Uracil-Peptide-Pyrene Conjugates as Cu²⁺-Sensitive Probes Targeting DNA, RNA, and Biorelevant Model Membranes

Area of Science:

• Supramolecular Chemistry
• Medicinal Chemistry
• Biophysical Chemistry

Background:

• Developing modular peptidomimetics for precise geometric control is crucial for targeted molecular applications.
• Uracil and pyrene moieties offer distinct recognition and coordination properties for nucleic acids and metal ions.
• Understanding structure-activity relationships in peptidomimetics is key for designing advanced functional materials.

Purpose of the Study:

• To synthesize and characterize novel uracil-triazole-pyrene peptidomimetics (compounds 2-4) with varying linker lengths and flexibility.
• To investigate the binding affinities of these compounds to double-stranded DNA (ds-DNA) and double-stranded RNA (ds-RNA).
• To evaluate their copper(II) (Cu(II)) coordination behavior, nucleic acid binding enhancement upon complexation, membrane interactions, and potential applications in sensing and therapy.

Main Methods:

• Synthesis of uracil-triazole-pyrene peptidomimetics with modular peptide linkers.
• Spectroscopic techniques (UV-Vis, fluorescence) to assess DNA/RNA binding and membrane interactions.
• Isothermal titration calorimetry (ITC) or similar methods to quantify Cu(II) binding affinities.
• Cytotoxicity assays to evaluate safety profiles.

Main Results:

• Compounds 2-4 exhibited submicromolar affinity for ds-DNA; compound 4 also bound strongly to ds-RNA.
• Pyrene-based ligands showed superior Cu(II) coordination compared to phenanthridine analogs.
• Cu(II) complexation significantly enhanced nucleic acid binding for compound 2, leading to high selectivity for poly rA-poly rU.
• Linker-dependent membrane interactions were observed, with compound 2 showing a 1400% fluorescence enhancement.

Conclusions:

• Uracil-triazole-pyrene peptidomimetics offer tunable geometric control and exhibit potent nucleic acid binding.
• The pyrene scaffold demonstrates advantageous Cu(II) coordination properties.
• These compounds, particularly in their Cu(II) complexes, show promise as multifunctional platforms for Cu2+ sensing and photoinduced therapeutic applications with low cytotoxicity.