Related Experiment Video
Updated: Jun 16, 2026
05:32
In Vitro Chemical Mapping of G-Quadruplex DNA Structures by Bis-3-Chloropiperidines
Published on: May 12, 2023
Chirality affects biological activity and interactions of azacryptands with alternative DNA structures
Jaroslav Malina1, Hana Kostrhunova1, Jakub Cervinka1
1Czech Academy of Sciences, Institute of Biophysics, CZ-61200 Brno, Czech Republic.
Bioorganic Chemistry
|June 13, 2026
Summary
Chiral azacryptands show selective DNA three-way junction (3WJ) binding. The (R,R)-enantiomer of 4,4'-TrisBP demonstrated superior anticancer activity and DNA damage induction in cancer cells.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Molecular Biology
Background:
- Azacryptands are ligands targeting alternative DNA structures like three-way junctions (3WJs).
- Stabilizing 3WJs in cancer cells can induce DNA damage and cell death.
- Previous azacryptands were achiral, limiting understanding of stereospecific interactions.
Purpose of the Study:
- Investigate chiral azacryptands for DNA binding affinity and selectivity.
- Determine the influence of chirality on azacryptand interactions with DNA 3WJs, bulges, and G-quadruplexes (G4s).
- Evaluate the biological activity and therapeutic potential of enantiomeric azacryptands.
Main Methods:
- Synthesis of chiral azacryptands from a valine-based derivative of tris(2-aminoethyl)amine (TREN).
- Assessing binding affinity and selectivity for DNA 3WJs, bulges, and G4s using biophysical methods.
- Evaluating antiproliferative activity against human cancer cells and toxicity toward normal cells.
- Investigating DNA damage induction and gene expression changes (c-MYC) at cellular level.
Main Results:
- All chiral azacryptands selectively stabilized fully base-paired DNA 3WJs.
- 4,4 -TrisBP enantiomers stabilized 3WJs with unpaired nucleotides and DNA bulges.
- (R,R)-enantiomers of 4,4 -TrisBP and TrisPOB showed stronger 3WJ stabilization than (S,S)-enantiomers.
- (R,R)-4,4 -TrisBP arrested DNA polymerization on G4 templates and exhibited enhanced antiproliferative activity against cancer cells with low toxicity.
- Chirality significantly impacted DNA interaction and biological activity, with (R,R)-4,4 -TrisBP showing superior efficacy.
Conclusions:
- Chirality is a critical factor in azacryptand-DNA interactions and biological outcomes.
- (R,R)-4,4 -TrisBP represents a promising chiral drug candidate for cancer therapy.
- Stereospecific design of azacryptands can optimize DNA-targeting drug development.
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