Metallointercalators as Probes of DNA Recognition and Reactions

Abstract

Here we describe studies of metallointercalators bound to DNA. These octahedral transition metal complexes primarily bind noncovalently by stacking within the DNA helix. Given the rich photophysics and photochemistry of the ruthenium and rhodium complexes we employ, we have used a variety of biophysical studies to characterize their interactions with DNA. X‐ray crystallography has also provided atomic resolution detail as to their binding to the duplex. Complexes have been designed that target DNA with high specificity. We have, for example, designed metal complexes that bind specifically to mismatched sites in the DNA duplex, and these have found application in the detection of single nucleotide polymorphisms and studies of mismatch repair deficiency. The photophysical properties of the metal complexes along with their intercalative stacking have been useful in particular as tools to characterize long‐range charge transport in DNA. Using metallointercalators tethered to the duplex, oxidative damage to DNA from a distance has been demonstrated. The metallointercalators may serve as models for DNA‐binding proteins, not only in binding DNA sites with high specificity, but also in carrying out electron transfer chemistry mediated by the DNA base‐pair stack. Certainly these metallointercalators have proven to be powerful probes of this chemistry.

Regression of Lung Cancer by Hypoxia-Sensitizing Ruthenium Polypyridyl Complexes

“…(18, 33) This low reduction potential means that RPCs are readily reduced by common cellular reductants, and we have shown that these reductions are centered on the tatpp ligand, not the Ru(II) ion, with concomitant formation of a carbon radical species. Because RPCs 3 2+ and 4 4+ as well as related complexes 2 4+ , [Ru(phen) 2 (dppz)] 2+ , and [Ru(phen) 2 (tpphz)] 2+ , are known to bind DNA via intercalation,(18) the tatpp carbon radical in the reduced species is in intimate contact with the DNA. We hypothesize that H atom abstraction from the deoxyribose unit as the likely mechanism of DNA damage.…”

“…These findings concur with the known subcellular localization of these compounds in the nucleus and mitochondria, and with previous studies of RPC 3 2+ and 4 4+ that binds DNA tightly (K b ~ 10 8 M −1 , in vitro ) via an intercalative mode, (45, 46) typical for RPCs with large planar aromatic rings. (18) Indeed, analysis of the whole cell (wc) and nuclear fractions (nf) of RPC treated (5 µM) H-358 cells for uptake of ruthenium by graphite furnace atomic absorption spectroscopy, a showed early concentration spikes in the nf. After 1 h incubation, cells revealed [Ru] of ~7 µg RPC/mg wc and ~27 µg RPC/mg nf for both Δ- 3 2+ and ΔΔ- 4 4+ .…”

“…(17) The 3,4,7,8-tetramethyl-1,10-pheanthroline derivative of 1 2+ was among the most cytotoxic of the derivatives found and was shown to inhibit the growth of dispersed tumor cells (Landshultz ascites) in mice. (14) Since these early studies, there have been numerous studies exploring the DNA-binding activity of RPCs (18) and to a lesser extent the cytotoxicity of RPCs,(19–23) however, the anti-cancer activity of these complexes in vivo has not been extensively studied. The paucity of follow up studies is due, in part, to their observed neurotoxicity, as 1 2+ has been shown to be a competitive inhibitor of acetyl cholinesterase (AChE) both in vitro and in vivo.…”

Luminescent Ir(III) Complex Exclusively Made of Polypyridine Ligands Capable of Intercalating into Calf-Thymus DNA

“…Design of luminescent metal complexes capable of intercalating between DNA base pairs is an extensively investigated topic. , Specific interaction of metal complexes with DNA strands, coupled with modification of luminescence outputs, allows such systems to efficiently perform the function of probes of DNA sites. Moreover, beside the probing function, interaction of photoactive metal complexes with DNA can also yield information on the DNA electron/hole transport ability, , obtain photoreactions involving DNA sites, leading to specific DNA damage, , and assemble elaborate, interesting supramolecular architectures …”

Cellular and cell-free studies of catalytic DNA cleavage by ruthenium polypyridyl complexes containing redox-active intercalating ligands

“…More recently, the DNA-binding and molecular-light switch behavior of [Ru(phen) 2 (dppz)] 2+ ( 6 2+ ) 37 and [Ru(phen) 2 (tpphz)] 2+ ( 7 2+ ) 38 , 39 has led to a resurgence in this area, with numerous studies of their uses as biological probes 40 – 45 and the inherent (non-light activated) cytotoxicity of RPCs. 34 , 39 , 43 , 46 – 54 Because of the tendency of RPCs to bind DNA, it is often assumed that this is the biological target, 55 – 58 although recent data reveal that other cellular organelles are sometimes targeted, including the mitochondria, 46 , 52 , 54 , 59 – 64 endoplasmic reticulum, 42 ribosomes 65 and cell membrane.…”