Red-light photosensitized cleavage of DNA by (l-lysine)(phenanthroline base)copper(II) complexes

Ternary copper(II) complexes [Cu(l-lys)B(ClO4)](ClO4)(1-4), where B is a heterocyclic base, viz. 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3) and dipyrido[3,2-a:2',3'-c]phenazene (dppz, 4), are prepared and their DNA binding and photo-induced DNA cleavage activity studied (l-lys =l-lysine). Complex 2, structurally characterized by X-ray crystallography, shows a square-pyramidal (4 + 1) coordination geometry in which the N,O-donor l-lysine and N,N-donor heterocyclic base bind at the basal plane and the perchlorate ligand is bonded at the elongated axial site. The crystal structure shows the presence of a pendant cationic amine moiety -(CH2)4NH3+ of l-lysine. The one-electron paramagnetic complexes display a d-d band in the range of 598-762 nm in DMF and exhibit cyclic voltammetric response due to Cu(II)/Cu(I) couple in the range of 0.07 to -0.20 V vs. SCE in DMF-Tris-HCl buffer. The complexes having phenanthroline bases display good binding propensity to the calf thymus DNA giving an order: 4 (dppz) > 3 (dpq) > 2 (phen)> 1 (bpy). Control cleavage experiments using pUC19 supercoiled DNA and distamycin suggest major groove binding for the dppz and minor groove binding for the other complexes. Complexes 2-4 show efficient DNA cleavage activity on UV (365 nm) or visible light (694 nm ruby laser) irradiation via a mechanistic pathway involving formation of singlet oxygen as the reactive species. The amino acid l-lysine bound to the metal shows photosensitizing effect at red light, while the heterocyclic bases are primarily DNA groove binders. The dpq and dppz ligands display red light-induced photosensitizing effects in copper-bound form.     

Mixed ligand copper(II) complexes of N,N-bis(benzimidazol-2-ylmethyl)amine (BBA) with diimine co-ligands: efficient chemical nuclease and protease activities and cytotoxicity

A series of mononuclear mixed ligand copper(II) complexes [Cu(bba)(diimine)](ClO(4))(2)1-4, where bba is N,N-bis(benzimidazol-2-ylmethyl)amine and diimine is 2,2'-bipyridine (bpy) (1), 1,10-phenanthroline (phen) (2), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp) (3), or dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) (4), have been isolated and characterized by analytical and spectral methods. The coordination geometry around copper(II) in 2 is described as square pyramidal with the two benzimidazole nitrogen atoms of the primary ligand bba and the two nitrogen atoms of phen (2) co-ligand constituting the equatorial plane and the amine nitrogen atom of bba occupying the apical position. In contrast, the two benzimidazole nitrogen atoms and the amine nitrogen atom of bba ligand and one of the two nitrogen atoms of 5,6-dmp constitute the equatorial plane of the trigonal bipyramidal distorted square based pyramidal (TBDSBP) coordination geometry of 3 with the other nitrogen atom of 5,6-dmp occupying the apical position. The structures of 1-4 have been optimized by using the density functional theory (DFT) method at the B3LYP/6-31G(d,p) level. Absorption spectral titrations with Calf Thymus (CT) DNA reveal that the intrinsic DNA binding affinity of the complexes depends upon the diimine co-ligand, dpq (4) > 5,6-dmp (3) > phen (2) > bpy (1). The DNA binding affinity of 4 is higher than 2 revealing that the π-stacking interaction of the dpq ring in between the DNA base pairs with the two bzim moieties of the bba ligand stacked along the DNA surface is more intimate than that of phen. The complex 3 is bound to DNA more strongly than 1 and 2 through strong hydrophobic interaction of the methyl groups on 5,6-positions of the phen ring in the DNA grooves. The extent of the decrease in relative emission intensities of DNA-bound ethidium bromide (EB) upon adding the complexes parallels the trend in DNA binding affinities. The large enhancement in relative viscosity of DNA upon binding to 3 and 4 supports the DNA binding modes proposed. Interestingly, the 5,6-dmp complex 3 is selective in exhibiting a positive induced CD band (ICD) upon binding to DNA suggesting that it induces a B to A conformational change. In contrast, 2 and 4 show induced CD responses indicating their involvement in strong DNA binding. Interestingly, only the dpq complex 4, which displays the strongest DNA binding affinity and is efficient in cleaving DNA in the absence of an activator with a rate constant of 5.8 ± 0.1 h(-1), which is higher than the uncatalyzed rate of DNA cleavage. All the complexes exhibit oxidative DNA cleavage ability, which varies as 4 > 2 > 3 > 1 (ascorbic acid) and 3 > 2 > 4 > 1 (H(2)O(2)). Also, the complexes cleave the protein bovine serum albumin in the presence of H(2)O(2) as an activator with the cleavage ability varying in the order 3 > 4 > 2 > 1. The highest efficiency of 3 to cleave both DNA and protein in the presence of H(2)O(2) is consistent with its strong hydrophobic interaction with the biopolymers. The IC(50) values of 1-4 against cervical cancer cell lines (SiHa) are almost equal to that of cisplatin, indicating that they have the potential to act as effective anticancer drugs in a time-dependent manner. The morphological assessment data obtained by using acridine orange/ethidium bromide (AO/EB) and Hoechst 33258 staining reveal that 3 induces apoptosis much more effectively than the other complexes. Also, the alkaline single-cell gel electrophoresis study (comet assay) suggests that the same complex induces DNA fragmentation more efficiently than others.     

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.     

Metal-assisted red light-induced DNA cleavage by ternary L-methionine copper(II) complexes of planar heterocyclic bases

Ternary copper(II) complexes [Cu(l-met)B(Solv)](ClO4) (1-4), where B is a N,N-donor heterocyclic base like 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3) and dipyrido[3,2-a:2'],3'-c]phenazene (dppz, 4), are prepared and their DNA binding and photo-induced DNA cleavage activity studied (L-Hmet =L-methionine). Complex 2, structurally characterized by X-ray crystallography, shows a square pyramidal (4 + 1) coordination geometry in which the N,O-donor L-methionine and N,N-donor heterocyclic base bind at the basal plane and a solvent molecule is coordinated at the axial site. The complexes display a d-d band at approximately 600 nm in DMF and exhibit a cyclic voltammetric response due to the Cu(II)/Cu(I) couple near -0.1 V in DMF-Tris-HCl buffer. The complexes display significant binding propensity to the calf thymus DNA in the order: 4(dppz) > 3(dpq) > 2(phen> 1(bpy). Control cleavage experiments using pUC19 supercoiled DNA and distamycin suggest major groove binding for the dppz and minor groove binding for the other complexes. Complexes 2-4 show efficient DNA cleavage activity on UV (365 nm) or red light (632.8 nm) irradiation via a mechanistic pathway involving formation of singlet oxygen as the reactive species. The DNA cleavage activity of the dpq complex is found to be significantly more than its dppz and phen analogues.     

Interaction of rac-[Cu(diimine)3]2+ and rac-[Zn(diimine)3]2+ complexes with CT DNA: effect of fluxional Cu(II) geometry on DNA binding, ligand-promoted exciton coupling and prominent DNA cleavage

The complexes [Cu(phen)(3)](ClO(4))(2) 1, [Cu(5,6-dmp)(3)](ClO(4))(2) 2, [Cu(dpq)(3)](ClO(4))(2) 3, [Zn(phen)(3)](ClO(4))(2) 4, [Zn(5,6-dmp)(3)](ClO(4))(2) 5 and [Zn(dpq)(3)](ClO(4))(2) 6, where phen = 1,10-phenanthroline, 5,6-dmp = 5,6-dimethyl-1,10-phenanthroline and dpq = dipyrido[3,2-d:2',3'-f]quinoxaline, have been isolated, characterized and their interaction with calf thymus DNA studied by using a host of physical methods. The X-ray crystal structures of rac-[Cu(5,6-dmp)(3)](ClO(4))(2) and rac-[Zn(5,6-dmp)(3)](ClO(4))(2) have been determined. While 2 possesses a regular elongated octahedral coordination geometry (REO), 5 possesses a distorted octahedral geometry. Absorption spectral titrations of the Cu(II) complexes with CT DNA reveal that the red-shift (12 nm) and DNA binding affinity of 3 (K(b), 7.5 x 10(4) M(-1)) are higher than those of 1 (red-shift, 6 nm; K(b), 9.6 x 10(3) M(-1)) indicating that the partial insertion of the extended phen ring of dpq ligand in between the DNA base pairs is deeper than that of phen ring. Also, 2 with a fluxional Cu(II) geometry interacts with DNA (K(b), 3.8 x 10(4) M(-1)) more strongly than 1 suggesting that the hydrophobic forces of interaction of 5,6 methyl groups on the phen ring is more pronounced than the partial intercalation of phen ring in the latter with a static geometry. The DNA binding affinity of 1 is lower than that of its Zn(ii) analogue 4, and, interestingly, the DNA binding affinity 2 of with a fluxional geometry is higher than that of its Zn(II) analogue 5 with a spherical geometry. It is remarkable that upon binding to DNA 3 shows an increase in viscosity higher than that the intercalator EthBr does, which is consistent with the above DNA binding affinities. The CD spectra show only one induced CD band on the characteristic positive band of CT DNA upon interaction with the phen (1,4) and dpq (3,6) complexes. In contrast, the 5,6-dmp complexes 2 and 5 bound to CT DNA show exciton-coupled biphasic CD signals with 2 showing CD signals more intense than 5. The Delta-enantiomer of rac-[Cu(5,6-dmp)(3)](2+) 2 binds specifically to the right-handed B-form of CT DNA at lower ionic strength (0.05 M NaCl) while the Lambda-enantiomer binds specifically to the left-handed Z-form of CT DNA generated by treating the B-form with 5 M NaCl. The complex 2 is stabilized in the higher oxidation state of Cu(II) more than its phen analogue 1 upon binding to DNA suggesting the involvement of electrostatic forces in DNA interaction of the former. In contrast, 3 bound to DNA is stabilized as Cu(I) rather than the Cu(II) oxidation state due to partial intercalative interaction of the dpq ligand. The efficiencies of the complexes to oxidatively cleave pUC19 DNA vary in the order, 3> 1 > 2 with 3 effecting 100% cleavage even at 10 microM complex concentration. However, interestingly, this order is reversed when the DNA cleavage is performed using H(2)O(2) as an activator and the highest cleavage efficiency of 2 is ascribed to its electrostatic interaction with the exterior phosphates of DNA.     

Metal-assisted red light-induced efficient DNA cleavage by dipyridoquinoxaline-copper(II) complex

Complete cleavage of double stranded pUC19 DNA by the complex [Cu(dpq)2(H2O)](ClO4)2 (dpq, dipyridoquinoxaline) has been observed on irradiation at 694 nm from a pulsed ruby laser, assisted by the metal d-band transition as well as the quinoxaline triplet states in the absence of any external additives.     

Steric protection of a photosensitizer in a N,N-bis[2-(2-pyridyl)ethyl]-2-phenylethylamine-copper(II) bowl that enhances red light-induced DNA cleavage activity

Ternary copper(II) complexes [Cu(py2phe)B](ClO4)2 (1-3), where py2phe is a tripodal ligand N,N-bis[2-(2-pyridyl)ethyl]-2-phenylethylamine and B is a heterocyclic base (viz., 1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2), or dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3)), are prepared and their DNA-binding and photoinduced DNA-cleavage activities are studied. Complex 1 has been structurally characterized by single crystal X-ray crystallography. The molecular structure shows an axially elongated square-pyramidal (4 + 1) coordination geometry in which the phen ligand binds at the basal plane. The tripodal ligand py2phe displays an axial-equatorial binding mode with the amine nitrogen bonded at the axial site. A chemically significant CH-pi interaction involving the CH moiety of the phenyl group of the tripodal ligand and the aromatic ring of phen is observed. The complexes display good binding propensity to calf thymus DNA giving a relative order of 3 (dppz) > 2 (dpq) > 1 (phen). The DNA binding constants (K(b)) for 1-3, determined from absorption spectral studies, are 6.2 x 10(3), 1.0 x 10(4), and 5.7 x 10(4) M(-1), respectively. The complexes show chemical nuclease activity in the presence of 3-mercaptopropionic acid as a reducing agent forming hydroxyl radicals as the cleavage active species. The photoinduced DNA-cleavage activity of the complexes has been studied using UV radiation of 365 nm and red light of 632.8 and 694 nm. The phen complex in absence of any photosensitizing moiety does not show any DNA cleavage upon photoirradiation. The dpq and dppz ligands with their photoactive quinoxaline and phenazine moieties display significant photoinduced DNA-cleavage activity. The dppz complex is more active than its dpq analogue because of the better steric protection of the DNA-bound photosensitizing dppz ligand from the solvent molecules. Control experiments reveal the formation of singlet oxygen in the light-induced DNA-cleavage reactions. The observed efficient photoinduced DNA-cleavage activity of 2 and 3 is akin to the "light switch" effect known for the tris-chelates of ruthenium(II).     

Symmetrical dinuclear complexes with high DNA affinity based on [Ru(dpq)2(phen)]2+

Symmetrical homometallic dinuclear complexes of the type [(Ru(dpq)2)2(phen-SOS-phen)]4+, with a flexible 2-mercaptoethyl ether linker joining the two [Ru(dpq)2(phen)]2+-based sub-units, have DNA dissociation constants (Kd) in the nM range.     

DNA cleavage on photoexposure at the d-d band in ternary copper(II) complexes using red-light laser

Ternary copper(II) complexes [Cu(L1)B](ClO4) (1, 2) and [Cu(L2)B](ClO4) (3, 4), where HL1 and HL2 are tridentate NSO- and ONO-donor Schiff bases and B is a heterocyclic base, viz. dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 1 and 3) or dipyrido[3,2-a:2',3'-c]phenazine (dppz, 2 and 4), were prepared and their DNA binding and photoinduced DNA cleavage activity studied. Complex 1, structurally characterized by single-crystal X-ray crystallography, shows an axially elongated square-pyramidal (4 + 1) coordination geometry in which the monoanionic L1 binds at the equatorial plane. The NN-donor dpq ligand exhibits an axial-equatorial binding mode. The complexes display good binding propensity to calf thymus DNA, giving a relative order 2 (NSO-dppz) > 4 (ONO-dppz) > 1 (NSO-dpq) > 3 (ONO-dpq). They cleave supercoiled pUC19 DNA to its nicked circular form when treated with 3-mercaptopropionic acid (MPA) by formation of hydroxyl radicals as the cleavage active species under dark reaction conditions. The photoinduced DNA cleavage activity of the complexes was investigated using UV radiation of 365 nm and red light of 633, 647.1, and 676.4 nm (CW He-Ne and Ar-Kr mixed gas ion laser sources) in the absence of MPA. Complexes 1 and 2, having photoactive NSO-donor Schiff base and dpq/dppz ligands, show dual photosensitizing effects involving both the photoactive ligands in the ternary structure with significantly better cleavage properties when compared to those of 3 and 4, having only photoactive dpq/dppz ligands. Involvement of singlet oxygen in the light-induced DNA cleavage reactions is proposed. A significant enhancement of the red-light-induced DNA cleavage activity is observed for the dpq and dppz complexes containing the sulfur ligand when compared to their earlier reported phen (1,10-phenanthroline) analogue. Enhancement of the cleavage activity on photoexposure at the d-d band indicates the occurrence of metal-assisted photosensitization processes involving the LMCT and d-d band in the ternary structure.     

Interaction of rac-[M(diimine)3]2+ (M=Co, Ni) complexes with CT DNA: role of 5,6-dmp ligand on DNA binding and cleavage and cytotoxicity

The complexes [Co(diimine)(3)](ClO(4))(2)1-3 and [Ni(diimine)(3)](ClO(4))(2)4-6, where diimine = 1,10-phenanthroline (phen) (1,4), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp) (2,5) and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) (3,6), have been isolated, characterized and their interaction with CT DNA studied by using a host of physical methods. The X-ray crystal structures of rac-[Co(5,6-dmp)(3)](ClO(4))(2)2 and rac-[Ni(5,6-dmp)(3)](ClO(4))(2)5 have been determined and the isostructural and also isomorphous complex cations possess distorted octahedral coordination geometries. The absorption spectral titrations of the complexes with DNA reveal that the CT DNA binding affinity (K(b)) of the complexes varies as 3>2>1; 6>5>4. The Ni(II) complexes display DNA binding stronger than the corresponding Co(II) analogues, which is expected of their bigger sizes. The higher DNA binding affinity of 3 and 6 is due to the involvement in partial insertion of the extended phen ring in between the DNA base pairs. In contrast, 2 and 5 interact with DNA in the major groove through hydrophobic forces involving the methyl groups on the 5,6 positions of phen ring. An enhancement in relative viscosities of DNA upon binding to 1-6 is consistent with the DNA binding affinities. The CD spectral studies show only an induced CD band on the characteristic positive band of CT DNA for both the phen (1,4) complexes. In contrast, the 5,6-dmp (2,5) and dpq (3,6) complexes bound to CT DNA exhibit biphasic CD signals in place of the positive CD band and the negative helicity band disappears. This reveals that the complexes bind to DNA enantiopreferentially and effect changes in secondary structure of DNA. The CV and DPV responses indicate that the DNA-bound dpq complexes are stabilized in the lower oxidation state of Co(II) more than in the Co(III) oxidation state. The prominent DNA cleavage abilities of 1-3 observed in the presence of H(2)O(2) (200 μM) follows the order 2>1>3 with efficiencies of more than 90% even at 10 μM complex concentration. Interestingly, Ni(II) complexes 4-6 exhibit higher cytotoxicity (IC(50): 1, 28.0; 2, 15.0; 3, 20.0; 4, 8.0; 5, 2.0; 6, 2.0 μM at 48 h; IC(50): 1, 30.0; 2, 20.0; 3, 25.0; 4, 10.0; 5, 3.0; 6, 3.0 μM at 24 h) against human breast cancer (MCF 7) cell lines than the Co(II) complexes 1-3 as well as cisplatin in spite of their inability to cleave DNA. Also, the 5,6-dmp complex 5 shows cytotoxicity higher than the dpq complex 6 at 24 h incubation time and both 5 and 6 display apoptotic and necrotic modes of cell death.     

Double-strand DNA cleavage from photodecarboxylation of (micro-oxo)diiron(III) L-histidine complex in visible light

The oxo-bridged diiron(III) complex [{Fe(L-his)(dpq)}(2)(micro-O)](2+) having L-histidine (L-his) and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) bound to Fe(III) exemplifies an iron-based model photonuclease that shows visible light-induced DNA double-strand cleavage in a photodecarboxylation pathway and models iron-bleomycin activity.     

DNA binding, prominent DNA cleavage and efficient anticancer activities of tris(diimine)iron(II) complexes

The complexes rac-[Fe(diimine)(3)](ClO(4))(2)1-4, where diimine = 2,2'-bipyridine (bpy) 1, 1,10-phenanthroline (phen) 2, 5,6-dimethyl-1,10-phenanthroline (5,6-dmp) 3 and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) 4, have been isolated, characterized and their interaction with calf thymus DNA studied by using a host of physical methods. The X-ray crystal structure of rac-[Fe(5,6-dmp)(3)](ClO(4))(2)3 has been determined and the packing diagram shows the presence of two enantiomeric forms of the complex cations in the same unit cell. The structures of 1-4 in solution have also been studied using UV-Visible, Cyclic Voltammetry and ESI-MS data and all data available suggests that they retain their solid state structures even in solution. The absorption spectral titrations of the iron(ii) complexes with CT DNA reveal that the DNA binding affinities of the complexes vary in the order, 4 (K(b): 9.0 × 10(3)) > 2 (6.8 × 10(3)) > 3 (4. 8 × 10(3)) > 1 (2.9 × 10(3) M(-1)). The DNA interaction of dpq complex (4) involves partial insertion of the extended phen ring in between the DNA base pairs, which is deeper than that of phen (2). The 5,6-dmp (3) complex is involved in groove binding in the major groove of DNA. The lower DNA binding affinity of 1 is due to electrostatic interaction of the cationic complexes with exterior phosphates of DNA. The EthBr displacement assay and DNA viscosity study support these DNA binding modes and the above trend in DNA binding affinities. The complexes of 1 and 2 show induced CD (ICD) upon interaction with CT DNA while 3 and 4 bound to DNA exhibit inversion in the positive band with the helicity band showing very small changes, which implies that 3 and 4 bind enantiopreferentially to DNA. The DNA cleavage abilities of 1-4 have been observed at 10 μM concentration of complexes in the presence of 100 μM H(2)O(2) and the DNA cleavage efficiency (> 90%) follows the order 3 > 1 > 2 > 4. The anticancer activity of 1-4 against human breast cancer cell line (MCF-7) has also been studied. The IC(50) values of the complexes at different incubation time intervals of 24 and 48 h follow the order, 3 (0.8, 0.6) < 4 (20.0, 17.0) < 2 (28.0, 22.0) < 1 (32.0, 29.0 μM). Interestingly, 3 exhibits anticancer activity more potent than 1, 2 and 4 and cisplatin for both 24 and 48 h. It induces cell death both through apoptosis and necrosis mechanisms, as revealed by morphological assessment data obtained by using AO/EB and Hoechst 33258 fluorescence staining methods.     

New insights into the visible-light-induced DNA cleavage activity of dipyridoquinoxaline complexes of bivalent 3d-metal ions

Dipyridoquinoxaline (dpq) complexes of bivalent 3d-metal ions, viz., [FeII(dpq)3](PF6)2 (1), [CoII(dpq)3](ClO4)2 (2), [NiII(dpq)3](ClO4)2 (3), [CuII(dpq)2(H2O)](ClO4)2 (4), [ZnII(dpq)3](ClO4)2 (5), and [ZnII(dpq)2(DMF)2](ClO4)2 (5a) (DMF = N,N-dimethylformamide), are prepared and their photoinduced DNA cleavage activity studied. Structural characterization for the complexes 1 and 5a is done by single-crystal X-ray crystallography. All the complexes show efficient binding propensity to calf thymus DNA with a binding constant (K) value of approximately 10(5) M(-1). Complexes 1, 2, and 4 show metal-based cyclic voltammetric responses at 1.2, 0.4, and 0.09 V (vs SCE) in DMF 0.1 M [Bun4N](ClO4) assignable to the respective FeIII/FeII, CoIII/CoII, and CuII/CuI couples. The NiII and ZnII complexes do not show any metal-based redox process. The dpq-based reductions are observed in the potential range of -1.0 to -1.7 V vs SCE. DNA melting and viscosity data indicate the groove-binding nature of the complexes. Control experiments using distamycin-A suggest a minor groove-binding propensity of the complexes. The complexes exhibit photoinduced cleavage of supercoiled pUC19 DNA in UV light of 365 nm. The diamagnetic d6-FeII and d10-ZnII complexes are cleavage-inactive on irradiation with visible light. The paramagnetic d7-CoII and d9-CuII complexes exhibit efficient DNA cleavage activity on photoirradiation at their respective d-d band. The paramagnetic d8-NiII complex displays only minor DNA cleavage activity on irradiation at its d-d band. The DNA cleavage reactions at visible light under aerobic conditions involve the formation of hydroxyl radical. The CoII complex shows photocleavage of DNA under an argon atmosphere. Theoretical calculations on the complexes suggest a photoredox pathway in preference to a type-2 process forming singlet oxygen for the visible-light-induced DNA cleavage activity of the 3d-metal complexes. The theoretical data also predict that the photoredox pathway is favorable for the 3d7-CoII and 3d9-CuII complexes to exhibit DNA cleavage activity, while the analogous 3d6-FeII and 3d8-NiII complexes are energetically unfavorable for the exhibition of such activity under visible light. The CoII and CuII complexes are better suited for designing and developing new metal-based PDT agents than their cleavage-inactive FeII, NiII, and ZnII analogues.     

Photophysical study of a family of [Ru(phen)2(Me n dpq)]2+ complexes in different solvents and DNA: a specific water effect promoted by methyl substitution

The synthesis and spectroscopic characterisation of a family of ruthenium complexes [Ru(phen)(2)(Me(n)dpq)](2+)(n= 0, 1, 2) are reported and the photophysical effect of the progressive methyl substitution on the dpq ligand ascertained in a range of solvents and in the presence of DNA: [Ru(phen)(2)(dpq)](2+)(1), [Ru(phen)(2)(Medpq)](2+)(2) and [Ru(phen)(2)(Me(2)dpq)](2+)(3)(where dpq is dipyrido[3,2-f:2',3'-h]-quinoxaline; Medpq is 2-methyldipyrido[3,2-f:2',3'-h]-quinoxaline; Me(2)dpq is 2,3-dimethyldipyrido[3,2-f:2',3'-h]-quinoxaline and phen is 1,10-phenanthroline). The increase in electron density following substitution renders the quinoxaline nitrogen atoms more basic in the ground state to yield pK(a) values of -1.9, -2.3, and -2.7 for 3, 2, and 1, respectively. The methyl groups have a pronounced effect on the excited state photophysics of 1-3. In organic solvents, the non-radiative decay constant correlates well with the solvent polarity parameter pi*, with the effect being more pronounced with increasing methyl substitution. On the contrary, in aqueous solution there is a ca. four-fold decrease in the non-radiative decay constant upon methyl substitution. This "specific water effect" may be explained in terms of deactivation of the excited state by hydrogen bonding interactions between water and the quinoxaline nitrogen atoms, which is reduced on moving from 1 to 3. The excited state lifetimes and luminescence intensities for substantially increase when bound to DNA in aerated aqueous solutions, with a six-fold increase, compared to a more moderate three-fold increase for 2 and 3.     

Synthesis,crystal structures,DNA/bovine serum albumin binding,DNA cleavage and cytotoxicity of five mononuclear zinc(II) complexes

Five new mononuclear zinc(II) complexes containing ligands with extended planar phenanthroline moieties (dipyrido‐[3,2‐a:2′,3′‐c]phenazine (dppz) or dipyrido[3,2‐d:2′,3′‐f] quinoxaline (dpq)), namely [Zn(dppz)(acac)₂]⋅CH₃OH ( 1 ), [Zn(dppz)(dbm)(OAc)] ( 2 ), [Zn(dpq)(dbm) (OAc)] 1.5H₂O ( 3 ), [Zn(dpq)(tfnb)(OAc)] ( 4 ) and [Zn(dpq)(tfnb)₂] ( 5 ), where acac = acetylacetonate, tfnb = benzoyltrifluoroacetone and dbm = dibenzoylmethane, were synthesized and structurally characterized. The binding ability of complexes 1 – 5 with calf thymus DNA was investigated by spectroscopic titration methods and viscosity measurements. Results indicate that all complexes bind to calf thymus DNA via intercalative mode, and the DNA binding affinities of dppz complexes 1 and 2 are apparently stronger than those of dpq complexes 3 – 5 . DNA photocleavage experiments reveal that these complexes are efficient DNA cleaving agents and they are more active in UV‐A (365 nm) than in visible light. In particular, the in vitro cytotoxicity of the complexes for human cancer cell line A549 demonstrates that the five compounds have anticancer activity with low IC₅₀ values. Meanwhile, interaction of the complexes with bovine serum albumin investigated using UV–visible and fluorescence methods indicates that all complexes can quench the intrinsic fluorescence of bovine serum albumin in a static quenching process.     

Synthesis, DNA binding, photo-induced DNA cleavage and cytotoxicity studies of europium(III) complexes

Two Eu(III) complexes, [Eu(acac)(3)(dpq)] (1) and [Eu(acac)(3)(dppz)] CH(3)OH (2) {viz. acetylacetonate (acac), dipyrido[3,2-d:20,30-f]quinoxaline (dpq), dipyrido[3,2-a:20,30-c] phenazine (dppz)}, have been synthesized and their DNA binding, photo-induced DNA cleavage activity and cell cytotoxicity are studied. The complexes display significant binding propensity to the calf thymus DNA in the order: 2(dppz) >1(dpq). Cleavage experiments using pBR322 supercoiled DNA suggest major groove binding for 2 and minor groove binding for 1. The mechanistic aspects on natural light (natural light in room during the day) and UV-A (365 nm) irradiation are via a mechanistic pathway involving formation of singlet oxygen and hydroxyl radical as the reactive species. The photo-induced DNA cleavage activity of 2 is also stronger than 1. The cytotoxicity of 1 and 2 against HeLa (cervical) cancer cells show that the IC(50) value of 19.11 ± 3.56 μM and 17.95 ± 5.47 μM, respectively.     

Mixed ligand cobalt(II) picolinate complexes: synthesis, characterization, DNA binding and photocleavage

Complexes of the type [Co(pic)(2)(NN)], where pic = picolinate, NN = dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) (4) and 4b,5,7,7a-tetrahydro-4b,7a-epiminomethanoimino-6H-imidazo[4,5-f][1,10]-phenanthroline-6,13-dione (bipyridyl-glycoluril) (bpg) (6) have been synthesized and characterized by elemental analysis, IR, UV-vis, NMR and ESI-MS spectroscopy and thermogravimetic analysis (TGA). Their physicochemical properties are compared with previously synthesized complexes, where NN = (H(2)O)(2) (1), 2,2'-bipyridine (bpy) (2), 1,10-phenanthroline (phen) (3) and dipyrido[3,2-a:2',3'-c]phenazine (dppz) (5). The crystal structures of the complexes 4-6 were solved by single-crystal X-ray diffraction. The complexes 4 and 5 crystallize from a mixture of chloroform and methanol in monoclinic and orthorhombic crystal systems, respectively, whereas complex 6 crystallizes from dimethyl sulfoxide (DMSO) in a tetragonal crystal system. The coordination sphere consists of two oxygen atoms and two nitrogen atoms from the two picolinates and two nitrogen atoms from the dpq, dppz or bpg ligand, respectively. Co(ii)/Co(iii) oxidation potentials have been determined by cyclic voltammetry. The DNA binding of complexes 1-5 has been investigated using thermal melting, fluorescence quenching and viscosity measurements, which indicate the partial intercalation of complex 5 with an apparent binding constant (k(app)) of 8.3 × 10(5) M(-1). DNA cleavage studies of complexes 1-5 have been investigated using gel electrophoresis in the presence of H(2)O(2) as an oxidizing agent and also by photoirradiation at 365 nm. The mechanistic investigations suggest that singlet oxygen ((1)O(2)) is the major species involved in the DNA cleavage by these complexes. The structures of complexes 2-6 were optimized with density functional theory (DFT) method (B3LYP/6-31G(d,p)). The low vertical ionization potential values indicate photoredox pathways for the DNA cleavage activity by complexes 4 and 5, which is corroborated by DNA cleavage experiments.     

新颖的[CuI(dpq)2]+配合物阳离子修饰的砷钒酸盐[Cu(dpq)2]4[As8V14O42(H2O)]·2H2O的水热合成与结构表征

采用水热方法制备了一个新颖的[CuI(dpq)2]+配合物阳离子修饰的砷钒酸盐[Cu(dpq)2]4[As8V14O42(H2O)]·2H2O, X射线单晶衍射结果表明, 该化合物的结构是由4个[CuI(dpq)2]+阳离子和1个[As8V14O42(H2O)]4-簇阴离子以及2个结晶水组成的, 簇阴离子内部包含一个孤立的水分子.     

DNA cleavage by new oxovanadium(IV) complexes of N-salicylidene alpha-amino acids and phenanthroline bases in the photodynamic therapy window

Oxovanadium(IV) complexes [VO(salmet)(B)] (1-3) and [VO(saltrp)(B)] (4-6), where salmet and saltrp are N-salicylidene-l-methionate and N-salicylidene-l-tryptophanate, respectively, and B is a N,N-donor heterocyclic base (viz. 1,10-phenanthroline (phen, 1, 4), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2, 5), and dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3, 6)) are prepared and characterized and their DNA binding and photoinduced DNA cleavage activity studied. Complexes 1, 2, and 4 are structurally characterized by single-crystal X-ray crystallography. The molecular structure shows the presence of a vanadyl group in the VO3N3 coordination geometry. The dianionic alpha-amino acid Schiff base acts as a tridentate O,N,O-donor ligand in a meridional binding mode. The N,N-donor heterocyclic base displays a chelating mode of bonding with a N-donor site trans to the oxo group. The complexes show a d-d band in the range of 680-710 nm in DMF with a shoulder near 840 nm. They exhibit an irreversible oxidative cyclic voltammetric response near 0.8 V assignable to the V(V)/V(IV) couple and a quasi-reversible V(IV)/V(III) redox couple near -1.1 V vs SCE in DMF-0.1 M TBAP. The complexes show good binding propensity to calf thymus DNA giving binding constant values in the range from 5.2 x 10(4) to 7.2 x 10(5) M(-1). The binding site size, thermal melting, and viscosity data suggest DNA surface and/or groove binding nature of the complexes. The complexes show poor "chemical nuclease" activity in the dark in the presence of 3-mercaptopropionic acid or hydrogen peroxide. The dpq and dppz complexes show efficient DNA cleavage activity on irradiation with UV-A light of 365 nm via a mechanistic pathway involving formation of singlet oxygen as the reactive species. They also show significant DNA cleavage activity on photoexcitation in red light (>750 nm) by (1)O2 species. Observation of red-light-induced cleavage of DNA is unprecedented in the vanadium chemistry. The DNA cleavage activity is metal promoted as the ligands or vanadyl sulfate alone are cleavage inactive on photoirradiation at these wavelengths.     

Synthesis, Crystal Structure, Spectroscopy and Electroluminescence of Zinc(II) Complexes Containing Bidentate 2-(2-pyridyl)quinoline Derivative Ligands

Three bidentate ligands, 4-phenyl-2-(2-pyridyl)-quinoline (ppq), 6-(carbazol-9-yl)-4-phenyl-2-(2-pyridyl)-quinoline (cpq) and 6-diphenylamino-4-phenyl-2-(2-pyridyl)-quinoline (dpq) and their zinc(II) complexes, have been designed and synthesized. The crystal structure of [Zn(ppq)₂Cl]PF₆ shows that the central zinc atom is coordinated with one chloride and four nitrogen atoms from two ligands. The introduction of an electron-donating substituent such as carbazole or an aromatic amine group at the 6-position of the quinoline moiety can generate colored tunable Zn complexes, and the photoluminescence (PL) wavelength was modulated from 418 nm for [Zn(ppq)₂Cl]PF₆ to 591 nm for [Zn(cpq)₂Cl]PF₆ and 638 nm for [Zn(dpq)₂Cl]PF₆ in CH₂Cl₂ solution. The electroluminescence spectrum of [Zn(dpq)₂Cl]PF₆ exhibits pure red light emission with the Commission Internationale de L’Eclairage (CIE) coordinates (0.63, 0.36) and a maximum at 648 nm.