Phenanthroline Bases Research Articles

Synthesis, characterization, and cancer cell-selective cytotoxicity of mixed-ligand cobalt(III) complexes of 8-hydroxyquinolines and phenanthroline bases.

Transition metal complexes exhibiting selective toxicity towards a broad range of cancer types are highly desirable as potential anticancer agents. Herein, we report the synthesis, characterization, and cytotoxicity studies of six new mixed-ligand cobalt(III) complexes of general formula [Co(B)2(L)](ClO4)2 (1-6), where B is a N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 3, 4), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 5, 6), and L is the monoanion of 8-hydroxyquinoline (HQ in 1, 3, 5) and 5-chloro-7-iodo-8-hydroxyquinoline (CQ in 2, 4, 6). The X-ray single crystal structures of complexes 1 and 2 as PF6- salts revealed a distorted octahedral CoN5O coordination environment. Complexes demonstrated good stability in an aqueous buffer medium and in the presence of ascorbic acid as a reductant. Cytotoxicity studies using a panel of nine cancer cell lines showed that complex 6, with the dppz and CQ ligands, was significantly toxic against most cancer cell types, yielding IC50 values in the range of 2 to 14 μM. Complexes 1, 3, and 5, containing the HQ ligand, displayed lower toxicity compared to their CQ counterparts. The phenanthroline complexes demonstrated marginal toxicity towards the tested cell lines, while the dpq complexes exhibited moderate toxicity. Interestingly, all complexes demonstrated negligible toxicity towards normal HEK-293 kidney cells (IC50 > 100 μM). The observed cytotoxicity of the complexes correlated well with their lipophilicities (dppz > dpq > phen). The cytotoxicity of complex 6 was comparable to that of the clinical drug cisplatin under similar conditions. Notably, neither the HQ nor the CQ ligands alone demonstrated noticeable toxicity against any of the tested cell lines. The Annexin-V-FITC and DCFDA assays revealed that the cell death mechanism induced by the complexes involved apoptosis, which could be attributed to the metal-assisted generation of reactive oxygen species. Overall, the dppz complex 6, with its remarkable cytotoxicity against a broad range of cancer cells and negligible toxicity toward normal cells, holds significant potential for cancer chemotherapeutic applications.

Photochemotherapeutic Properties of Cu(II) Complexes of L‐Lysine and L‐Arginine Appended to Anthracene

AbstractCu(II) complexes of positively charged amino acids L–Lysine and L‐Arginine appended to an anthracene unit and phenanthroline bases, namely [Cu(Anth‐Lys)(L)(ClO4)] (1, 2) and [Cu(Anth‐Arg)(L)(ClO4)] (3, 4) where L is 1,10‐phenanthroline (phen, 1 and 3), dipyrido[3,2‐a : 2′,3′‐c]phenazine (dppz, 2 and 4) were synthesized and fully characterized by various spectral and analytical methods. Cu(II) centered broad and weak d‐d band in the visible region along with phenanthroline based π→π* and n→π* bands in the UV region were observed in the electronic spectra of the complexes recorded in DMF‐Tris‐HCl buffer (1 : 4 v/v) (pH 7.2). The complexes 1–4 show efficient DNA binding propensity. They also demonstrated strong binding affinity for human serum albumin (HSA). The complexes showed efficient visible light‐induced cytotoxicity against A549 (human lung carcinoma), HaCaT (human epidermal keratinocytes) and MDA‐MB‐231(human breast cancer cells) cells with low dark toxicity. They generate both singlet oxygen (1O2) and hydroxyl radical (⋅OH) as reactive oxygen species (ROS) upon excitation with visible light which is believed to be responsible for killing cancer cells. Significant changes in the nuclear morphology of the HaCaT cells were observed when treated with complexes 2 and 4 in visible light compared to the non‐irradiated cells.

Synthesis, characterization, in vitro biological evaluation and molecular docking studies of newly synthesized mononuclear lanthanum(III) complexes of N,N'-bis(2-aminoethyl)oxamide and phenanthroline bases

Four lanthanum(III) complexes were newly synthesized using the ligand N,N'-bis(2-aminoethyl)oxamide (1) and phenanthroline bases [La(oxae)2(NO3)2](NO3) (2) [La(oxae)(bpy)](NO3)3 (3), [La(oxae)(phen)](NO3)3 (4) and [La(oxae)2(dppz)](NO3)3 (5) and characterized by 1H-NMR, IR, UV–Visible spectroscopic analyses, ESI-Mass spectrometric measurements, molar conductivities, and cyclic voltammetric measurements. Complex 2 was found to be 1:1 electrolyte and complexes 3, 4 and 5 were 1:3 electrolytes. The redox ehavior of the complexes was confirmed by cyclic voltammetry. The interactions of 1 and its complexes (2, 3, 4 and 5) with calf thymus DNA (CT-DNA) were studied by UV–Visible absorption spectroscopy, cyclic voltammetric studies, viscosity measurements and molecular docking studies. The studies confirmed the highest binding propensity for complex 5 (Kb = 2.26 × 106 ± 7) in the reduced state through the intercalation method. Molecular docking studies revealed that complex 5 was found to bind strongly with the DNA molecule due to intercalation with a more negative binding energy ΔG = - 8.6 kcal/mol having an association constant (Ka) = 0.892 µM. The oxidative cleavage of SC pUC19 DNA by La(III) complexes was confirmed by the Agarose gel electrophoresis method. Of all the compounds tested, complex 5 exhibited the highest cleavage ability (94%) in the presence of H2O2 in the major groove region. The MTT assay revealed the highest antiproliferative activity of complex 5 against MCF-7 cell lines at IC50 value is 21.86 µM. The complexes have been tested for antibacterial activities wherein at 50 µg mL−1, complex 5 inhibits the growth of K. pneumonia and at 100 µg mL−1, ligand oxae (1) and its complex 2 were active against E. coli and K. pneumonia; complex 4 inhibited the growth of E. coli, K. pneumonia and B. subtilis. The antioxidant activities showed that complex 2 had the highest chelation ability towards Fe2+.

Co(II) complexes of curcumin and a ferrocene-based curcuminoid: a study on photo-induced antitumor activity.

Co(II) complexes having a ferrocene-based curcuminoid (Fc-curH) ligand viz. [Co(L)2(Fc-cur)]ClO4 (1, 2), where L is phenanthroline base, namely, 1,10-phenanthroline (phen in 1) and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 2) have been synthesized, characterized and evaluated as photochemotherapeutic agents in vitro. The corresponding Co(II) complexes of the naturally occurring polyphenol curcumin (curH), namely, [Co(L)2(cur)]ClO4 (3, 4), where L is phen (in 3) and dppz (in 4) were synthesized and their photo-induced anticancer activities compared with their ferrocene containing counterparts 1 and 2. The Co(II) acetylacetonato complex viz. [Co(phen)2(acac)]ClO4 (5) was structurally characterized through X-ray crystallography and used as control for cellular experiments. The Co(II) complexes having ferrocene-based curcuminoid are remarkably stable at physiological condition with higher lipophilicity compared to their curcumin analogues. The complexes display significant binding propensity to calf thymus (ct) DNA and human serum albumin (HSA). The complexes 1-4 display remarkable visible light induced cytotoxicity with the ferrocenyl analogues showing more phototoxic index (PI). The Co(II) curcumin complexes localize in the nucleus and mitochondria of A549 cells. The primary cell death mechanism is believed to be apoptotic in nature induced by light assisted generation of reactive oxygen species (ROS).Graphic abstract.

Mixed-Ligand Cobalt(III) Complexes of a Naturally Occurring Coumarin and Phenanthroline Bases as Mitochondria-Targeted Dual-Purpose Photochemotherapeutics.

The bioessential nature of cobalt and the rich photochemistry of its coordination complexes can be exploited to develop potential next-generation photochemotherapeutics. A series of six novel mixed-ligand cobalt(III) complexes of the formulation [Co(B)2(L)]ClO4 (1-6), where B is an N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1 and 4), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 2 and 5), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 3 and 6), and L is an O,O-donor dianionic ligand derived from catechol (1,2-dihydroxybenzene, cat2-, in 1-3) or esculetin (6,7-dihydoxycoumarin, esc2-, in 4-6), have been prepared and characterized, and their light-triggered cytotoxicity has been studied in cancer cells. The single-crystal X-ray diffraction structures of complexes 1 (as PF6- salt, 1a) and 2 show distorted octahedral geometries around the cobalt(III) center formed by the set of N4O2 donor atoms. The low-spin and 1:1 electrolytic complexes 1-6 display a d-d transition around 700 nm. Complexes 4-6 with a coordinated esc2- ligand additionally display a π → π* intraligand transition centered at 403 nm. Complexes 4-6 possessing a naturally occurring and photoactive esc2- ligand show high visible-light-triggered cytotoxicity against HeLa and MCF-7 cancer cells, yielding remarkably low micromolar IC50 values while being much less toxic under dark conditions. Control complexes 1-3 possessing the photoinactive cat2- ligand show significantly less cytotoxicity either in the presence of light or in the dark. The complex-induced cell death is apoptotic in nature caused by the formation of reactive oxygen species via a type 1 photoredox pathway. Fluorescence microscopy of HeLa cells treated with complex 6 reveals mitochondrial localization of the complex. A significant decrease in the dark toxicity of free esculetin and dppz base is observed upon coordination to cobalt(III). Complexes bind to calf-thymus DNA with significant affinity, but 6 binds with the greatest affinity. Complex 6 efficiently photocleaves supercoiled DNA to its nicked circular form when irradiated with visible light via a photoredox type 1 pathway involving hydroxyl radicals (HO•). Thus, complex 6 showing remarkable visible-light-triggered cytotoxicity but negligible toxicity in the dark is a good candidate for cancer photochemotherapy applications.

Preparation, Characterization and Biological Activity Studies for Some Mixed Ligands Complexes of 1, 10- Phenanthroline and Schiff Base Ligand with Metal Ions

Preparation, Characterization and Biological Activity Studies for Some Mixed Ligands Complexes of 1, 10- Phenanthroline and Schiff Base Ligand with Metal Ions

Synthesis, DNA interactions and antibacterial PDT of Cu(II) complexes of phenanthroline based photosensitizers via singlet oxygen generation

Cu(II) complexes [Cu(mqt)(B)H2O]ClO4(1–3) of 2-thiol 4-methylquinoline and phenanthroline bases (B), viz 1,10-phenanthroline (phen in 1), Dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 2) and Dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 3) have been prepared and characterized by elemental analysis, IR, UV–Vis, magnetic moment values, EPR spectra and conductivity measurements. The spectral data reveal that all the complexes exhibit square-pyramidal geometry. The DNA-binding behaviors of the three complexes were investigated by absorption spectra, viscosity measurements and thermal denaturation studies. The DNA binding constants for complexes (1), (2) and (3) were determined to 2.2×103, 1.3×104 and 8.6×104M−1 respectively. The experimental results suggest that these complexes interact with DNA through groove-binding mode. The photo induced cleavage studies shows that the complexes possess photonuclease property against pUC19 DNA under UV–Visible irradiation via a mechanistic pathway involving formation of singlet oxygen as the reactive species. Antimicrobial photodynamic therapy was studied using photodynamic antimicrobial chemotherapy (PACT) assay against Escherichiacoli and all complexes exhibited significant reduction in bacterial growth on photoirradiation.

Ferrocene-Conjugated Copper(II) Complexes of l-Methionine and Phenanthroline Bases: Synthesis, Structure, and Photocytotoxic Activity

Ferrocene-conjugated reduced Schiff base (Fc-metH) copper(II) complexes of l-methionine and phenanthroline bases, namely, [Cu(Fc-met)(B)](NO3), where B is 1,10-phenanthroline (phen in 1), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 2), dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 3), and 2-(naphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (nip in 4), were prepared and characterized and their photocytotoxicity studied (Fc = ferrocenyl moiety). Complexes [Cu(Ph-met)(B)](NO3) of the reduced Schiff base from benzaldehyde and l-methionine (Ph-metH) and B (phen in 5, dppz in 6) were prepared and used as control species. Complexes 1 and 5 were structurally characterized by X-ray crystallography. Complex 1 as a discrete monomer has a CuN3OS core with the thiomethyl group as the axial ligand. Complex 5 has a polymeric structure with a CuN3O2 core in the solid state. Complexes 5 and 6 are formulated as [Cu(Ph-met)(B)(H2O)](NO3) in an aqueous phase based on the mass spectral data. Complexes 1–4 showed the Cu(II)–Cu(I) and Fc+–Fc redox couples at ∼0.0 and ∼0.5 V vs SCE, respectively, in DMF–0.1 M [Bun4N](ClO4). A Cu(II)-based weak d–d band near 600 nm and a relatively strong ferrocenyl band at ∼450 nm were observed in DMF–Tris-HCl buffer (1:4 v/v). The complexes bind to calf thymus DNA, exhibit moderate chemical nuclease activity forming •OH radical species, and are efficient photocleavers of pUC19 DNA in visible light of 454, 568, and 647 nm, forming •OH radical as the reactive oxygen species. They are cytotoxic in HeLa (human cervical cancer) and MCF-7 (human breast cancer) cells, showing an enhancement of cytotoxicity upon visible light irradiation. Significant change in the nuclear morphology of the HeLa cells was observed with 3 in visible light compared to the nonirradiated sample. Confocal imaging using 4 showed its nuclear localization within the HeLa cells.

Mononuclear copper(II) complex with terpyridine and an extended phenanthroline base, [Cu(tpy)(dppz)] 2+: Synthesis, crystal structure, DNA binding and cytotoxicity activity

The new dipyrido[3,2- a:2′,3′- c]phenazine (dppz) copper(II) complex, [Cu(tpy)(dppz)] 2+, where tpy is 2,2′:6′,2″-terpyridine, has been prepared and fully characterized by spectroscopic methods and single-crystal X-ray diffraction. Its DNA binding and in vitro cytotoxicity have been also studied. The molecular structure shows a distorted trigonal bipyramidal CuN 5 coordination geometry around the copper atom. The bidentate dppz ligand binds in the equatorial plane, while tpy exhibits axial–equatorial bonding. The interaction of the complex with DNA has been investigated by electronic absorption, competitive fluorescence titration, linear dichroism, voltammetric techniques and a gel electrophoresis mobility shift assay. It is proposed that the binding mode of the complex to DNA is of an intercalation nature with the planar dppz ligands located between the base pairs of double-stranded DNA. An in vitro cytotoxicity study of the complex on human breast adenocarcinoma (MCF7) cell line by an MTT assay indicates that the title complex may have the potency to act as an effective anticancer drug, with an IC 50 value of 4.57 μM (3.62–5.77).

Remarkable photocytotoxicity in hypoxic HeLa cells by a dipyridophenazine copper(II) Schiff base thiolate

Copper(II) complexes [Cu(satp)(L)] ( 1– 3) of a Schiff base thiolate (salicylidene-2-aminothiophenol, H 2satp) and phenanthroline bases (L), viz. 1,10-phenanthroline (phen in 1), dipyrido[3,2- d:2′,3′- f]quinoxaline (dpq in 2) and dipyrido[3,2- a:2′,3′- c]phenazine (dppz in 3), were prepared, characterized and their anaerobic DNA photocleavage activity and hypoxic photocytotoxicity studied. The redox active complexes show the Cu(II)–Cu(I) couple near − 0.5 V for 1 and near 0.0 V vs. SCE (saturated calomel electrode) for 2 and 3. The one-electron paramagnetic complexes (~ 1.85 μ B) are avid DNA binders giving K b values within 1.0 × 10 5 − 8.0 × 10 5 M − 1 . Thermal melting and viscosity data along with molecular docking calculations suggest DNA groove and/or partial intercalative binding of the complexes. The complexes show anaerobic DNA cleavage activity in red light under argon via type-I pathway, while DNA photocleavage in air proceeds via hydroxyl radical pathway. The DFT (density functional theory) calculations reveal a thyil radical pathway for the anaerobic DNA photocleavage activity and suggest the possibility of generation of a transient copper(I) species due to bond breakage between the copper and sulfur to generate the thyil radical. An oxidation of the copper(I) species is likely by oxygen in an aerobic medium or by the buffer medium in an anaerobic condition. Complex 3 exhibits significant photocytotoxicity in HeLa cells (IC 50 = 8.3(± 1.0) μM) in visible light, while showing lower dark toxicity (IC 50 = 17.2(± 1.0) μM). A significant reduction in the dark toxicity is observed under hypoxic cellular conditions (IC 50 = 30.0(± 1.0) μM in dark), while retaining its photocytotoxicity (IC 50 = 8.0(± 1.0) μM).

Dicopper(II) complexes showing DNA hydrolase activity and monomeric adduct formation with bis(4-nitrophenyl)phosphate

Ferromagnetic dicopper(II) complexes [Cu2(μ-O2CCH3)(μ-OH)(L)2(μ-L1)](PF6)2, where L=1,10-phenanthroline (phen), L1=H2O in 1 and L=dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq), L1=CH3CN in 2, are prepared and structurally characterized. Crystals of 1 and 2 belong to the monoclinic space group of P21/n and P21/m, respectively. The copper(II) centers display distorted square-pyramidal geometry having a phenanthroline base and two oxygen atoms of the bridging hydroxo and acetate group in the basal plane. The fifth coordination site has weak axially bound bridging solvent molecule H2O in 1 and CH3CN in 2. The Cu···Cu distances are 3.034 and 3.046Å in 1 and 2, respectively. The complexes show efficient hydrolytic cleavage of supercoiled pUC19 DNA as evidenced from the mechanistic studies that include T4 DNA ligase experiments. The binuclear complexes form monomeric copper(II) adducts [Cu(L)2(BNPP)](PF6) (L=phen, 3; dpq, 4) with bis(4-nitrophenyl)phosphate (BNPP) as a model phosphodiester. The crystal structures of 3 and 4 reveal distorted trigonal bipyramidal geometry in which BNPP binds through the oxygen atom of the phosphate. The kinetic data of the DNA cleavage reactions of the binuclear complexes under pseudo- and true-Michaelis–Menten conditions indicate remarkable enhancement in the DNA hydrolysis rate in comparison to the control data.

Ferrocene-Promoted Photoactivated DNA Cleavage and Anticancer Activity of Terpyridyl Copper(II) Phenanthroline Complexes

Ferrocene-appended copper(II) complexes [Cu(Fc-tpy)(B)](ClO4)2 (1−3) and [Cu(Ph-tpy)(dppz)](ClO4)2 (4) as control, where Fc-tpy is 4′-ferrocenyl-2,2′:6′,2′′-terpyridine, Ph-tpy is 4′-phenyl-2,2′:6′,2′′-terpyridine, and B is a phenanthroline base, viz., 1,10-phenanthroline (phen, 1), dipyridoquinoxaline (dpq, 2), and dipyridophenazine (dppz, 3), were prepared and structurally characterized, and their DNA binding, photoactivated DNA cleavage activity, and cytotoxic properties were studied [Fc = (η5-C5H4)FeII(η5-C5H5)]. Complexes 1 and 3 as hexafluorophosphate salts were structurally characterized by X-ray crystallography. Molecular structures of [Cu(Fc-tpy)(phen)](PF6)2 (1a) and [Cu(Fc-tpy)(dppz)](PF6)2·MeCN (3a·MeCN) show a distorted square-pyramidal geometry at copper(II), with the Fc-tpy ligand and the phenanthroline base showing respective tridentate and bidentate binding modes. The phenanthroline base exhibits axial−equatorial bonding, while the Fc-tpy ligand binds at the basal plane. The complexes sho...

DNA photocleavage and anticancer activity of terpyridine copper(II) complexes having phenanthroline bases

Copper(II) complexes [Cu(ph-tpy)(B)](ClO 4) ( 1– 3), where ph-tpy is (4′-phenyl)-2,2′:6′,2″-terpyridine and B is N, N-donor phenanthroline base, viz. 1,10-phenanthroline (phen, 1), dipyridoquinoxaline (dpq, 2), and dipyridophenazine (dppz, 3), were prepared and characterized from analytical and spectral data. Complex 1, characterized by X-ray crystallography, shows a distorted square-pyramidal (4 + 1) CuN 5 coordination geometry having the tridentate ph-tpy ligand at the basal plane and bidentate phen bound to the axial-equatorial sites. The complexes display a d– d band near 650 nm in aqueous DMF. The complexes are avid binders to calf thymus DNA giving the binding order: 3 (dppz) > 2 (dpq) > 1 (phen). The dpq and dppz complexes show photo-induced DNA cleavage activity in red light via photo-redox pathway forming hydroxyl radicals. The cytotoxicity of the dppz complex 3 was studied by MTT assay in HeLa cancer cells. The IC 50 values are 3.7 and 12.4 μM in visible light of 400–700 nm and dark, respectively.

Photocytotoxic and anaerobic DNA cleavage activity of binuclear 3,3′-dithiodipropionic acid cobalt(II) complexes having phenanthroline bases

Dicobalt(II) complexes [{(B)Co II} 2(μ-dtdp) 2] ( 1– 3) of 3,3′-dithiodipropionic acid (dtdp) and phenanthroline bases (B), viz. 1,10-phenanthroline (phen in 1), dipyrido[3,2- d:2′,3′- f]quinoxaline (dpq in 2) and dipyrido[3,2- a:2′,3′- c]phenazine (dppz in 3), have been prepared, characterized and their photo-induced anaerobic DNA cleavage activity studied. The elemental analysis and mass spectral data suggest binuclear formulation of the complexes. The redox inactive complexes have magnetically non-interacting dicobalt(II) core showing magnetic moment of ∼3.9 μ B per cobalt(II) center. The complexes show good binding propensity to calf thymus DNA giving K b values within 4.3 × 10 5–4.0 × 10 6 M −1. Thermal melting and viscosity data predict DNA groove binding and/or partial intercalative nature of the complexes. The complexes show significant anaerobic DNA cleavage activity in green light under argon atmosphere possibly involving radical species generated from the disulfide moiety in a type-I pathway. The DNA cleavage reaction under aerobic medium in green light is found to involve hydroxyl radical species. The dppz complex 3 exhibits significant photocytotoxicity in HeLa cervical cancer cells with an IC 50 value of 2.3 μM in UV-A light of 365 nm, while it is essentially non-toxic in dark giving an IC 50 value of >200 μM. A significant reduction of the dark toxicity of the organic dppz base (IC 50 = 8.3 μM in dark) is observed on binding to the cobalt(II) center while essentially retaining its photocytotoxicity in UV-A light (IC 50 = 0.4 μM).

Photocytotoxic Lanthanum(III) and Gadolinium(III) Complexes of Phenanthroline Bases Showing Light-Induced DNA Cleavage Activity

Lanthanide complexes of formulation [La(B)(2)(NO(3))(3)] (1-3) and [Gd(B)(2)(NO(3))(3)] (4-6), where B is a N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1, 4), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 2, 5) and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 3, 6), have been prepared, characterized from physicochemical data, and their photoinduced DNA and protein cleavage activity studied. The photocytotoxicity of the dppz complexes 3 and 6 has been studied using HeLa cancer cells. The complexes exhibit ligand centered bands in the UV region. The dppz complexes show the lowest energy band at 380 nm in N,N-dimethylformamide (DMF). The La(III) complexes are diamagnetic. The Gd(III) complexes (4-6) have magnetic moments that correspond to seven unpaired electrons. The complexes are 1:1 electrolytic in aqueous DMF. The dpq and dppz complexes in DMF show ligand-based reductions. The complexes display moderate binding propensity to calf thymus DNA giving binding constant values in the range of 5.7 x 10(4)-5.8 x 10(5) M(-1) with a relative order: 3, 6 (dppz) > 2, 5 (dpq) > 1, 4 (phen). The binding data suggest DNA surface and/or groove binding nature of the complexes. The complexes do not show any hydrolytic cleavage of plasmid supercoiled pUC19 DNA. The dpq and dppz complexes efficiently cleave SC DNA to its nicked circular form on exposure to UV-A light of 365 nm at nanomolar complex concentration. Mechanistic studies reveal the involvement of singlet oxygen ((1)O(2)) and hydroxyl radical (HO*) as the cleavage active species. The complexes show binding propensity to bovine serum albumin (BSA) protein giving K(BSA) values of approximately 10(5) M(-1). The dppz complexes 3 and 6 show BSA protein cleavage activity in UV-A light of 365 nm. The dppz complexes 3 and 6 exhibit significant photocytotoxicity in HeLa cells giving respective IC(50) values of 341 nM and 573 nM in UV-A light of 365 nm for an exposure time of 15 min (IC(50) > 100 microM in dark for both the complexes). Control experiments show significant dark and phototoxicity of the dppz base alone (IC(50) = 413 nM in light with 4 h incubation in dark and 11.6 microM in dark with 24 h incubation). A significant decrease in the dark toxicity of the dppz base is observed on binding to the lanthanide ions while retaining similar phototoxicity.

Photocytotoxicity and near-IR light DNA cleavage activity of oxovanadium(IV) Schiff base complexes having phenanthroline bases

Oxovanadium(IV) complexes [VO(L)(B)] ( 1– 3), where H 2L is a Schiff base ligand 2-(2-hydroxybenzylideneamino)phenol and B is 1,10-phenanthroline (phen for 1), dipyrido[3,2- d:2′,3′- f]quinoxaline (dpq for 2) or dipyrido[3,2- a:2′,3′- c]phenazine (dppz for 3), have been prepared, characterized and their DNA binding property and photo-induced DNA cleavage activity studied. Complex 3 which is structurally characterized by X-ray crystallography shows the presence of an oxovanadium(IV) moiety in a six coordinate VO 3N 3 coordination geometry. The complexes show a d–d band within 800–850 nm in DMF. The complexes display an oxidative response near 0.7 V versus SCE for V(V)–V(IV) and a reductive response within −1.1 to −1.3 V due to V(IV)–V(III) couple in DMF–0.1 M TBAP. The complexes are avid binders to calf thymus DNA giving binding constant values of 4.2 × 10 4 to 1.2 × 10 5 M −1. The complexes do not show any “chemical nuclease” activity in dark. The dpq and dppz complexes are photocleavers of plasmid DNA in UV-A light of 365 nm via 1O 2 pathway and in near-IR light (752.5 to 799.3 nm IR optics) by HO • pathway. Complex 3 exhibits significant photocytotoxicity in visible light in HeLa cells giving IC 50 value of 13 μM, while it is less toxic in dark (IC 50 = 97 μM).

Photocytotoxicity and DNA cleavage activity of l-arg and l-lys Schiff base oxovanadium(iv) complexes having phenanthroline bases

Oxovanadium(IV) complexes [VO(sal-argH)(B)]Cl (1-3) and [VO(sal-lysH)(B)]Cl (4-6), where sal-argH2 and sal-lysH2 are N-salicylidene-L-arginine and N-salicylidene-L-lysine Schiff bases and B is a phenanthroline base, viz. 1,10-phenanthroline (phen in 1 and 4); dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 2 and 5) and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 3 and 6), have been prepared, characterized and their DNA photocleavage activity studied. Complex 1, characterized by X-ray crystallography, shows the presence of a vanadyl group in V(IV)O3N3 coordination geometry with a tridentate Schiff base having a pendant guanidinium moiety and bidentate phen ligand. The complexes exhibit a d-d band at 715 nm in 20% DMF-Tris-HCl buffer. The complexes are redox active showing cathodic and anodic responses near -1.0 V and 0.85 V (vs. SCE) for the V(IV)-V(III) and V(V)-V(IV) couples, respectively, in DMF-Tris-HCl buffer. The complexes bind to calf thymus DNA giving Kb values in the range of 3.8 x 10(4) to 1.6 x 10(5) M(-1). Thermal denaturation and viscosity data suggest DNA groove binding nature of the complexes. The complexes do not show any "chemical nuclease" activity in dark in the presence of 3-mercaptopropionic acid or H2O2. The dpq and dppz complexes are efficient photocleavers of plasmid DNA in UV-A (365 nm) and red light (676 nm) via singlet oxygen pathway. The dppz complexes exhibit photocytotoxicity in HeLa cancer cells giving IC50 values of 15.4 microM for 3 and 17.5 microM for 6 in visible light while being non-toxic in dark giving IC50 values of >100 microM.

Photoinduced DNA and Protein Cleavage Activity of Ferrocene-Conjugated Ternary Copper(II) Complexes

Ferrocene-conjugated ternary copper(II) complexes [Cu(L)(B)](ClO4)2, where L is FcCH2N(CH2Py)2 (Fc = (η5-C5H4)FeII(η5-C5H5)) and B is a phenanthroline 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]phenazine (dppz, 4), have been synthesized and characterized by various spectroscopic and analytical techniques. The bpy complex 1, as its hexafluorophosphate salt, has been structurally characterized by X-ray crystallography. The molecular structure shows the copper(II) center having an essentially square-pyramidal coordination geometry in which L with a pendant ferrocenyl (Fc) moiety and bpy show respective tridentate and bidentate modes of binding to the metal center. The complexes are redox active, showing a reversible cyclic voltammetric response of the Fc+−Fc couple near 0.5 V vs SCE and a quasi-reversible Cu(II)−Cu(I) couple near 0.0 V. Complexes 2−4 show binding affinity to calf thymus (CT) DNA, giving binding constant (Kb) values in the range of 4.2 × 104 to 2.5 × 105 M−1. Thermal denaturation and viscometric titration data suggest groove binding and/or a partial intercalative mode of binding of the complexes to CT DNA. The complexes show good binding propensity to the bovine serum albumin (BSA) protein, giving KBSA values of ∼104 M−1 for the bpy and phen complexes and ∼105 M−1 for the dpq and dppz complexes. Complexes 2−4 exhibit efficient chemical nuclease activity in the presence of 3-mercaptopropionic acid (MPA) as a reducing agent or hydrogen peroxide (H2O2) as an oxidizing agent. Mechanistic studies reveal formation of hydroxyl radicals as the reactive species. The dpq and dppz complexes are active in cleaving supercoiled (SC) pUC19 DNA on photoexposure to visible light of different wavelengths including red light using an argon−krypton mixed gas ion laser. Mechanistic investigations using various inhibitors reveal the formation of hydroxyl radicals in the DNA photocleavage reactions. The dppz complex 4, which shows efficient photoinduced BSA cleavage activity, is a potent multifunctional model nuclease and protease in the chemistry of photodynamic therapy (PDT) of cancer.

An Iron Complex of Dipyridophenazine as a Potent Photocytotoxic Agent in Visible Light

Ternary iron(III) complexes [FeL(B)] (1-3) of a trianionic tetradentate phenolate-based ligand (L) and phenanthroline base (B), namely, 1,10-phenanthroline (phen, 1), dipyridoquinoxaline (dpq, 2), and dipyridophenazine (dppz, 3), have been prepared and structurally characterized and their DNA binding, cleavage, and photocytotoxic properties studied. The complexes with a FeN(3)O(3) core show the Fe(III)/Fe(II) redox couple near -0.6 V in DMF, a magnetic moment value of approximately 5.9 micro(B), and a binding propensity to both calf thymus DNA and bovine serum albumin (BSA) protein. They exhibit red-light-induced DNA cleavage activity following a metal-assisted photoredox pathway forming HO(*) radicals but do not show any photocleavage of BSA in UV-A light. Complex 3 displays photocytotoxicity in the human cervical cancer cell line (HeLa) and human keratinocyte cell line (HaCaT) with respective IC(50) values of 3.59 microM and 6.07 microM in visible light and 251 nM and 751 nM in UV-A light of 365 nm. No significant cytotoxicity is observed in the dark. The photoexposed HeLa cells, treated prior with complex 3, have shown marked changes in nuclear morphology as demonstrated by Hoechst 33258 nuclear stain. Generation of reactive oxygen species has been evidenced from the fluorescence enhancement of dichlorofluorescein upon treatment with 3 followed by photoexposure. Nuclear chromatin cleavage has been observed in acridine orange/ethidium bromide dual staining of treated HeLa cells and from alkaline single-cell gel electrophoresis. Caspase 3/7 activity in HeLa cells has been found to be upregulated by only 4 fold after photoirradiation, signifying the fact that cell death through a caspase 3/7 dependent pathway may not be solely operative.

Anaerobic Photocleavage of DNA in Red Light by Dicopper(II) Complexes of 3,3′-Dithiodipropionic Acid

Binuclear copper(II) complexes [{(phen)Cu(II)}(2)(mu-dtdp)(2)] (1), [{(dpq)Cu(II)}(2)(mu-dtdp)(2)] (2), [{(phen)Cu(II)}(2)(mu-az)(2)] (3), and [{(dpq)Cu(II)}(2)(mu-az)(2)] (4) and a zinc(II) complex [{(phen)Zn(II)}(2)(mu-dtdp)(2)] (5), having 3,3'-dithiodipropionic acid (H(2)dtdp), azelaic acid (nonanedioic acid), 1,10-phenanthroline (phen), and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), were prepared and characterized by physicochemical methods. Complex 1 has been structurally characterized by X-ray crystallography. The complexes have each metal center bound to a chelating phenanthroline base and two bridging carboxylate ligands giving a square-planar MN(2)O(2) coordination geometry. The molecular structure of complex 1 shows two sterically constrained disulfide moieties of the dtdp ligands. The complexes show good binding propensity to calf thymus DNA in the major groove. The photoinduced DNA cleavage activity of the complexes has been studied using 365 nm UV light and 647.1 nm and >750 nm red light under both aerobic and anaerobic conditions. The phen complex 1, having dtdp ligand, cleaves supercoiled (SC) DNA to its nicked circular (NC) form. The dpq analogue 2 shows formation of a significant quantity of linear DNA resulting from double-strand breaks (dsb) in air. Mechanistic studies reveal the involvement of HO(*) and (1)O(2) as the reactive species under an aerobic medium. The dsb of DNA is rationalized from the docking studies on 2, showing a close proximity of two photosensitizers, namely, the disulfide moiety of dtdp and the quinoxaline ring of dpq to the complementary strands of DNA. The copper(II) complexes of the dtdp ligand cleave SC DNA to its NC form upon exposure to UV or red light under an argon atmosphere. An enhancement of the DNA cleavage activity under argon has been observed upon increasing the concentration of the DMF solvent in the DMF-Tris buffer medium. Theoretical studies suggest the possibility of sulfide anion radical formation from a copper(II)-bound dtdp ligand in >750 nm red light, which further cleaves the DNA. The copper(II) azelate complexes are inactive under similar reaction conditions. The azelate complex of the dpq ligand cleaves DNA in air following the (1)O(2) pathway. The zinc(II) complex of the dtdp ligand (5) does not show any photoinduced DNA cleavage activity in red light.