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The novel binuclear η6-arene-Ru(II) complexes with the general formula {[(η6-cym)Ru(L)]2(μ-BL)}(PF6)4, and their corresponding water soluble {[(η6-cym)Ru(L)]2(μ-BL)}Cl4, where cym = p-cymene, L = 2,2′-bipyridine (bpy) and 1,10-phenanthroline (phen), BL = 4,4′-bipyridine (BL-1), 1,2-bis(4-pyridyl)ethane (BL-2) and 1,3-bis(4-pyridyl)propane (BL-3), were synthesized and characterized. The structure of {[(η6-cym)Ru(phen)]2(μ-BL-1)}(PF6)4 was determined by X-ray single crystal methods. The interaction of {[(η6-cym)Ru(phen)]2(μ-BL-i)}Cl4 (i = 1, 2, 3; (4), (5) and (6) correspondingly) with the DNA duplex d(5′-CGCGAATTCGCG-3′)2 was studied by means of NMR techniques and fluorescence titrations. The results show that complex (4) binds with a Kb = 12.133 × 103 M−1 through both intercalation and groove binding, while (5) and (6) are groove binders (Kb = 2.333 × 103 M−1 and Kb = 3.336 × 103 M−1 correspondingly). Comparison with the mononuclear complex [(η6-cym)Ru(phen)(py)]2+ reveals that it binds to the d(5′-CGCGAATTCGCG-3′)2 with a Kb value two orders of magnitude lower than (4) (Kb = 0.158 × 103 M−1), indicating that for the binuclear complexes both ruthenium moieties participate in the binding. The complexes were found to be cytotoxic against the A2780 and A2780 res. cancer cell line with a selectivity index (SI) in the range of 3.0–5.9. [ABSTRACT FROM AUTHOR]

Although the interactions of oligopyridine ruthenium complexes with DNA have been widely studied, the biological activity of similar diruthenium oligopyridine complexes conjugated with peptides has not been investigated. Herein, we report the stepwise synthesis and characterization of diruthenium complexes with the general formula [(La)Ru(tppz)Ru(Lb)]n+ (tppz = 2,3,5,6-tetra(2-pyridyl)pyrazine, La = 2,2′:6′,2′′-terpyridine or 4-phenyl-2,2′:6′,2′′-terpyridine and Lb = 2,2′:6′,2′′-terpyridine-4′-CO(Gly1-Gly2-Gly3-LysCONH2) (5), (6), n = 5; 2,2′:6′,2′′-terpyridine-4′-CO(Gly1-Gly2-Lys1-Lys2CONH2) (7), (8), n = 6; 2,2′:6′,2′′-terpyridine-4′-CO(Ahx-Lys1Lys2CONH2) (9), (10), n = 5, Ahx = 6-aminohexanoic acid). The compounds [(trpy)Ru(tppz)Ru(trpy-CO2H)](PF6)4, (2)(PF6)4, [(ptrpy)Ru(tppz)Ru(trpy-CO2H)](PF6)4, (3)(PF6)4 and [(ptrpy)Ru(tppz)Ru(trpy)](PF6)4, (4)(PF6)4 were also characterized by single crystal X-ray methods. Moreover, the interactions of the chloride salts (5), (6) and (4) with the self-complementary dodecanucleotide duplex d(5′-CGCGAATTCGCG-3′)2 were studied by NMR spectroscopic techniques. The results show that complex (4) binds in the central part of the oligonucleotide, from the minor groove through the ligand ptrpy, while the ligand trpy, which was located on the other side of the diruthenium core, does not contribute to the binding. Complex (5) binds similarly, through the ligand ptrpy. However, the induced upfield shifts of the ptrpy proton signals are significantly lower than the corresponding ones in the case of (4), indicating much lower binding affinity. This is clear evidence that the tethered peptide Gly1-Gly2-Gly3-Lys1CONH2 hinders the complex binding, even though it contains groups that are able to assist it (e.g., the positively charged amino group of lysine, the peptidic backbone, the terminal amide). Complex (6) shows a non-specific binding, interacting through electrostatic forces. The chloride salts of (4), (5) and (6) had insignificant effects on the cell cycle distribution and marginal cytotoxicity (IC50 ＞ 750 μM) against human lung cancer cell lines H1299 and H1437, indicating that their binding to the oligonucleotide is not a sufficient condition for their cytotoxicity. [ABSTRACT FROM AUTHOR]

Platinum(ii) complexes of the formula PtLCl2 [L = 2-(2′-pyridyl)quinoxaline, (pqx) (1), 2,(2′-pyridyl)benzo[g]quinoxaline, (pbqx) (3) and 2,(2′-pyridyl)quinoline, (pqn) (5)] were synthesized and characterized by spectroscopic and X-ray diffraction methods. Also, monodentate coordination of the ligands pqx and pbqx formed the complexes trans-Pt(DMSO)pqxCl2 (2) and trans-Pt(DMSO)pbqxCl2 (4) as it is indicated from X-ray crystal structure and NMR studies. The reaction of the complexes (1), (3) and (5) with DMSO-d6 revealed a ligand-release solvolysis, which was studied by means of NMR techniques. Correlation between the crystal structures of (1), (3), and (5) and the kinetic or thermodynamic parameters of the solvolysis reactions showed that the tendency of the ligands pqx, pbqx, and pqn to return to the anti-configuration in addition to their ability to form non-classical H-bonds are crucial factors for the ligand-release solvolysis. Instantaneous DMSO-d6 solvolysis for the complexes (1) and (3) and slow kinetics solvolysis for (5) (k = 10−4± 6.4 × 10−6 s−1) reflect their structural differences in ligand planarity. Based on NMR techniques a two-step mechanism of the chelate ring opening was suggested with equilibrium constants of the overall reaction at 298 K, Keq = 4.1 ± 0.2 × 10−4 M−1 (1) and Keq = 1.7 ± 0.2 × 10−4 M−1 (2). [ABSTRACT FROM AUTHOR]

The synthesis, characterization and DNA binding properties of the complex [Ru(terpy)(4,4′-(COLysCONH2)2bpy)Cl]3+(1) have been studied. Complex (1) hydrolyzes to (2) with a calculated rate constant Kh= 2.35 ± 0.08 × 10−4s−1and binds coordinatively to ct-DNA, with a saturation r-value at about 0.1. Stabilization of the ct-DNA helix at low electrolyte (NaClO4) concentration (10 mM) and destabilization at higher electrolyte concentrations (50–200 mM) was observed. Circular dichroism studies indicate that the hydrolyzed complex binds to DNA, increasing the unwinding of the DNA helix with an unwinding angle calculated as Φ = 12 ± 2°. The positive LD signal observed at 350 nm indicates some kind of specificity in complex orientation towards the global DNA axis. Complex (2) binds specifically to G4 on the central part of the oligonucleotide duplexes d(CGCGCG)2and d(GTCGAC)2, as evidenced by NMR spectroscopy. Both lysine moieties were found to interact most likely electrostatically with the DNA phosphates, assisting the coordinative binding and increasing the DNA affinity of the complex. Photoinduced DNA cleavage by (2), upon UVA irradiation was observed, but despite its relative high DNA affinity, it was incomplete (∼12%). [ABSTRACT FROM AUTHOR]

Diastereomeric oligopyridine–ruthenium(ii)–amino acid conjugated complexes of the general formulas Λ- and Δ-[Ru(bpy)2(4,4′(CO2Y)2-bpy)]2+, where Y = l-AlaCONH2, l-LysCONH2, l-HisCONH2, l-TyrCONH2), were synthesized and characterized. Their binding properties with ct-DNA and the oligonucleotide duplex d(5′CGCGCG-3′)2, by means of circular dichroism (CD), NMR spectroscopy and DNA thermal denaturation (Tm) curves were studied. CD and Tmdata indicate that all diastereomeric complexes bind to the DNA major groove, Δ-diastereomers in a similar manner, while Λ-diastereomers in dependence of the nature of the amino acid. NMR studies of d(5′CGCGCG-3′)2, and the complexes Δ-1, Δ-2, Λ-1and Λ-2indicate that Δ-1and Δ-2were bound having the ancillary bpy ligands towards the DNA groove, while the corresponding Λ-1and Λ-2were orientated in a similar way, facing the ligand 4,4′(CO2Y)2bpy towards the DNA major groove. Photoinduced DNA cleavage was observed in all cases studied, which take place through singlet oxygen production. Δ-4and Λ-4show the lower photoinduced cleavage yield, probably because the singlet oxygen (1O2) oxidizes not only the DNA phosporodiesteric bonds but the tyrosine's phenolic OH bond as well. [ABSTRACT FROM AUTHOR]

The novel binuclear η 6 -arene-Ru(II) complexes with the general formula {[(η 6 -cym)Ru(L)] 2 (μ-BL)}(PF 6 ) 4 , and their corresponding water soluble {[(η 6 -cym)Ru(L)] 2 (μ-BL)}Cl 4 , where cym = p -cymene, L = 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen), BL = 4,4'-bipyridine (BL-1), 1,2-bis(4-pyridyl)ethane (BL-2) and 1,3-bis(4-pyridyl)propane (BL-3), were synthesized and characterized. The structure of {[(η 6 -cym)Ru(phen)] 2 (μ-BL-1)}(PF 6 ) 4 was determined by X-ray single crystal methods. The interaction of {[(η 6 -cym)Ru(phen)] 2 (μ-BL- i )}Cl 4 ( i = 1, 2, 3; (4), (5) and (6) correspondingly) with the DNA duplex d(5'-CGCGAATTCGCG-3') 2 was studied by means of NMR techniques and fluorescence titrations. The results show that complex (4) binds with a K b = 12.133 × 10 3 M -1 through both intercalation and groove binding, while (5) and (6) are groove binders ( K b = 2.333 × 10 3 M -1 and K b = 3.336 × 10 3 M -1 with a 6 -cym)Ru(phen)(py)] 2+ reveals that it binds to the d(5'-CGCGAATTCGCG-3') 2 with a K ), indicating that for the binuclear complexes both ruthenium moieties participate in the binding. The complexes were found to be cytotoxic against the A2780 and A2780 res. cancer cell line with a selectivity index (SI) in the range of 3.0-5.9.b value two orders of magnitude lower than (4) ( K b = 0.158 × 10 3 M -1 ), indicating that for the binuclear complexes both ruthenium moieties participate in the binding. The complexes were found to be cytotoxic against the A2780 and A2780 res. cancer cell line with a selectivity index (SI) in the range of 3.0-5.9.

Although the interactions of oligopyridine ruthenium complexes with DNA have been widely studied, the biological activity of similar diruthenium oligopyridine complexes conjugated with peptides has not been investigated. Herein, we report the stepwise synthesis and characterization of diruthenium complexes with the general formula [(L a )Ru(tppz)Ru(L b )] n+ (tppz = 2,3,5,6-tetra(2-pyridyl)pyrazine, L a = 2,2':6',2''-terpyridine or 4-phenyl-2,2':6',2''-terpyridine and L b = 2,2':6',2''-terpyridine-4'-CO(Gly 1 -Gly 2 -Gly 3 -LysCONH 2 ) (5), (6), n = 5; 2,2':6',2''-terpyridine-4'-CO(Gly 1 -Gly 2 -Lys 1 -Lys 2 CONH 2 ) (7), (8), n = 6; 2,2':6',2''-terpyridine-4'-CO(Ahx-Lys 1 Lys 2 CONH 2 ) (9), (10), n = 5, Ahx = 6-aminohexanoic acid). The compounds [(trpy)Ru(tppz)Ru(trpy-CO 2 H)](PF 6 ) 4 , (2)(PF 6 ) 4 , [(ptrpy)Ru(tppz)Ru(trpy-CO 2 H)](PF 6 ) 4 , (3)(PF 6 ) 4 and [(ptrpy)Ru(tppz)Ru(trpy)](PF 6 ) 4 , (4)(PF 6 ) 4 were also characterized by single crystal X-ray methods. Moreover, the interactions of the chloride salts (5), (6) and (4) with the self-complementary dodecanucleotide duplex d(5'-CGCGAATTCGCG-3') 2 were studied by NMR spectroscopic techniques. The results show that complex (4) binds in the central part of the oligonucleotide, from the minor groove through the ligand ptrpy, while the ligand trpy, which was located on the other side of the diruthenium core, does not contribute to the binding. Complex (5) binds similarly, through the ligand ptrpy. However, the induced upfield shifts of the ptrpy proton signals are significantly lower than the corresponding ones in the case of (4), indicating much lower binding affinity. This is clear evidence that the tethered peptide Gly 1 -Gly 2 -Gly 3 -Lys 1 CONH 2 hinders the complex binding, even though it contains groups that are able to assist it (e.g., the positively charged amino group of lysine, the peptidic backbone, the terminal amide). Complex (6) shows a non-specific binding, interacting through electrostatic forces. The chloride salts of (4), (5) and (6) had insignificant effects on the cell cycle distribution and marginal cytotoxicity (IC 50 > 750 μM) against human lung cancer cell lines H1299 and H1437, indicating that their binding to the oligonucleotide is not a sufficient condition for their cytotoxicity.

Platinum(ii) complexes of the formula PtLCl 2 [L = 2-(2'-pyridyl)quinoxaline, (pqx) (1), 2,(2'-pyridyl)benzo[g]quinoxaline, (pbqx) (3) and 2,(2'-pyridyl)quinoline, (pqn) (5)] were synthesized and characterized by spectroscopic and X-ray diffraction methods. Also, monodentate coordination of the ligands pqx and pbqx formed the complexes trans-Pt(DMSO)pqxCl 2 (2) and trans-Pt(DMSO)pbqxCl 2 (4) as it is indicated from X-ray crystal structure and NMR studies. The reaction of the complexes (1), (3) and (5) with DMSO-d 6 revealed a ligand-release solvolysis, which was studied by means of NMR techniques. Correlation between the crystal structures of (1), (3), and (5) and the kinetic or thermodynamic parameters of the solvolysis reactions showed that the tendency of the ligands pqx, pbqx, and pqn to return to the anti-configuration in addition to their ability to form non-classical H-bonds are crucial factors for the ligand-release solvolysis. Instantaneous DMSO-d 6 solvolysis for the complexes (1) and (3) and slow kinetics solvolysis for (5) (k = 10 -4 ± 6.4 × 10 -6 s -1 ) reflect their structural differences in ligand planarity. Based on NMR techniques a two-step mechanism of the chelate ring opening was suggested with equilibrium constants of the overall reaction at 298 K, K eq = 4.1 ± 0.2 × 10 -4 M -1 (1) and K eq = 1.7 ± 0.2 × 10 -4 M -1 (2).

The synthesis, characterization and DNA binding properties of the complex [Ru(terpy)(4,4'-(COLysCONH(2))(2)bpy)Cl](3+) (1) have been studied. Complex (1) hydrolyzes to (2) with a calculated rate constant K(h) = 2.35 ± 0.08 × 10(-4) s(-1) and binds coordinatively to ct-DNA, with a saturation r-value at about 0.1. Stabilization of the ct-DNA helix at low electrolyte (NaClO(4)) concentration (10 mM) and destabilization at higher electrolyte concentrations (50-200 mM) was observed. Circular dichroism studies indicate that the hydrolyzed complex binds to DNA, increasing the unwinding of the DNA helix with an unwinding angle calculated as Φ = 12 ± 2°. The positive LD signal observed at 350 nm indicates some kind of specificity in complex orientation towards the global DNA axis. Complex (2) binds specifically to G4 on the central part of the oligonucleotide duplexes d(CGCGCG)(2) and d(GTCGAC)(2), as evidenced by NMR spectroscopy. Both lysine moieties were found to interact most likely electrostatically with the DNA phosphates, assisting the coordinative binding and increasing the DNA affinity of the complex. Photoinduced DNA cleavage by (2), upon UVA irradiation was observed, but despite its relative high DNA affinity, it was incomplete (~12%).

Diastereomeric oligopyridine-ruthenium(II)-amino acid conjugated complexes of the general formulas Lambda- and Delta-[Ru(bpy)(2)(4,4'(CO(2)Y)(2)-bpy)](2+), where Y = L-AlaCONH(2), L-LysCONH(2), L-HisCONH(2), L-TyrCONH(2)), were synthesized and characterized. Their binding properties with ct-DNA and the oligonucleotide duplex d(5'CGCGCG-3')(2), by means of circular dichroism (CD), NMR spectroscopy and DNA thermal denaturation (T(m)) curves were studied. CD and T(m) data indicate that all diastereomeric complexes bind to the DNA major groove, Delta-diastereomers in a similar manner, while Lambda-diastereomers in dependence of the nature of the amino acid. NMR studies of d(5'CGCGCG-3')(2), and the complexes Delta-1, Delta-2, Lambda-1 and Lambda-2 indicate that Delta-1 and Delta-2 were bound having the ancillary bpy ligands towards the DNA groove, while the corresponding Lambda-1 and Lambda-2 were orientated in a similar way, facing the ligand 4,4'(CO(2)Y)(2)bpy towards the DNA major groove. Photoinduced DNA cleavage was observed in all cases studied, which take place through singlet oxygen production. Delta-4 and Lambda-4 show the lower photoinduced cleavage yield, probably because the singlet oxygen ((1)O(2)) oxidizes not only the DNA phosporodiesteric bonds but the tyrosine's phenolic OH bond as well.

The complex cis-(Cl,Cl)-[RuCl2(terpy)(NO)]Cl (1) has been synthesized by the reaction of [RuCl3(H2O)2(NO)] with terpyridine (terpy) and characterized by various spectroscopic, analytical techniques and using electronic structure calculation (DFT) methods. The cytotoxic activity and the DNA-binding properties of have also been studied using biochemical techniques. The results establish unequivocally that corresponds to a so-called [RuNO]6 species, which readily releases the nitrosyl ligand upon irradiation with a mercury lamp in acetonitrile solution. DFT calculations provided a satisfactory description of structural, bonding, electronic and related properties of the new compound and throw light on the mechanism of the photo-induced NO release. Screening on A2780 (human ovarian carcinoma) cell lines showed significant cytotoxicity with an IC50 value of 0.49 microM. 31P and 23Na NMR spectroscopy along with electrophoretic mobility studies illustrated that complex primarily binds by coordination to DNA without any pi-interaction between the planar terpy ligand and the DNA bases, while weak electrostatic interactions could not be excluded. Studies on the inhibition of the restriction enzymes DraI and SmaI revealed that prefers the guanine and cytosine bases of DNA.

A general method for the synthesis of chloro(polypyridyl)ruthenium conjugated peptide complexes via a solid-phase strategy is described. The method is applied to synthesize two positional isomers of the complex [Ru(terpy)(4-CO2H-4'-Mebpy-Gly-L-His-L-LysCONH2)Cl](PF6). Even though the separation of the isomers was only partially achieved chromatographically, the isomers were unambiguously assigned by NMR spectroscopy. The interactions of the complex [Ru(terpy)(4-CO2H-4'-Mebpy-Gly-L-His-L-LysCONH2)Cl](PF6) with CT-DNA and plasmid DNA, have been studied with various spectroscopic techniques, showing that (i) the complexes coordinatively bind to DNA preferring the bases guanine and cytosine over the bases thymine and adenine after hydrolysis of the coordinated chloride, (ii) electrostatic interactions between the complex cation and the polyanionic DNA chain assist this binding (iii) only in the case of one isomer the peptide does interact further with DNA as evidenced from 31P NMR spectroscopy, (iv) DNA unwinding occurs in all cases with high binding ratio (Ru/base) values (r > 0.3).