacy.
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