Cytotoxicity, Cellular Uptake, and DNA Interactions of New Monodentate Ruthenium(II) Complexes Containing Terphenyl Arenes

Abstract

We have compared the cancer cell cytotoxicity, cell uptake, and DNA binding properties of the isomeric terphenyl complexes [(eta(6)-arene)Ru(en)Cl](+), where the arene is ortho- (2), meta- (3), or para-terphenyl (1) (o-, m-, or p-terp). Complex 1, the X-ray crystal structure of which confirms that it has the classical "piano-stool" geometry, has a similar potency to cisplatin but is not cross-resistant and has a much higher activity than 2 or 3. The extent of Ru uptake into A2780 or A2780cis cells does not correlate with potency. Complex 1 binds to DNA rapidly and quantitatively, preferentially to guanine residues, and causes significant DNA unwinding. Circular and linear dichroism, competitive binding experiments with ethidium bromide, DNA melting, and surface-enhanced Raman spectroscopic data are consistent with combined intercalative and monofunctional (coordination) binding mode of complex 1. This unusual DNA binding mode may therefore make a major contribution to the high potency of complex 1.

Energetics, Conformation, and Recognition of DNA Duplexes Modified by Monodentate RuII Complexes Containing Terphenyl Arenes

“…In contrast, complex 2, which is much less cytotoxic, binds to DNA through only a monofunctional coordination to DNA bases. Therefore, the results of our initial work [13] have further supported the view that the presence of the -m-terphenyl)] + (2) to elucidate in detail the DNA-binding mode of these Ru II arene complexes. We compare previously obtained cytotoxicity data [13] with new data obtained in the present work on conformational distortions induced by single, site-specific monofunctional adducts of the Ru II in short oligodeoxyribonucleotide duplexes, associated alterations in the thermodynamic stability of these duplexes, recognition and repair of these adducts by two specific proteins, that is, the important factors that modulate the antitumor effects of antitumor metallodrugs already used in clinic.…”

“…Complexes 1 and 2 were selected for an initial study focused on global modification of natural, high-molecular-mass DNA. [13] The results of this study have revealed that, concomitant with the relatively high cytotoxicity of 1 in tumor cells, its DNA-binding mode involves combined intercalative and monofunctional (coordination) binding modes. In contrast, complex 2, which is much less cytotoxic, binds to DNA through only a monofunctional coordination to DNA bases.…”

“…[13] Importantly, the complex containing para-terphenyl as the arene ligand (complex 1) exhibits promising cytotoxic effects in several human tumor cell lines, including those resistant to conventional cisplatin. In contrast, complexes containing meta-or ortho-terphenyl arene ligands (complexes 2 and 3, respectively) are much less cytotoxic.…”

“…Some of these Ru II complexes, in particular those containing multi-A C H T U N G T R E N N U N G ring arenes, bind to DNA not only through coordination to the N7 atoms of guanine (G), but also noncovalently through hydrophobic interactions between the arene and DNA. [9,10,13] These hydrophobic interactions might include intercalation of the noncoordinated arenes between DNA bases and minor-groove binding.…”

Isomer separation and gas-phase configurations of organoruthenium anticancer complexes: Ion mobility mass spectrometry and modeling

“…The difference in conformation of 1 (more elongated) compared with that of 2 and 3 (more compact) correlates with the different (increased) anticancer activity of 1 compared with the other two complexes [15]. See Section S3 of the supplementary material for further discussion.…”