Selective Recognition of G‐Quadruplex DNAs by Protoporphyrin IX: NMR Insights into 3′‐Terminal G‐Quartet Binding

Protoporphyrin IX (PPIX), a naturally occurring porphyrin, exhibits selective molecular recognition of G‐quadruplex (G4) DNA structures. Herein, the binding behavior toward all‐parallel G4 DNAs is investigated using NMR spectroscopy. PPIX is found to selectively bind to the 3′‐terminal G‐quartets of tetrameric [d(TTAGGG)] 4 (6mer) and monomeric d(TAGGGTGGGTTGGGTGIG) (18mer(G17I)), forming stable 1:1 complexes with binding constants around 1 μM −1 . In contrast, only minimal spectral changes of PPIX are observed in the presence of [d(TTAGGGT)] 4 (6mer/T), suggesting that the 3′‐terminal thymine impedes complex formation. These findings represent the first NMR‐based structural characterization of PPIX–G4 DNA complexes and provide new insights into the molecular determinants of porphyrin selectivity for G‐quadruplex targets, which may contribute to the development of porphyrin‐based G‐quadruplex targeting agents.