Cu(II) flavonoids as potential photochemotherapeutic agents.

Flavonoids, naturally derived polyphenolic compounds, have received significant attention due to their remarkable biochemical properties that offer substantial health benefits to humans. In this work, a series of six Cu(II) flavonoid complexes of the formulation [Cu(L1)(L2)](ClO4) where L1 is 3-hydroxy flavone (HF1, 1 and 4), 4-fluoro-3-hydroxy flavone (HF2, 2 and 5), and 2,6-difluoro-3-hydroxy flavone (HF3, 3 and 6); L2 is 1,10-phenanthroline (phen, 1-3) and 2-(anthracen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip, 4-6) were successfully synthesized, fully characterized and also evaluated for their in vitro photo-triggered cytotoxicity in cancer cells. The single-crystal X-ray diffraction structure of complex 2 shows square pyramidal geometry around the Cu(II) center. The complexes 1-6 showed quasi-reversible cyclic voltammetric responses for the Cu(II)/Cu(I) couple at ∼-0.230 V with a very large ΔEp value of ∼350-480 mV against the Ag/AgCl reference electrode in DMF-0.1 M tetrabutylammonium perchlorate (TBAP) at a scan rate of 50 mV s-1. The complexes were found to have considerable binding propensity for human serum albumin (HSA) and calf thymus DNA (ct-DNA). The complexes displayed remarkable dose-dependent photocytotoxicity in visible light (400-700 nm) in both A549 (human lung cancer) and MCF-7 (human breast cancer) cell lines while remaining significantly less toxic in darkness. They were found to be much less toxic to HPL1D (immortalized human peripheral lung epithelial) normal cells compared to A549 and MCF-7 cancer cells. Upon exposure to visible light, they generate reactive oxygen species, which are thought to be the main contributors to the death of cancer cells. In the presence of visible light, the complexes predominantly elicit an apoptotic mode of cell death. Complex 6 preferentially localizes in the mitochondria of A549 cells.

Copper(ii) curcumin complexes for endoplasmic reticulum targeted photocytotoxicity.

Three copper(ii) complexes viz. [Cu(cur)(L)(ClO4)] (1-3), where Hcur is curcumin and L is 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) were synthesized, fully characterized by various physicochemical methods and evaluated for their light-assisted chemotherapeutic potential. The complexes [Cu(acac)(L)(ClO4)] (4-6), where Hacac is acetylacetone and L is phen (in 4), dpq (in 5) and dppz (in 6), were synthesized and used as controls. The solid state structures of complexes 4 and 5 were determined by single crystal X-ray diffraction. The curcumin complexes (1-3) were redox inactive at the copper centre, whereas the acetylacetonato complexes (4-6) displayed a Cu(ii)/Cu(i) couple at ∼0.1 V vs. Ag/AgCl reference electrode in DMF. Complexes 1-3 showed an intense curcumin-based band at ∼440 nm in DMF-Tris-HCl buffer (pH = 7.2) (1 : 9 v/v) which masks the copper based d-d band. The complexes bind to human serum albumin (HSA) with moderate efficacy. They also displayed significant binding affinity for calf-thymus (CT) DNA. The lipophilic curcumin complexes show remarkable visible light induced cytotoxicity (IC50 = ∼4 µM) with high phototoxic indices (PI) with low dark toxicity in human cervical carcinoma (HeLa) and human lung carcinoma (A549) cells. The corresponding acetylacetonato controls (4-6) did not show significant cytotoxicity in the dark or light. DCFDA and annexin V-FITC/PI assays using flow cytometry confirm the induction of significant apoptosis in cancer cells via generation of cytotoxic reactive oxygen species upon photoactivation. Confocal microscopic images using complex 3 demonstrate localization of the complexes predominantly in the endoplasmic reticulum of HeLa cells.

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.

Ni(II) curcumin complexes for cellular imaging and photo-triggered in vitro anticancer activity.

Nickel(II) complexes [Ni(cur)(L)2](OAc) (1-3) where L is N,N-donor heterocyclic bases namely 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 Hcur is curcumin were prepared, fully characterized and light-induced in vitro anticancer activity studied. Three nickel(II) complexes containing acetylacetonato (Hacac) ligand, viz.[Ni(acac)(L)2](OAc) (4-6) where L is phen (in 4), dpq (in 5), dppz (in 6) were prepared and used as controls. Complex 4 was structurally characterized by single crystal X-ray diffraction technique, which revealed an octahedral NiN4O2 geometry around the metal centre. Complexes 1-3 showed an intense curcumin-based band at ∼440 nm in DMSO-Tris-HCl buffer (pH = 7.2) (1:4 v/v) which masks the nickel based d-d band. The curcumin comlexes (1-3) were redox inactive at the nickel centre, whereas the acetylacetonato complexes (4-6) displayed an irreversible voltammetric response at ∼1.00 V vs. Ag/AgCl reference electrode in DMF. The complexes bind to calf thymus DNA (ct-DNA) with considerable affinity and interacted with human serum albumin (HSA) with moderate affinity. The Ni(II) curcumin complexes display significant in vitro light-induced cytotoxicity in HeLa (human cervical carcinoma) and A549 (lung cancer cells) involving reactive oxygen species (ROS), with very low dark toxicity. The complexes were found to be much less toxic to immortalized lung epithelial normal cells (HPL1D). Confocal microscopic images using complex 2 and 3 showed that they primarily localize in the cytosol of A549 cells. The mechanism of cell death is mainly apoptosis in nature showing arrest of sub-G1 phase of cell cycle progression in A549 cells under visible light exposure and involves significant loss of mitochondrial membrane potential as observed from JC-1 assay.

Visible light-induced cytotoxicity studies on Co(ii) complexes having an anthracene-based curcuminoid ligand.

Herein, two ternary cobalt(ii) complexes, namely [Co(9-accm)(phen)2](OAc) (1) and [Co(9-accm)(dppz)2](OAc) (2), where 9-accmH is 1,7-(di-9-anthracene-1,6-heptadiene-3,5-dione), phen is 1,10-phenanthroline and dppz is dipyrido[3,2-a:2',3'-c]phenazine, having an anthracene-based curcuminoid and phenanthroline bases were synthesized and fully characterized, and their in vitro photocytotoxicities were studied in cancer cells. To understand the role of the curcuminoid ligand 9-accm in photo-activated cytotoxicity, two control complexes, viz. [Co(dbm)(phen)2](OAc) (3) and [Co(dbm)(dppz)2](OAc) (4), where dbmH is 1,3-diphenyl-1,3-propanedione (dibenzoylmethane), were prepared and used for the control experiments. Complex 3 was structurally characterized by X-ray crystallography. The complexes displayed a quasi-reversible Co(i)/Co(ii) redox couple at ∼-1.1 V and an irreversible Co(ii)/Co(iii) couple at ∼1.3 V vs. Ag/AgCl in DMF-0.1 M [Bun4N](ClO4). Highly intense 9-accm ligand-centred bands were observed at ∼250-450 nm, which masked the Co(ii)-based weak d-d bands in the DMF-Tris-HCl buffer (1 : 9 v/v). The complexes displayed a significant binding propensity for calf-thymus (ct) DNA with binding constants in the range from (2.42 ± 0.10) × 105 to (3.24 ± 0.13) × 106 M-1. They also showed a moderate binding affinity for human serum albumin (HSA), displaying Kb values in the order of ∼104-105 M-1. The complexes 1 and 2 showed prodigious photoenhanced cytotoxicity in human cervical cancer (HeLa) and breast cancer (MCF-7 and MDA-MB-231) cells with low dark toxicity, whereas they were non-toxic to immortalized lung epithelial normal cells (HPL1D). Flow cytometric studies showed a time-dependent uptake of the complexes 1 and 2 in HeLa cells. The complexes generated reactive oxygen species (ROS) upon excitation with low energy visible light, thereby killing the cancer cells. The results from DAPI staining, AO/EB dual staining and Annexin-V-FITC experiments suggested that the complexes induce cell death primarily via an apoptotic mechanism in HeLa cells.

Cell-Penetrating Protein/Corrole Nanoparticles.

Recent work has highlighted the potential of metallocorroles as versatile platforms for the development of drugs and imaging agents, since the bioavailability, physicochemical properties and therapeutic activity can be dramatically altered by metal ion substitution and/or functional group replacement. Significant advances in cancer treatment and imaging have been reported based on work with a water-soluble bis-sulfonated gallium corrole in both cellular and rodent-based models. We now show that cytotoxicities increase in the order Ga < Fe < Al < Mn < Sb < Au for bis-sulfonated corroles; and, importantly, that they correlate with metallocorrole affinities for very low density lipoprotein (VLDL), the main carrier of lipophilic drugs. As chemotherapeutic potential is predicted to be enhanced by increased lipophilicity, we have developed a novel method for the preparation of cell-penetrating lipophilic metallocorrole/serum-protein nanoparticles (NPs). Cryo-TEM revealed an average core metallocorrole particle size of 32 nm, with protein tendrils extending from the core (conjugate size is ~100 nm). Optical imaging of DU-145 prostate cancer cells treated with corrole NPs (≤100 nM) revealed fast cellular uptake, very slow release, and distribution into the endoplasmic reticulum (ER) and lysosomes. The physical properties of corrole NPs prepared in combination with transferrin and albumin were alike, but the former were internalized to a greater extent by the transferrin-receptor-rich DU-145 cells. Our method of preparation of corrole/protein NPs may be generalizable to many bioactive hydrophobic molecules to enhance their bioavailability and target affinity.

Photocytotoxic copper(II) complexes of N-salicylyl-l-tryptophan and phenanthroline bases.

Four ternary copper(II) complexes of N-salicylyl-l-Tryptophan (Sal-TrpH) and phenanthroline bases of general formula [Cu(Sal-Trp)(L)], where L is 1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2), dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3) and 2-(anthracen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip, 4), were synthesized and fully characterized. The complexes were evaluated for their affinity for biomolecules and photocytotoxic activities. Single crystal X-ray diffraction studies of complex 1 revealed that it has a square pyramidal CuN3O2 core with the phenolate oxygen of salicylaldehyde occupying the axial coordination site in the solid state. Complexes 1-4 displayed the Cu(II)-Cu(I) redox couples at ~-0.3 V vs. Ag/AgCl reference electrode in DMF-0.1 M [Bun4N](ClO4). A Cu(II)-based weak d-d band ~650 nm and a moderately strong ligand to metal charge transfer band at ~430 nm were observed in DMF-Tris-HCl buffer (pH 7.2) (1:4 v/v). The complexes are efficient binders to calf thymus DNA and model proteins such as bovine serum albumin and lysozyme. They cleave supercoiled plasmid DNA efficiently when exposed to 446 and 660 nm laser radiation. They are cytotoxic to HeLa (human cervical cancer) and MCF-7 (human breast cancer) cells showing significant enhancement of cytotoxicity upon photo-excitation with low energy visible light. The complexes are found to kill cancer cells through generation of reactive oxygen species (ROS) as confirmed by DCFDA (2',7'-dichlorofluorescin diacetate) assay. The apoptotic cell death induced by complex 4 was confirmed by Annexin V-Fluorescein isothiocyanate-Propidium iodide assay. Confocal microscopic images using 4 showed its primary cytosolic localization in the HeLa and MCF-7 cells.

Ferrocenyl-L-amino acid copper(II) complexes showing remarkable photo-induced anticancer activity in visible light.

Ferrocene-conjugated copper(ii) complexes [Cu(Fc-aa)(aip)](ClO4) () and [Cu(Fc-aa)(pyip)](ClO4) () of l-amino acid reduced Schiff bases (Fc-aa), 2-(9-anthryl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip) and 2-(1-pyrenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (pyip), where Fc-aa is ferrocenylmethyl-l-tyrosine (Fc-Tyr in , ), ferrocenylmethyl-l-tryptophan (Fc-Trp in , ) and ferrocenylmethyl-l-methionine (Fc-Met in , ), were prepared and characterized, and their photocytotoxicity was studied (Fc = ferrocenyl moiety). Phenyl analogues, viz. [Cu(Ph-Met)(aip)](ClO4) () and [Cu(Ph-Met)(pyip)](ClO4) (), were prepared and used as control compounds. The bis-imidazophenanthroline copper(ii) complexes, viz. [Cu(aip)2(NO3)](NO3) () and [Cu(pyip)2(NO3)](NO3) (), were also prepared and used as controls. Complexes having a redox inactive cooper(ii) center showed the Fc(+)-Fc redox couple at ∼0.5 V vs. SCE in DMF-0.1 mol [Bu(n)4N](ClO4). The copper(ii)-based d-d band was observed near 600 nm in DMF-Tris-HCl buffer (1 : 1 v/v). The ferrocenyl complexes showed low dark toxicity, but remarkably high photocytotoxicity in human cervical HeLa and human breast adenocarcinoma MCF-7 cancer cells giving an excellent photo-dynamic effect while their phenyl analogues were inactive. The photo-exposure caused significant morphological changes in the cancer cells when compared to the non-irradiated ones. The photophysical processes were rationalized from the theoretical studies. Fluorescence microscopic images showed and localizing predominantly in the endoplasmic reticulum (ER) of the cancer cells, thus minimizing any undesirable effects involving nuclear DNA.

Photocytotoxicity of copper(II) complexes of curcumin and N-ferrocenylmethyl-L-amino acids.

Copper(II) complexes [Cu(Fc-aa)(cur)] (1-3) of curcumin (Hcur) and N-ferrocenylmethyl-L-amino acids (Fc-aa), viz., ferrocenylmethyl-L-tyrosine (Fc-TyrH), ferrocenylmethyl-L-tryptophan (Fc-TrpH) and ferrocenylmethyl-L-methionine (Fc-MetH), were prepared and characterized. The DNA photocleavage activity, photocytotoxicity and cellular localization in HeLa and MCF-7 cancer cells of these complexes were studied. Acetylacetonate (acac) complexes [Cu(Fc-aa)(acac)] (4-6) were prepared and used as controls. The chemical nuclease inactive complexes showed efficient pUC19 DNA cleavage activity in visible light. Complexes 1-3 showed high photocytotoxicity with low dark toxicity thus giving remarkable photodynamic effect. FACScan analysis showed apoptosis of the cancer cells. Fluorescence microscopic studies revealed primarily cytosolic localization of the complexes.

Photo-induced anticancer activity of polypyridyl platinum(II) complexes.

Polypyridyl platinum(II) complexes (1-5), viz., [Pt(pyphen)Cl]Cl (1), [Pt(pyphen)(C≡CFc)]Cl (2), [Pt(pydppz)Cl]Cl (3), [Pt(pydppz)(C≡CPh)]Cl (4) and [Pt(pydppz)(C≡CFc)]Cl (5), where pyphen is 6-(2-pyridyl)-1,10-phenanthroline, pydppz is 6-(2-pyridyl)-dipyrido-[3,2-a:2',3'-c]-phenazine, FcC≡CH is ferrocenyl acetylene and PhC≡CH is phenyl acetylene, were synthesized, characterized and their DNA binding and photocytotoxic properties studied. The complexes showed strong binding affinity to calf-thymus DNA giving K(app) of ∼10(6)-10(7) M(-1). Complexes 4 and 5 showed dual mode of binding to ct-DNA. The pydppz complexes 3-5 having a photoactive phenazine moiety showed photocytotoxicity in HeLa and MCF-7 cells in UV-A light of 365 nm with apoptotic cell death as evidenced from the acridine orange/ethidium bromide dual staining and the FACS data.

Photoactivated DNA cleavage and anticancer activity of pyrenyl-terpyridine lanthanide complexes.

Lanthanide(III) complexes [Ln(R-tpy)(acac)(NO(3))(2)] (Ln = La(III) in 1, 2; Gd(III) in 4, 5) and [Ln(py-tpy)(sacac)(NO(3))(2)] (Ln = La(III), 3; Gd(III), 6), where R-tpy is 4'-phenyl-2,2':6',2″-terpyridine (ph-tpy in 1, 4), 4'-(1-pyrenyl)-2,2':6',2″-terpyridine (py-tpy in 2, 3, 5 and 6), acac is acetylacetonate and sacac is 4-hydroxy-6-{4-[(ß-d-glucopyranoside)oxy]phenyl}hex-3,5-dien-2-onate, were prepared to study their DNA photocleavage activity and photocytotoxicity. Complexes [La(ph-tpy)(acac)(EtOH)(NO(3))(2)] (1a) and [Gd(ph-tpy)(acac)(NO(3))(2)] (4) were characterized by X-ray crystallography. The 1:1 electrolytic complexes bind to calf thymus DNA. The py-tpy complexes cleave pUC19 DNA and exhibit remarkable photocytotoxicity in HeLa cells in UV-A light of 365 nm with apoptotic cell death (IC(50): ∼40 nM in light, >200 µM in dark). Confocal microscopy using HeLa cells reveal primarily cytosolic localization of the complexes.

Photo-induced DNA cleavage activity and remarkable photocytotoxicity of lanthanide(III) complexes of a polypyridyl ligand.

Lanthanide(III) complexes [Ln(pyphen)(acac)(2)(NO(3))] (1, 2), [Ln(pydppz)(acac)(2)(NO(3))] (3, 4) and [La(pydppz)(anacac)(2)(NO(3))] (5), where Ln is La(III) (in 1, 3, 5) and Gd(III) (in 2, 4), pyphen is 6-(2-pyridyl)-1,10-phenanthroline, pydppz is 6-(2-pyridyl)-dipyrido[3,2-a:2',3'-c]phenazine, anacac is anthracenylacetylacetonate and acac is acetylacetonate, were prepared, characterized and their DNA photocleavage activity and photocytotoxicity studied. The crystal structure of complex 2 displays a GdO(6)N(3) coordination. The pydppz complexes 3-5 show an electronic spectral band at ~390 nm in DMF. The La(III) complexes are diamagnetic, while the Gd(III) complexes are paramagnetic with seven unpaired electrons. The molar conductivity data suggest 1 : 1 electrolytic nature of the complexes in aqueous DMF. They are avid binders to calf thymus DNA giving K(b) in the range of 5.4 × 10(4)-1.2 × 10(6) M(-1). Complexes 3-5 efficiently cleave supercoiled DNA to its nicked circular form in UV-A light of 365 nm via formation of singlet oxygen ((1)O(2)) and hydroxyl radical (HO˙) species. Complexes 3-5 also exhibit significant photocytotoxic effect in HeLa cancer cells giving respective IC(50) value of 0.16(±0.01), 0.15(±0.01) and 0.26±(0.02) µM in UV-A light of 365 nm, while they are less toxic in dark with an IC(50) value of >3 µM. The presence of an additional pyridyl group makes the pydppz complexes more photocytotoxic than their dppz analogues. FACS analysis of the HeLa cells treated with complex 4 shows apoptosis as the major pathway of cell death. Nuclear localization of complex 5 having an anthracenyl moiety as a fluorophore is evidenced from the confocal microscopic studies.

Impact of metal on the DNA photocleavage activity and cytotoxicity of ferrocenyl terpyridine 3d metal complexes.

Ferrocenyl terpyridine 3d metal complexes and their analogues, viz. [M(Fc-tpy)(2)](ClO(4))(2) (1-4), [Zn(Ph-tpy)(2)](ClO(4))(2) (5) and [Zn(Fc-dpa)(2)]X(2) (X = ClO(4), 6; PF(6), 6a), where M = Fe(II) in 1, Co(II) in 2, Cu(II) in 3 and Zn(II) in 4, Fc-tpy is 4'-ferrocenyl-2,2':6',2''-terpyridine, Ph-tpy is 4'-phenyl-2,2':6',2''-terpyridine and Fc-dpa is ferrocenyl-N,N-dipicolylmethanamine, are prepared and their DNA binding and photocleavage activity in visible light studied. Complexes 2, 4, 5 and 6a that are structurally characterized by X-ray crystallography show distorted octahedral geometry with the terpyridyl ligands binding to the metal in a meridional fashion, with Fc-dpa in 6a showing a facial binding mode. The Fc-tpy complexes display a charge transfer band in the visible region. The ferrocenyl (Fc) complexes show a quasi-reversible Fc(+)-Fc redox couple within 0.48 to 0.66 V vs. SCE in DMF-0.1 M TBAP. The DNA binding constants of the complexes are ∼10(4) M(-1). Thermal denaturation and viscometric data suggest DNA surface binding through electrostatic interaction by the positively charged complexes. Barring the Cu(II) complex 3, the complexes do not show any chemical nuclease activity in the presence of glutathione. Complexes 1-4 exhibit significant plasmid DNA photocleavage activity in visible light via a photoredox pathway. Complex 5, without the Fc moiety, does not show any DNA photocleavage activity. The Zn(II) complex 4 shows a significant PDT effect in HeLa cancer cells giving an IC(50) value of 7.5 µM in visible light, while being less toxic in the dark (IC(50) = 49 µM).

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, H2satp) 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 µB) are avid DNA binders giving Kb 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 (IC50=8.3(±1.0) µM) in visible light, while showing lower dark toxicity (IC50=17.2(±1.0) µM). A significant reduction in the dark toxicity is observed under hypoxic cellular conditions (IC50=30.0(±1.0) µM in dark), while retaining its photocytotoxicity (IC50=8.0(±1.0) µM).

Ferrocene-conjugated L-tryptophan copper(II) complexes of phenanthroline bases showing DNA photocleavage activity and cytotoxicity.

Ferrocene-conjugated L-tryptophan (L-Trp) reduced Schiff base (Fc-TrpH) copper(II) complexes [Cu(Fc-Trp)(L)](ClO(4)) of phenanthroline bases (L), viz. 2,2'-bipyridine (bpy in 1), 1,10-phenanthroline (phen in 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 3), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 4), were prepared and characterized and their photocytotoxicity studied. Cationic reduced Schiff base (Ph-TrpH) complexes [Cu(Ph-Trp)(L)(H(2)O)](ClO(4)) (L = phen in 5; dppz in 6) having the ferrocenyl moiety replaced by a phenyl group and the Zn(II) analogue (7) of complex 4 were prepared and used as control species. The crystal structures of 1 and 5 with respective square-planar CuN(3)O and square-pyramidal CuN(3)O(2) coordination geometry show significantly different core structures. Complexes 1-4 exhibit a Cu(II)-Cu(I) redox couple near -0.1 V and the Fc(+)-Fc couple at ~0.5 V vs SCE in DMF-0.1 M [Bu(n)(4)N](ClO(4)) (Fc = ferrocenyl moiety). The complexes display a copper(II)-based d-d band near 600 nm and a Fc-centered band at ~450 nm in DMF-Tris-HCl buffer. The complexes are efficient binders to calf thymus DNA. They are synthetic chemical nucleases in the presence of thiol or H(2)O(2), forming hydroxyl radicals. The photoactive complexes are cleavers of pUC19 DNA in visible light, forming hydroxyl radicals. Complexes 2-6 show photocytotoxicity in HeLa cancer cells, giving IC(50) values of 4.7, 10.2, 1.3, 4.8, and 4.3 µM, respectively, in visible light with the appearance of apoptotic bodies. The complexes also show photocytotoxicity in MCF-7 cancer cells. Nuclear chromatin cleavage has been observed with acridine orange/ethidium bromide (AO/EB) dual staining with complex 4 in visible light. The complexes induce caspase-independent apoptosis in the HeLa cells.