Dataset Information

Stabilization of Long-Looped i-Motif DNA by Polypyridyl Ruthenium Complexes.

ABSTRACT: A spectroscopic study of the interactions of ?- and ?-[Ru(phen)₂(dppz)]²⁺ with i-motif DNA containing thymine loops of various lengths. In the presence of i-motifs, the luminescence of the ? enantiomer was enhanced much more than the ?. Despite this, the effect of each enantiomer on i-motif thermal stability was comparable. The sequences most affected by [Ru(phen)₂(dppz)]²⁺ were those with long thymine loops; this suggests that long-looped i-motifs are attractive targets for potential transition metal complex drugs and should be explored further in drug design.

SUBMITTER: Pages BJ

PROVIDER: S-EPMC6848161 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Stabilization of Long-Looped i-Motif DNA by Polypyridyl Ruthenium Complexes.

Pages Benjamin J BJ Gurung Sarah P SP McQuaid Kane K Hall James P JP Cardin Christine J CJ Brazier John A JA

Frontiers in chemistry 20191105

A spectroscopic study of the interactions of Λ- and Δ-[Ru(phen)2(dppz)]2+ with i-motif DNA containing thymine loops of various lengths. In the presence of i-motifs, the luminescence of the Λ enantiomer was enhanced much more than the Δ. Despite this, the effect of each enantiomer on i-motif thermal stability was comparable. The sequences most affected by [Ru(phen)2(dppz)]2+ were those with long thymine loops; this suggests that long-looped i-motifs are ...[more]

PMID: 31750292

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Project description:The ruthenium(ii) polypyridyl complexes (RPCs), [(phen)2Ru(tatpp)]2+ (32+ ) and [(phen)2Ru(tatpp)Ru(phen)2]4+ (44+ ) are shown to cleave DNA in cell-free studies in the presence of a mild reducing agent, i.e. glutathione (GSH), in a manner that is enhanced upon lowering the [O2]. Reactive oxygen species (ROS) are involved in the cleavage process as hydroxy radical scavengers attenuate the cleavage activity. Cleavage experiments in the presence of superoxide dismutase (SOD) and catalase reveal a central role for H2O2 as the immediate precursor for hydroxy radicals. A mechanism is proposed which explains the inverse [O2] dependence and ROS data and involves redox cycling between three DNA-bound redox isomers of 32+ or 44+ . Cultured non-small cell lung cancer cells (H358) are sensitive to 32+ and 44+ with IC50 values of 13 and 15 μM, respectively, and xenograft H358 tumors in nude mice show substantial (∼80%) regression relative to untreated tumors when the mice are treated with enantiopure versions of 32+ and 44+ (Yadav et al. Mol Cancer Res, 2013, 12, 643). Fluorescence microscopy of H358 cells treated with 15 μM 44+ reveals enhanced intracellular ROS production in as little as 2 h post treatment. Detection of phosphorylated ATM via immunofluorescence within 2 h of treatment with 44+ reveals initiation of the DNA damage repair machinery due to the ROS insult and DNA double strand breaks (DSBs) in the nuclei of H358 cells and is confirmed using the γH2AX assay. The cell data for 32+ is less clear but DNA damage occurs. Notably, cells treated with [Ru(diphenylphen)3]2+ (IC50 1.7 μM) show no extra ROS production and no DNA damage by either the pATM or γH2AX even after 22 h. The enhanced DNA cleavage under low [O2] (4 μM) seen in cell-free cleavage assays of 32+ and 44+ is only partially reflected in the cytotoxicity of 32+ and 44+ in H358, HCC2998, HOP-62 and Hs766t under hypoxia (1.1% O2) relative to normoxia (18% O2). Cells treated with RPC 32+ show up to a two-fold enhancement in the IC50 under hypoxia whereas cells treated with RPC 44+ gave the same IC50 whether under hypoxia or normoxia.

Dataset Information

Stabilization of Long-Looped i-Motif DNA by Polypyridyl Ruthenium Complexes.

Publications

Stabilization of Long-Looped i-Motif DNA by Polypyridyl Ruthenium Complexes.

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