Tris(tetramethylphenanthroline)ruthenium(II): a chiral probe that cleaves A-DNA conformations.

Abstract

A-Tris (3,4,7,8-tetramethyl-1,10-phenanthroline)ruthenium(ll) [A-Ru(TMP)2+] was found to be a distinctive molecular tool to examine the local variations in conformation along the strand. The metal complex binds cooperatively to A-form helices of various base sequences under conditions where little or no binding was found to analogous B-form DNAs. Photoactivated DNA cleavage may be coupled to this conformation-specific binding by taking advantage of the photophysical properties of ruthenium(ll) complexes. ARu(TMP)2+ cleaves preferentially 3H-labeled A-form polynucleotides upon irradiation with visible light. The photoinduced DNA strand scission is likely to be mediated by singlet oxygen, which leads to a preferential cleavage of guanine residues. Comparative mapping of cleavage sites on a linear pBR322 fragment for tris(phenanthroline)ruthenium(II), which binds to B-DNA and cleaves also by sensitization of singlet oxygen, and for Ru(TMP)2 I shows the selective binding of ARu(TMP)2+ to conformationally distinct sites along the fragment. These sites correspond to 5-to 13-base-pair homopyrimidine stretches.It has become increasingly clear that a remarkable conformational heterogeneity may be present along the DNA strand. Local variations in DNA structure include bends, kinks, cruciform loops, and even left-handed Z-DNA (1-5). Segments of altered conformation may serve as recognition sites for the binding of regulatory proteins, and indeed the correlation of conformationally distinct sites with the borders of gene coding regions has been observed (6-9).Small molecules that recognize and react at distinct sites along the DNA strand provide sensitive probes for the local variations in DNA structure. We have focused on chiral metal complexes in developing tools to map local DNA secondary structure (10). A-tris(4,7-diphenyl-1,10-phenanthroline)cobalt(III), for example, has been shown to cleave conformationally distinct sites, such as Z-DNA, and has been used to examine altered conformations along the simian virus 40 genome (6, 7, 11). We have determined that tris(3,4, 7,8-tetramethylphenanthroline)ruthenium(II) [Ru(TMP)"+] binds preferentially to A-form polynucleotides, displays chiral discrimination in its binding, favoring the A-isomer in binding to right-handed helices, and upon photoactivation promotes cleavage of the bound polymer (12). The complex associates with the polymer in a surface or groove-bound mode rather than through intercalation, the primary mode of binding for the parent chiral complex tris(phenanthroline)ruthenium(II) [Ru(phen)2+] (13). We report here the application of Ru(TMP)2+ to synthetic polynucleotides and to probe local A-form sites through photoactivated cleavage. Abbreviations: Ru(TMP)3 +, tris(3,4,7,8-tetramethylphenanthroline)ruthenium(II); Ru(phen)3+, tris(phenanthroline)ruthenium(II).

A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress GeneCHOP

“…It is important to understand the mode of action of anticancer drugs to improve their design and their use in combinatory or tumor-selective treatments. Numerous studies indicated that ruthenium-derived compounds interact with DNA (20)(21)(22), which is consistent with our previous finding that RDCs induce p53 (23). RDC11 can also induce p53 protein levels (Fig.…”

“…Based on the similarities with platinum compounds (19), studies on the mode of action of ruthenium-containing compounds focused on their interaction with DNA (20)(21)(22). Indeed, several ruthenium-containing drugs interact with DNA and modify its structure, suggesting that they might induce DNA damages.…”

DNA binding, cytotoxicity, and apoptotic-inducing activity of ruthenium(II) polypyridyl complex

“…But normal lung cells of MRC-5 were only slightly affected by the interaction of the Ru(II) complex with DNA in contrast to A549 tumor cells in the presence of the Ru(II) complex. It has been reported that the quercetin zinc(II) complex [39], hedamycin [40], and tris(tetramethylphenanthroline) Ru(II) [41] intercalate into the GC-rich core promoter region of survivin, down-regulating surviving gene expression and promoting tumor cells apoptosis. Therefore, we deduced that the Ru(II) complex intercalated into DNA and thereby induced apoptosis in tumor cells.…”

Synthesis, DNA Binding, and DNA Photocleavage of the Ruthenium(II) Complexes [Ru(bpy)(btip)]2+ and [Ru(dmb)(btip)]2+ (bpy = 2,2′‐Bipyridine; btip = 2‐Benzo[b]thien‐2‐yl‐1H‐imidazo[4,5‐f] [1,10]phenanthroline; dmb = 4,4′‐Dimethyl‐2,2′‐bipyridine)

“…It is of interest to note that [Ru(phen) 3 ]Cl 2 has been reported to involve a singletoxygen ( 1 O 2 )-mediated DNA-photocleavage mechanism [42]. To identify the nature of the reactive species responsible for photo-activated cleavage of plasmid DNA, we further investigated the influence of different potentially inhibiting agents.…”