Title
Porphyrin Bound to i-motifs: Intercalation versus External Groove Binding
Author
Tingxiao Qin, Kunhui Liu, Di Song, Chunfan Yang, Hongmei Su
Year
2017
Journal
Chemistry An Asian Journal
Abstract
G-rich and C-rich DNA can fold into the tetrastranded helical structures G-quadruplex or C-quadruplex (i-motif) that are considered as specific drug targets for cancer therapy. A large number of small molecules (the so-called ligands), which could bind and modulate the stability of G-quadruplexes structures, have been widely examined. Hitherto, much less is known for the ligand binding interactions with the relatively young C-quadruplex (i-motif). Here by combining steady-state measurements (UV-vis, fluorescence, and ICD) with time-resolved laser flash photolysis spectroscopy, we study the binding interactions of cationic porphyrin (TMPyP4) with i-motifs (C₃TA₂)₃C₃T and (C₄A₄C₄)2. The intercalation binding mode via π-π stacking of porphyrin macrocyle and the C:C+ hemiprotonated base-pair has been identified for the first time. The coexisted binding modes of intercalation (~80%) versus external major groove binding (~20%) are determined quantitatively, allowing a full picture understanding of the porphyrin/i-motif interactions. Ionic strength is found to play important roles affecting the binding modes, with the progressive increase of the ionic strength resulting in gradual decrease of the intercalation percentage and increase of groove binding percentage. Further, extended study for the porphyrin derivative with four bulky side arm substituents (T4), suggests a complete prohibition of the intercalation mode due to large steric hindrance, and thus providing a novel groove-binding ligand with site selectivity. These results provide in-depth mechanistic insights for understanding the ligand interactions with i-motifs and guidance for related applications in anticancer drug design.
Instrument
J-815
Keywords
Circular dichroism, Induced CD, DNA structure, Ligand binding, Biochemistry, Pharmaceutical