Uracil–Peptide–Pyrene Conjugates as Cu 2+ ‐Sensitive Probes Targeting DNA, RNA, and Biorelevant Model Membranes

We report a series of uracil‐triazole–pyrene peptidomimetics ( 2 – 4 ) designed to achieve modular geometric control through peptide linkers of varying length and flexibility. All three compounds exhibited submicromolar affinity for ds‐DNA, while compound 4 also showed strong binding to ds‐RNA, demonstrating the advantage of combining a uracil recognition unit with an extended pyrene aromatic surface compared to the Pyr‐Trp reference ligand and the phenanthridine analog 4′ . Structural variations strongly affected Cu(II) coordination. Although Pyr‐Trp bound Cu(II) approximately 1000‐fold more strongly than the short, rigid compound 2 , elongation and increased linker flexibility restored high affinity in 4 . Notably, replacing phenanthridine ( 4′ ) with pyrene ( 4 ) enhanced Cu(II) binding by nearly 100‐fold, highlighting the superior coordination properties of the pyrene scaffold. Cu(II) complexation significantly enhanced nucleic acid binding exclusively for compound 2 , increasing its DNA/RNA affinity 15‐fold. The resulting 2 –Cu(II) complex displayed exceptional selectivity for poly rA–poly rU, exceeding that of the Pyr‐Trp –Cu(II) analog by more than 10‐fold, consistent with uracil‐mediated Hoogsteen‐type recognition. Membrane interactions with POPC MLVs were linker‐dependent, producing fluorescence enhancements of up to 1400% ( 2 ), 650% ( 3 ), and 100% ( 4 ). Together with negligible cytotoxicity, these findings indicate that compounds 2 – 4 represent promising multifunctional platforms for Cu 2+ sensing and photoinduced therapeutic applications.