Supramolecular Approach to Enantioselective DNA Recognition Using Enantiomerically Resolved Cationic 4‑Amino-1,8-naphthalimide-Based Tröger’s Bases

The
synthesis and photophysical studies of two cationic Tröger’s
base (TB)-derived bis-naphthalimides 1 and 2 and the TB derivative 6, characterized by X-ray crystallography,
are presented. The enantiomers of 1 and 2 are separated by cation-exchange chromatography on Sephadex C25
using sodium (−)-dibenzoyl-l-tartarate as the chiral
mobile phase. The binding of enantiomers with salmon testes (st)-DNA
and synthetic polynucleotides are studied by a variety of spectroscopic
methods including UV/vis absorbance, circular dichroism, linear dichroism,
and ethidium bromide displacement assays, which demonstrated binding
of these compounds to the DNA grooves with very high affinity (K ∼ 106 M–1) and preferential
binding of (−)-enantiomer. In all cases, binding to DNA resulted
in a significant stabilization of the double-helical structure of
DNA against thermal denaturation. Compound (±)-2 and its enantiomers possessed significantly higher binding affinity
for double-stranded DNA compared to 1, possibly due to
the presence of the methyl group, which allows favorable hydrophobic
and van der Waals interactions with DNA. The TB derivatives exhibited
marked preference for AT rich sequences, where the binding affinities
follow the order (−)-enantiomer > (±) > (+)-enantiomer.
The compounds exhibited significant photocleavage of plasmid DNA upon
visible light irradiation and are rapidly internalized into malignant
cell lines.