Energetics, conformation, and recognition of DNA duplexes modified by monodentate Ru(II) complexes containing terphenyl arenes.

We studied the thermodynamic properties, conformation, and recognition of DNA duplexes site-specifically modified by monofunctional adducts of Ru(II) complexes of the type [Ru(II)(eta(6)-arene)(Cl)(en)](+), in which arene=para-, meta-, or ortho-terphenyl (complexes 1, 2, and 3, respectively) and en=1,2-diaminoethane. It has been shown (J. Med. Chem. 2008, 51, 5310) that 1 exhibits promising cytotoxic effects in human tumor cells, whereas 2 and 3 are much less cytotoxic; concomitantly with the high cytotoxicity of 1, its DNA binding mode involves combined intercalative and monofunctional (coordination) binding modes, whereas less cytotoxic compounds 2 and 3 bind to DNA only through a monofunctional coordination to DNA bases. An analysis of conformational distortions induced in DNA by adducts of 1 and 2 revealed more extensive and stronger distortion and concomitantly greater thermodynamic destabilization of DNA by the adducts of nonintercalating 2. Moreover, affinity of replication protein A to the DNA duplex containing adduct of 1 was pronouncedly lower than to the adduct of 2. On the other hand, another damaged-DNA-binding protein, xeroderma pigmentosum protein A, did not recognize the DNA adduct of 1 or 2. Importantly, the adducts of 1 induced a considerably lower level of repair synthesis than the adducts of 2, which suggests enhanced persistence of the adducts of the more potent and intercalating 1 in comparison with the adducts of the less potent and nonintercalating 2. Also interestingly, the adducts of 1 inhibited DNA polymerization more efficiently than the adducts of 2, and they could also be bypassed by DNA polymerases with greater difficulty. Results of the present work along with those previously published support the view that monodentate Ru(II) arene complexes belong to a class of anticancer agents for which structure-pharmacological relationships might be correlated with their DNA-binding modes.

Ruthenium(II) arene anticancer complexes with redox-active diamine ligands.

The synthesis and characterization of ruthenium(II) arene complexes of the general formula [(eta(6)-arene)Ru(XY)Z](+), where arene = p-cymene (p-cym), hexamethylbenzene (hmb), or biphenyl (bip), XY = o-phenylenediamine (o-pda), o-benzoquinonediimine (o-bqdi), or 4,5-dimethyl-o-phenylenediamine (dmpda), and Z = Cl, Br, or I, are reported (complexes 1-6). In addition, the X-ray crystal structures of [(eta(6)-p-cym)Ru(o-pda)Cl]PF(6) (1) and [(eta(6)-hmb)Ru(o-bqdi)Cl]PF(6) (3PF(6)) are described. The Ru-N distances in 3PF(6) are significantly shorter [2.033(4) and 2.025(4) A] compared to those in 1 [2.141(2) and 2.156(2) A]. All of the imine complexes (3-5) exhibit a characteristic broad (1)H NMR NH resonance at ca. delta 14-15. Complex 1 undergoes concomitant ligand-based oxidation and hydrolysis (38% after 24 h) in water. The oxidation also occurs in methanol. The iodido complex [(eta(6)-p-cym)Ru(o-bqdi)I]I (4) did not undergo hydrolysis, whereas the chlorido complex 3 showed relatively fast hydrolysis (t(1/2) = 7.5 min). Density functional theory calculations showed that the total bonding energy of 9-EtG in [(eta(6)-p-cym)Ru(o-pda)(9-EtG-N7)](2+) (1EtG) is 23.8 kJ/mol lower than that in [(eta(6)-p-cym)Ru(o-bqdi)(9-EtG-N7)](2+) (3EtG). The greater bonding energy is related to the contribution from strong hydrogen bonding between the NH proton of the chelating ligand and O6 of 9-EtG (1.69 A). A loss of cytotoxic activity was observed upon oxidation of the amine ligand to an imine (e.g., IC(50) = 11 microM for 1 and IC(50) > 100 microM for 3, against A2780 ovarian cancer cells). The relationship between the cytotoxic activity and the solution and solid state structures of the imine and amine complexes is discussed.

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

We have used ion mobility-mass spectrometry combined with molecular modeling for the separation and configurational analysis of three low-molecular-weight isomeric organoruthenium anticancer complexes containing ortho-, meta-, or para-terphenyl arene ligands. The isomers were separated using ion mobility based on traveling-wave technology and the experimentally determined collision cross sections were compared to theoretical calculations. Excellent agreement was observed between the experimentally and theoretically derived measurements.

The contrasting chemistry and cancer cell cytotoxicity of bipyridine and bipyridinediol ruthenium(II) arene complexes.

The synthesis and characterization of ruthenium(II) arene complexes [(eta(6)-arene)Ru(N,N)Cl](0/+), where N,N = 2,2'-bipyridine (bipy), 2,2'-bipyridine-3,3'-diol (bipy(OH)(2)) or deprotonated 2,2'-bipyridine-3,3'-diol (bipy(OH)O) as N,N-chelating ligand, arene = benzene (bz), indan (ind), biphenyl (bip), p-terphenyl (p-terp), tetrahydronaphthalene (thn), tetrahydroanthracene (tha) or dihydroanthracene (dha), are reported, including the X-ray crystal structures of [(eta(6)-tha)Ru(bipy)Cl][PF(6)] (1), [(eta(6)-tha)Ru(bipy(OH)O)Cl] (2) and [(eta(6)-ind)Ru(bipy(OH)(2))Cl][PF(6)] (8). Complexes 1 and 2 exibit CH (arene)/pi (bipy or bipy(OH)O) interactions. In the X-ray structure of protonated complex 8, the pyridine rings are twisted (by 17.31 degrees). In aqueous solution (pH = 2-10), only deprotonated (bipy(OH)O) forms are present. Hydrolysis of the complexes was relatively fast in aqueous solution (t(1/2) = 4-15 min, 310 K). When the arene is biphenyl, initial aquation of the complexes is followed by partial arene loss. Complexes with arene = tha, thn, dha, ind and p-terp, and deprotonated bipyridinediol (bipy(OH)O) as chelating ligands, exhibited significant cytotoxicity toward A2780 human ovarian and A549 human lung cancer cells. Complexes [(eta(6)-bip)Ru(bipy(OH)O)Cl] (7) and [(eta(6)-bz)Ru(bipy(OH)O)Cl] (5) exhibited moderate cytotoxicity toward A2780 cells, but were inactive toward A549 cells. These activity data can be contrasted with those of the parent bipyridine complex [(eta(6)-tha)Ru(bipy)Cl][PF(6)] (1) which is inactive toward both A2780 ovarian and A549 lung cell lines. DFT calculations suggested that hydroxylation and methylation of the bipy ligand have little effect on the charge on Ru. The active complex [(eta(6)-tha)Ru(bipy(OH)O)Cl] (2) binds strongly to 9-ethyl-guanine (9-EtG). The X-ray crystal structure of the adduct [(eta(6)-tha)Ru(bipy(OH)O)(9-EtG-N7)][PF(6)] shows intramolecular CH (arene)/pi (bipy(OH)O) interactions and DFT calculations suggested that these are more stable than arene/9-EtG pi-pi interactions. However [(eta(6)-ind)Ru(bipy(OH)(2))Cl][PF(6)] (8) and [(eta(6)-ind)Ru(bipy)Cl][PF(6)] (16) bind only weakly to DNA. DNA may therefore not be the major target for complexes studied here.

Cytotoxicity, cellular uptake, and DNA interactions of new monodentate ruthenium(II) complexes containing terphenyl arenes.

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.