Cytotoxic Ruthenium(II) Complexes Containing a Dangling Pyridine: Selectivity for Diseased Cells Mediated by pH-Dependent DNA Binding.

Ruthenium(II) complexes of the type [Ru(bpy)2(L1/L2/L3)]PF6 [where bpy = 2,2'-bipyridine, H(L1) = N-(pyrid-2-yl)salicylaldimine (1), H(L2) = N-(6-methylpyrid-2-yl)salicylaldimine (2), and H(L3) = N-(4,6-dimethylpyrid-2-yl)salicylaldimine (3)] have been isolated. The X-ray structures of 1-3 reveal distorted octahedral coordination geometry with a planar ruthenium phenolate moiety. They exhibit interpair dimeric association in their solid state such as (a) π-π-stacking interactions (1-3) and (b) C-H···π interactions (2). The 1H NMR spectral data shed light on the characteristics of metal-ligand bonding and chelate ring conformations. The complexes exhibit strong metal-to-ligand charge-transfer transitions in the visible region. The complexes also undergo two successive metal-based oxidative processes corresponding to the RuII/RuIII and RuIII/RuIV couples. Resonance Raman studies strongly suggest that the lowest unoccupied molecular orbital of 1-3 is localized at the bpy ligand. Absorption, emission, and circular dichroic spectral measurements for 1-3 with calf-thymus DNA reveal a groove binding mode of interaction. Interestingly, all of the complexes exhibit pH-dependent DNA damage, and the pH at which the damage is highest corresponds to the pH conditions of the cancer cells. The DNA damage is in the order of 3 > 2 > 1, in which a hydrolytic mechanism dominates. The protein binding properties of the complexes examined by the tryptophan quenching measurements suggest a static mechanism. The positive ΔH and ΔS values indicate that the force acting between the complexes and bovine serum albumin (BSA) is mainly a hydrophobic interaction, and thus BSA may act as a targeted drug-delivery vehicle for ruthenium(II) complexes (K ∼ 105). It is noteworthy that 3 exhibits selectivity with high cytotoxicity against breast cancer cells (EVSA-T and MCF-7), and its potency is comparable to that of cisplatin.

Fate of model complexes with monocopper center towards the functional properties of type 2 and type 3 copper oxidases.

Green colored mononuclear copper(II) complexes viz. [Cu(L)(bpy)](ClO4) (1) or [Cu(L)(phen)](ClO4) (2) (where H(L) is 2-((2-dimethylamino)ethyliminomethyl)naphthol) show distorted square pyramidal (4 + 1) geometry with CuN4O chromophore. The existence of self-assembled molecular associations indicates the formation of the dimer. Dimeric nature in solution is retained due to the binding of the substrate, encourages steric match between substrate and Cu(II) active site, which favors electron transfer. Interestingly, both the complexes exhibit high-positive redox potential. Therefore, the presence of self-assembled molecular association along with the positive redox potential enhances the catalytic oxidation of ascorbic acid to dehydroascorbic acid or benzylamine to benaldehyde or catechol to o-quinone thereby model the functional properties of type 2 and type 3 copper oxidases. Notably, catalytic activity is effective when compared with other reported mononuclear copper(II) complexes and even superior to many binuclear copper(II) complexes. Existence of self-assembled molecular association in solution along with high-positive redox potential favors electron transfer process in mononuclear copper(II) complexes and models the functional properties of type 2 and type 3 copper oxidases.

Non-covalent DNA binding, protein interaction, DNA cleavage and cytotoxicity of [Cu(quamol)Cl]·H2O.

A copper(II) complex [CuII(quamol)Cl]·H2O, where H(quamol) is N-2-(quinolyl-methylidene)aminophenol, has been isolated. The solution structure of the complex has been assessed to be distorted square-planar. The complex displays a ligand field band in the visible region (608nm) and also show axial EPR spectrum in DMF at 77K with g||>g⊥ indicating a dx2-y2 ground state. The g|| and A|| values of 2.265 and 153×10-4cm-1, respectively, conform to a square-based CuN2OCl chromophore. The interaction of the complex with calf thymus (CT) DNA has been explored by using absorption (Kb=2.48×105M-1), emission (Kapp=7.72×104M-1) and circular dichroic (CD) spectral measurements, which reveals that a complex interacts strongly with DNA through partial intercalation. The electrochemical studies indicate that Cu(II) binds to DNA more strongly than Cu(I). It cleaves ϕX174 supercoiled phage DNA in the presence of ascorbic acid as a reducing agent. Meanwhile, the interaction of the complex with bovine serum albumin (BSA) indicates that the complex can markedly quench the intrinsic fluorescence of BSA via a static quenching process and cause its conformational change. Interestingly, the observed IC50 values for the cell lines EVSA-T (breast cancer) and M19 MEL (melanoma) are in the range of those observed with cisplatin while M19 MEL cancer cell line, complex is more active than 5-fluorouracil. The complex is non-toxic to healthy cells.

Discrete tetrairon(III) cluster exhibiting a square-planar Fe4(mu4-O) core: structural and magnetic properties.

The aerobic reaction of the Schiff-base ligand N-(benzimidazol-2-yl)salicylaldimine (Hbisi) with iron(II) perchlorate in methanol leads to the formation of the remarkable coordination compound [Fe(4)(mu(4)-O)(mu-MeO)(4)(bisi)(4)](ClO(4))(2) x 4 MeOH (1), whose single-crystal X-ray structure reveals the presence of a discrete Fe(III)(4)(mu(4)-O) core. Magnetic and Mossbauer studies both show that the exchange interaction within the square tetranuclear iron(III) unit is dominated by the central bridging mu(4)-oxido ligand, the involvement of the mu-methoxido bridges being negligible.

Mixed ligand ruthenium(II) complexes of bis(pyrid-2-yl)-/bis(benzimidazol-2-yl)-dithioether and diimines: study of non-covalent DNA binding and cytotoxicity.

A series of mixed ligand ruthenium(II) complexes [Ru(pdto)(diimine)](ClO4)2/(PF6)2 1-3 and [Ru(bbdo)(diimine)](ClO4), 4-6, where pdto is 1,8-bis(pyrid-2-yl)-3,6-dithiooctane, bbdo is 1,8-bis(benzimidazol-2-yl)-3,6-dithiooctane and diimine is 1,10-phenanthroline (phen), dipyrido-[3,2-d:2',3'-f]-quinoxaline (dpq) and dipyrido[3,2-a:2',3'-c]phenazine (dppz), have been isolated and characterised by analytical and spectral methods. The complexes [Ru(pdto)(phen)](PF6)2 la, [Ru(pdto)(dpq)(Cl](PF6) 2a, [Ru(bbdo)(phen)](PF6)2 4a and [Ru(bbdo)(dpq)](ClO4)2 5 have been structurally characterized and their coordination geometries around ruthenium(II) are described as distorted octahedral. In la, 4a and 5 the two thioether sulfur and two py/bzim nitrogen atoms of the tetradentate pdto/bbdo ligand are folded around Ru(II) to give predominantly a "cis-alpha" configuration. (I)H NMR spectral data of the complexes support this configuration in solution. In [Ru(pdto)(dpq)Cl](PF6) 2a with a distorted octahedral coordination geometry, one of the two py nitrogens of pdto is not coordinated. The DNA binding constants (Kb: 2, 2.00 +/- 0.02 x 10(4) M(-1), s = 1.0; 3, 3.00 +/- 0.01 x 10(6) M(-1), s = 1.3) determined by absorption spectral titrations of the complexes with CT DNA reveal that 3 interacts with DNA more tightly than 2 through partial intercalation of the extended planar ring of coordinated dppz with the DNA base stack. The DNA binding affinities of the complexes increase with increase in the number of planar aromatic rings in the co-ligand, and on replacing both the py moieties in pdto complexes (1-3) by bzim moieties to give bbdo complexes (4-6). Upon interaction with CT DNA the complexes 1, 2, 5 and 6 show a decrease in anodic current in the cyclic voltammograms. On the other hand, interestingly, 3 and 4 show an increase in anodic current suggesting their involvement in electrocatalytic guanine oxidation. Interestingly, of all the complexes, only 6 alters the superhelicity of DNA upon binding with supercoiled pBR322 DNA. The cytotoxicities of the dppz complexes 3 and 6, which avidly bind to DNA, have been examined by screening them against cell lines of different cancer origins. It is noteworthy that 6 exhibits selectivity with higher cytotoxicity against the melanoma cancer cell line (A375) than other cell lines, potency approximately twice that of cisplatin and toxicity to normal cells 3 and 90 times less than cisplatin and adriamycin respectively.

Non-covalent DNA binding and cytotoxicity of certain mixed-ligand ruthenium(II) complexes of 2,2'-dipyridylamine and diimines.

A series of mixed ligand ruthenium(II) complexes [Ru(Hdpa)2(diimine)](ClO4)2, 1-5 where Hdpa is 2,2'-dipyridylamine and diimine is 1,10-phenanthroline (phen) and a modified/extended 1,10-phenanthroline such as, 5,6-dimethyl-1,10-phenanthroline (5,6-dmp), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), 5-methyldipyrido[3,2-d:2',3'-f]quinoxaline (mdpq) and dipyrido[3,2-a:2',3'-c]phenazine (dppz) have been isolated and characterized by analytical and spectral methods. The complex [Ru(Hdpa)2(phen)](PF6)2 1 has been structurally characterized and the coordination geometry around Ru(II) in it is described as distorted octahedral. 1H NMR spectral data reveal that 1-5 should have a C2 symmetry lying on the diimine plane due to the rapid flapping of the coordinated Hdpa ligands. The interaction of the complexes with calf thymus (CT) DNA has been explored by using absorption and emission spectral and viscometry and electrochemical techniques and the mode of DNA binding of the complexes has been proposed. The DNA binding affinity of the complexes decreases with decrease in number of planar aromatic rings in the co-ligand supporting the intercalation of the diimine co-ligands in between the DNA base pairs. Circular dichroic spectral studies reveal that the complexes 3-5 exhibit induced circular dichroism upon binding to CT DNA. Interestingly, upon interaction with CT DNA all the complexes show an increase in anodic current in the cyclic voltammograms suggesting that they are involved in electrocatalytic guanine oxidation. Interestingly, of all the complexes, only 5 alters the DNA superhelicity upon binding with supercoiled pBR322 DNA, which is consistent with its higher DNA binding affinity. Further, the cytotoxicities of the complexes against human cervical epidermoid carcinoma cell line (ME180) have been examined. Interestingly, 5 exhibits a cytotoxicity against ME180 higher than other complexes with potency approximately 8 times more than cisplatin for 24 h incubation but 4 times lower than cisplatin for 48 h incubation.

Synthesis, structure and spectral and redox properties of new mixed ligand monomeric and dimeric Ru(II) complexes: predominant formation of the "cis-alpha" diastereoisomer and unusual 3MC emission by dimeric complexes.

The tetradentate ligands 1,8-bis(pyrid-2-yl)-3,6-dithiaoctane (pdto) and 1,8-bis(benzimidazol-2-yl)-3,6-dithiaoctane (bbdo) form the complexes [Ru(pdto)(mu-Cl)](2)(ClO(4))(2) 1 and [Ru(bbdo)(mu-Cl)](2)(ClO(4))(2) 2 respectively. The new di-mu-chloro dimers 1 and 2 undergo facile symmetrical bridge cleavage reactions with the diimine ligands 2,2'-bipyridine (bpy) and dipyridylamine (dpa) to form the six-coordinate complexes [Ru(pdto)(bpy)](ClO(4))(2) 3, [Ru(bbdo)(bpy)](ClO(4))(2) 4, [Ru(pdto)(dpa)](ClO(4))(2) 5 and [Ru(bbdo)(dpa)](ClO(4))(2) 6 and with the triimine ligand 2,2':6,2''-terpyridine (terpy) to form the unusual seven-coordinate complexes [Ru(pdto)(terpy)](ClO(4))(2) 7 and [Ru(bbdo)(terpy)](ClO(4))(2) 8. In 1 the dimeric cation [Ru(pdto)(mu-Cl)](2)(2+) is made up of two approximately octahedrally coordinated Ru(II) centers bridged by two chloride ions, which constitute a common edge between the two Ru(II) octahedra. Each ruthenium is coordinated also to two pyridine nitrogen and two thioether sulfur atoms of the tetradentate ligand. The ligand pdto is folded around Ru(II) as a result of the cis-dichloro coordination, which corresponds to a "cis-alpha" configuration [DeltaDelta/LambdaLambda(rac) diastereoisomer] supporting the possibility of some attractive pi-stacking interactions between the parallel py rings at each ruthenium atom. The ruthenium atom in the complex cations 3a and 4 exhibit a distorted octahedral coordination geometry composed of two nitrogen atoms of the bpy and the two thioether sulfur and two py/bzim nitrogen atoms of the pdto/bbdo ligand, which is actually folded around Ru(II) to give a "cis-alpha" isomer. The molecule of complex 5 contains a six-coordinated ruthenium atom chelated by pdto and dpa ligands in the expected distorted octahedral fashion. The (1)H and (13)C NMR spectral data of the complexes throw light on the nature of metal-ligand bonding and the conformations of the chelate rings, which indicates that the dithioether ligands maintain their tendency to fold themselves even in solution. The bis-mu-chloro dimers 1 and 2 show a spin-allowed but Laporte-forbidden t(2g)(6)((1)A(1g))--> t(2g)(5) e(g)(1)((1)T(1g), (1)T(2g)) d-d transition. They also display an intense Ru(II) dpi--> py/bzim (pi*) metal-to-ligand charge transfer (MLCT) transition. The mononuclear complexes 3-8 exhibit dpi-->pi* MLCT transitions in the range 340-450 nm. The binuclear complexes 1 and 2 exhibit a ligand field ((3)MC) luminescence even at room temperature, whereas the mononuclear complexes 3 and 4 show a ligand based radical anion ((3)MLCT) luminescence. The binuclear complexes 1 and 2 undergo two successive oxidation processes corresponding to successive Ru(II)/Ru(III) couples, affording a stable mixed-valence Ru(II)Ru(III) state (K(c): 1, 3.97 x 10(6); 2, 1.10 x 10(6)). The mononuclear complexes 3-7 exhibit only one while 8 shows two quasi-reversible metal-based oxidative processes. The coordinated 'soft' thioether raises the redox potentials significantly by stabilising the 'soft' Ru(II) oxidation state. One or two ligand-based reduction processes were also observed for the mononuclear complexes.