Metal anthracycline complexes as a new class of anthracycline derivatives. Pd(II)-adriamycin and Pd(II)-daunorubicin complexes: physicochemical characteristics and antitumor activity

Pd(II) complexes of two anthracyclines, adriamycin and daunorubicin, have been studied. Using potentiometric absorption, fluorescence, and circular dichroism measurements, we have shown that adriamycin can form two complexes with Pd(II). The first complex (I) involves two molecules of drug per Pd(II) ion; one of the molecules is chelated to Pd(II) through the carbonyl oxygen on C12 and the phenolate oxygen on C11, and the other one is bound to Pd(II) through the nitrogen of the amino sugar. This complexation induces a stacking of the two molecules of drug. In the second complex (II), two Pd(II) ions are bound to two molecules of drug (A1 and A2). One Pd(II) is bound to the oxygen on the carbons C11 and C12 of molecule A1 and the amino sugar of molecule A2 whereas the second Pd(II) ion is bound to the oxygen on C11 and C12 of molecule A2 and the amino sugar of molecule A1. The same complexes are formed between Pd(II) and daunorubicin. The stability constant for complex II is beta = (1.3 +/- 0.5) X 10(22). Interaction with DNA has been studied, showing that almost no modification of the complex occurred. This complex displays antitumor activity against P-388 leukemia that compares with that of the free drug. Complex II, unlike adriamycin, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase.     

Iron corrolates: unambiguous chloroiron(III) (corrolate)(2-.) pi-cation radicals

The structures, electron configurations, magnetic susceptibilities, spectroscopic properties, molecular orbital energies and spin density distributions, redox properties and reactivities of iron corrolates having chloride, phenyl, pyridine, NO and other ligands are reviewed. It is shown that with one very strong donor ligand such as phenyl anion the electron configuration of the metal is d(4)S=1 Fe(IV) coordinated to a (corrolate)(3-) anion, while with one weaker donor ligand such as chloride or other halide, the electron configuration is d(5)S=3/2 Fe(III) coordinated to a (corrolate)(2-.) pi-cation radical, with antiferromagnetic coupling between the metal and corrolate radical electron. Many of these complexes have been studied by electrochemical techniques and have rich redox reactivity, in most cases involving two 1-electron oxidations and two 1-electron reductions, and it is not possible to tell, from the shapes of cyclic voltammetric waves, whether the electron is added or removed from the metal or the macrocycle; often infrared, UV-Vis, or EPR spectroscopy can provide this information. (1)H and (13)C NMR spectroscopic methods are most useful in delineating the spin state and pattern of spin density distribution of the complexes listed above, as would also be expected to be the case for the recently-reported formal Fe(V)O corrolate, if this complex were stable enough for characterization by NMR spectroscopy. Iron, manganese and chromium corrolates can be oxidized by iodosylbenzene and other common oxidants used previously with metalloporphyrinates to effect efficient oxidation of substrates. Whether the "resting state" form of these complexes, most generally in the case of iron [FeCl(Corr)], actually has the electron configuration Fe(IV)(Corr)(3-) or Fe(III)(Corr)(2-.) is not relevant to the high-valent reactivity of the complex.     

Iron(III) Schiff base complexes of arginine and lysine as netropsin mimics showing AT-selective DNA binding and photonuclease activity

Iron(III) complexes [Fe(L)₂]Cl (1-3), where L is monoanionic N-salicylidene-arginine (sal-argH for 1), hydroxynaphthylidene-arginine (nap-argH for 2) and N-salicylidene-lysine (sal-lysH for 3), were prepared and their DNA binding and photo-induced DNA cleavage activity studied. Complex 3 as its hexafluorophosphate salt [Fe(sal-lysH)₂](PF₆)·6H₂O (3a) was structurally characterized by single crystal X-ray crystallography. The crystals belonged to the triclinic space group P-1. The complex has two tridentate ligands in FeN₂O₄ coordination geometry with two pendant cationic amine moieties. Complexes 1 and 2 with two pendant cationic guanidinium moieties are the structural models for the antitumor antibiotics netropsin. The complexes are stable and soluble in water. They showed quasi-reversible Fe(III)/Fe(II) redox couple near 0.6 V in H₂O-0.1 M KCl. The high-spin 3d⁵-iron(III) complexes with μ_eff value of ∼5.9 μ_B displayed ligand-to-metal charge transfer electronic band near 500 nm in Tris-HCl buffer. The complexes show binding to Calf Thymus (CT) DNA. Complex 2 showed better binding propensity to the synthetic oligomer poly(dA)·poly(dT) than to CT-DNA or poly(dG)·poly(dC). All the complexes displayed chemical nuclease activity in the presence of 3-mercaptopropionic acid as a reducing agent and cleaved supercoiled pUC19 DNA to its nicked circular form. They exhibited photo-induced DNA cleavage activity in UV-A light and visible light via a mechanistic pathway that involves the formation of reactive hydroxyl radical species.     

Differences in Fe(III) reduction in the hyperthermophilic archaeon, Pyrobaculum islandicum, versus mesophilic Fe(III)-reducing bacteria

The discovery that all hyperthermophiles that have been evaluated have the capacity to reduce Fe(III) has raised the question of whether mechanisms for dissimilatory Fe(III) reduction have been conserved throughout microbial evolution. Many studies have suggested that c-type cytochromes are integral components in electron transport to Fe(III) in mesophilic dissimilatory Fe(III)-reducing microorganisms. However, Pyrobaculum islandicum, the hyperthermophile in which Fe(III) reduction has been most intensively studied, did not contain c-type cytochromes. NADPH was a better electron donor for the Fe(III) reductase activity in P. islandicum than NADH. This is the opposite of what has been observed with mesophiles. Thus, if previous models for dissimilatory Fe(III) reduction by mesophilic bacteria are correct, then it is unlikely that a single strategy for electron transport to Fe(III) is present in all dissimilatory Fe(III)-reducing microorganisms.     

Physicochemical studies of the iron(III)-carminomycin complex and evidence of the lack of stimulated superoxide production by NADH deydrogenase

Fe(III) complex of an antitumoral antibiotic carminomycin has been studied. Using potentiometric and spectroscopic measurements we have shown that carminomycin forms with Fe(III) a well-defined species in which three molecures of drug are chelated to one Fe(III) ion. This occurs with the release of one proton per molecule of drug. Magnetic susceptibility measurements suggest that six oxygen atoms are bound to iron. The stability constant is 3·10³⁴. The in vitro inhibition of P 388 leukemia cell growth by this complex compares with that of the free drug. This complex, unlike the free drug, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase.     

Aluminium(III), chromium(III) and iron(III) complexes with 5-iodouracil and 5-iodouracil-histidine and their antitumour activity

Complexes of the type [Al(HL)(OH)Cl(2)], [M(HL)(OH)(2)Cl] and [M'(HL)(L')(OH)Cl], where HL = 5-iodouracil; HL' = histidine; M = Cr(III), Fe(III) and M' = Al(III), Cr(III), Fe(III), were synthesized and characterized. The complexes are polymeric showing high decomposition points and are insoluble in water and common organic solvents. The mu(eff) values, electronic spectral bands and ESR spectra suggest a polymeric 6-coordinate spin-free octahedral stereochemistry for the Cr(III) and Fe(III) complexes. 5-Iodouracil acts as a monodentate ligand coordinating to the metal ion through the O atom of C((4)) = O while histidine through the O atom of -COO(- ) and the N atom of -NH(2) group. In vivo antitumour effect of 5-iodouracil and its complexes was examined on C(3)H /He mice against P815 murine mastocytoma. As evident from their T/C values, Cr(III) and Fe(III) complexes display significant and higher antitumour activity compared to the 5-iodouracil ligand. The in vitro results of the complexes on the same cells indicate that Cr(III) and Fe(III) complexes show higher inhibition on (3)H-thymidine and (3)H-uridine incorporation in DNA and RNA replication, respectively, at a dose of 5 microg/mL.     

Isolation and biochemical characterization of two soluble iron(III) reductases from Paracoccus denitrificans.

Two soluble enzymes (FerA and FerB) catalyzing the reduction of a number of iron(III) complexes by NADH, were purified to near homogeneity from the aerobically grown iron-limited culture of Paracoccus denitrificans using a combination of anion-exchange chromatography (Sepharose Q), chromatofocusing (Mono P), and gel permeation chromatography (Superose 12). FerA is a monomer with a molecular mass of 19 kDa, whereas FerB exhibited a molecular mass of about 55 kDa and consists of probably two identical subunits. FerA can be classified as an NADH:flavin oxidoreductase with a sequential reaction mechanism. It requires the addition of FMN or riboflavin for activity on Fe(III) substrates. In these reactions, the apparent substrate specificity of FerA seems to stem exclusively from different chemical reactivities of Fe(III) compounds with the free reduced flavin produced by the enzyme. Observations on reducibility of Fe(III) chelated by vicinal dihydroxy ligands support the view that FerA takes part in releasing iron from the catechol type siderophores synthesized by P. denitrificans. Contrary to FerA, the purified FerB contains a noncovalently bound redox-active FAD coenzyme, can utilize NADPH in place of NADH, does not reduce free FMN at an appreciable rate, and gives a ping-pong type kinetic pattern with NADH and Fe(III)-nitrilotriacetate as substrates. FerB is able to reduce chromate, in agreement with the fact that its N-terminus bears a homology to the previously described chromate reductase from Pseudomonas putida. Besides this, it also readily reduces quinones like ubiquinone-0 (Q0) or unsubstituted p-benzoquinone.     

Iron(III) complexes of certain meridionally coordinating tridentate ligands as models for non-heme iron enzymes: the role of carboxylate coordination

The iron(III) complexes [Fe(pda)Cl(H(2)O)(2)] (1), [Fe(tpy)Cl(3)] (2), and [Fe(bbp)Cl(3)] (3), where H(2)pda is pyridine-2,6-dicarboxylic acid, tpy is 2,2':6,2'-terpyridine and bbp is 2,6-bis(benzimidazolyl)pyridine, have been isolated and studied as functional models for the intradiol-cleaving catechol dioxygenase enzymes. Mixed ligand complexes of H(2)pda with the bidentate ligands 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen) have been also prepared and studied. All the complexes have been characterized using absorption spectral and electrochemical methods. The spectral changes in the catecholate adducts of the complexes generated in situ have been investigated. Upon interacting the complexes with catecholate anions a low energy catecholate to iron(III) charge transfer band appears, which is similar to that observed for enzyme-substrate complexes. All the complexes catalyze the oxidative intradiol cleavage of 3,5-di-tert-butylcatechol (H(2)dbc) in the presence of dioxygen. Interestingly, on replacing the pyridyl groups in 2 and the bulky benzimidazole groups in 3 by the carboxylate groups, the yields of the intradiol cleavage products of dioxygenation increases, 1 (50%)>2 (20%)>3 (10%). The higher intradiol yield for 1 has been ascribed to the meridional coordination of two carboxylate groups of pda(2-). In contrast to the trend in the intradiol cleavage yields, a tremendous decrease in the rate (200 times) is observed on replacing the two pyridyl moieties in 2 by two carboxylates as in 1 and a significant decrease in rate is observed on replacing the pyridyl moieties in 2 by strongly sigma-donating benzimidazole moieties as in 3. This is in conformity with the decrease in Lewis acidities of the iron(III) centers.     

Reduction of Fe(III) ions complexed to physiological ligands by lipoyl dehydrogenase and other flavoenzymes in vitro: implications for an enzymatic reduction of Fe(III) ions of the labile iron pool

Enzymatic reduction of physiological Fe(III) complexes of the "labile iron pool" has not been studied so far. By use of spectrophotometric assays based on the oxidation of NAD(P)H and formation of [Fe(II) (1,10-phenanthroline)3]2+ as well as by utilizing electron paramagnetic resonance spectrometry, it was demonstrated that the NAD(P)H-dependent flavoenzyme lipoyl dehydrogenase (diaphorase, EC 1.8.1.4) effectively catalyzes the one-electron reduction of Fe(III) complexes of citrate, ATP, and ADP at the expense of the co-enzymes NAD(P)H. Deactivated or inhibited lipoyl dehydrogenase did not reduce the Fe(III) complexes. Likewise, in the absence of NAD(P)H or in the presence of NAD(P)+, Fe(III) reduction could not be detected. The fact that reduction also occurred in the absence of molecular oxygen as well as in the presence of superoxide dismutase proved that the Fe(III) reduction was directly linked to the enzymatic activity of lipoyl dehydrogenase and not mediated by O2. Kinetic studies revealed different affinities of lipoyl dehydrogenase for the reduction of the low molecular weight Fe(III) complexes in the relative order Fe(III)-citrate > Fe(III)-ATP > Fe(III)-ADP (half-maximal velocities at 346-485 microm). These Fe(III) complexes were enzymatically reduced also by other flavoenzymes, namely glutathione reductase (EC 1.6.4.2), cytochrome c reductase (EC 1.6.99.3), and cytochrome P450 reductase (EC 1.6.2.4) with somewhat lower efficacy. The present data suggest a (patho)physiological role for lipoyl dehydrogenase and other flavoenzymes in intracellular iron metabolism.     

Role of quinone-iron(III) interaction in NADPH-dependent enzymatic generation of hydroxyl radicals.

To study the effect of chelation of iron ions by quinones on the generation of OH radicals in biological redox systems, we have synthesized quinones that can form complexes with Fe(III) ions: 2-phenyl-4-(butylamino)naphtho[2,3-h]quinoline-7,12-dione (Qbc) and 2-phenyl-4-(octylamino)naphtho[2,3-h]quinoline-7,12-dione (Qoc). A quinone with a similar structure without chelating group was synthesized as a control sample: 2-phenyl-5-nitronaphtho[2,3-g]indole-6,11-dione (Qn). Using optical spectroscopy, we determined the stability constant of Qbc with Fe(III) [Ks = (7 +/- 1) x 10(18) M-3] and the stoichiometry of the complex Fe(Qbc)3 in chloroform solutions. One-electron reduction potentials of Qbc, Qn, and adriamycin in dimethyl sulfoxide were measured by cyclic voltammetry. In the presence of Fe(III) the one-electron reduction potentials shifted toward positive values by 0.16 and 0.1 V for Qbc and adriamycin, respectively. Using the spin trap 5,5'-dimethyl-1-pyroline N-oxide (DMPO) and EPR, it was found that Qbc in the Fe(III) complex stimulated the formation of OH radicals in the enzymatic system consisting of NADPH and NADPH-cytochrome P-450 reductase more efficiently than adriamycin and quinone Qn. This is indicated by the absence of a lag period in the spin adduct appearance for Qbc and by a significantly higher rate of the spin adduct production, as well as by a larger absolute concentration of the spin adduct obtained for Qbc in comparison with Qn in the presence of Fe(III).(ABSTRACT TRUNCATED AT 250 WORDS)     

The adriamycin-iron(III) complex is a potent inhibitor of protein kinase C

Using Triton X-100/lipid mixed micellar methods, we observed that the adriamycin-iron(III) complex was a potent inhibitor of protein kinase C while uncomplexed adriamycin itself was a poor inhibitor in the absence of heavy metal contaminants. The 3:1 adriamycin-iron complex was more potent than 2:1, 1:1, and 1:0 complexes. Inhibition of protein kinase C was reversible, and 50% inhibition occurred at 13 microM (adriamycin)3Fe3+. Both the catalytic and the regulatory domain of protein kinase C were affected by adriamycin-iron(III). Adriamycin-iron(III) was a competitive inhibitor of the catalytic domain of protein kinase C with respect to MgATP but not with respect to magnesium (IC50 350 microM). The predominant interaction of adriamycin-iron(III) with native protein kinase C was as a competitive inhibitor with respect to diacylglycerol. Inhibition was not competitive with respect to phosphatidylserine, calcium, magnesium, MgATP, or histone. Interaction with the regulatory domain was demonstrated by the ability of adriamycin-iron(III) to inhibit phorbol dibutyrate binding. Other adriamycin transitional metal complexes showed little inhibition of protein kinase C activity. Acetylation of the amine on the daunosamine moeity of adriamycin did not preclude the formation of a ferric complex but resulted in total loss of inhibitory activity. These results suggest that the presence of free amines in a highly structured adriamycin-iron complex is necessary for inhibition. The implications of inhibition of protein kinase C by adriamycin-iron(III) are discussed.     

Iron(III) and nickel(II) complexes of tetradentate thiosemicarbazones: Synthesis,structure, cytotoxicity,and lipophilicity

Eighteen of the iron(III) and nickel(II) complexes with tetradentate thiosemicarbazidato ligands were synthesized and described, by analytical and spectroscopic methods. Two complexes as an example to the iron and nickel centered ones were crystallographically analyzed to confirm the molecular structures. Cytotoxic effects of the complexes on K562 chronic myeloid leukemia cells were determined by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. For comparison, human umbilical vein endothelial cells (HUVECs) was used as a noncancerous cell line. While four of the iron(III) complexes exhibited the antileukemic effect with 50% inhibition of cell growth (IC₅₀) values in the 3.4 to 6.9 μg/mL range on K562 cell line, the nickel(II) complexes showed no significant effect on both cell lines. The complexes Fe4, Fe5, and Fe6, bearing 4‐methoxy substituent exhibited relatively high antiproliferative activity on both cell lines. Complex Fe3 with 3‐methoxy and S‐allyl groups exhibited a selectivity between K562 and HUVEC cells by IC₅₀ values of 6.9 and >10 μg/mL, respectively. Lipophilicity, a key parameter for bioavailability and oral administration, was found in the range of ?0.3 and +1.3 that desired for drug active ingredients. The results were discussed in the context of a structure‐activity relationship.     

Iron(III) protoporphyrin IX complexes of the antimalarial Cinchona alkaloids quinine and quinidine

The antimalarial properties of the Cinchona alkaloids quinine and quinidine have been known for decades. Surprisingly, 9-epiquinine and 9-epiquinidine are almost inactive. A lack of definitive structural information has precluded a clear understanding of the relationship between molecular structure and biological activity. In the current study, we have determined by single crystal X-ray diffraction the structures of the complexes formed between quinine and quinidine and iron(III) protoporphyrin IX (Fe(III)PPIX). Coordination of the alkaloid to the Fe(III) center is a key feature of both complexes, and further stability is provided by an intramolecular hydrogen bond formed between a propionate side chain of Fe(III)PPIX and the protonated quinuclidine nitrogen atom of either alkaloid. These interactions are believed to be responsible for inhibiting the incorporation of Fe(III)PPIX into crystalline hemozoin during its in vivo detoxification. It is also possible to rationalize the greater activity of quinidine compared to that of quinine.     

Complexation of 3,4-hydroxypyridinecarboxylic acids with Iron(III)

The chemical interactions of 3-hydroxy-4-pyridinecarboxylic acid (3H4P) and 4-hydroxy-3-pyridinecarboxylic acid (4H3P) with Fe(III) were investigated in aqueous 0.6 m (Na)Cl at 25 °C by means of potentiometric titrations and UV-Vis spectrophotometry. A large number of mononuclear complexes were formed in solution; one of the Fe/3H4P species was obtained as a solid and characterised by elemental analysis. In view of a possible application to iron(III) chelation therapy, the efficiencies of the ligands to chelate iron(III) were evaluated in vitro at physiological pH. Chelation efficiency with iron was low and less than previously observed with aluminium(III).     

Interactions of selected gold(III) complexes with calf thymus DNA

DNA represents the primary target for platinum antitumor metal complexes and is the probable target for newly developed cytotoxic gold(III) complexes. To test this hypothesis the reactions with calf thymus DNA of five representative gold(III) complexes--namely [Au(en)(2)]Cl(3), [Au(dien)Cl]Cl(2), [Au(cyclam)](ClO(4))(2)Cl, [Au(terpy)Cl]Cl(2) and [Au(phen)Cl(2)]Cl--were analyzed in vitro through various physicochemical techniques including circular dichroism, absorption spectroscopy, DNA melting, and ultradialysis. It is shown that all tested complexes interact with DNA and modify significantly its solution behavior. The solution conformation of DNA is affected to variable extents by the individual complexes as shown by CD titration experiments. Notably, in all cases, the gold(III) chromophore is not largely perturbed by addition of calf thymus DNA ruling out occurrence of gold(III) reduction. Ultradialysis experiments point out that the binding affinity of the various complexes for the DNA double helix is relatively low; in most cases the gold(III)/DNA interaction is electrostatic in nature and reversible. The implications of these findings for the mechanism of action of antitumor gold(III) complexes are discussed.     

Fe(III) and Cu(II) conalbumin visible circular dichroism spectra.

The single polypeptide chain of conalbumin strongly binds two Fe(III) or two Cu(II) ions to yield intense absorption in the visible region similar to that shown by the related protein transferrin. Comparison of the metal-ion-binding sites in the two proteins is made by exploiting the sensitivity to ligand geometry of circular dichroism (CD). For the Fe(III) proteins strong similarities of the CD spectra outweigh marginal differences. For Cu(II) conalbumin an additional negative extremum near 506 nm appears between two positive ones at 634 and 410 nm suggesting greater subtraction of oppositely signed CD components leading to lesser magnitudes for the two positive peaks than are found in Cu(II)-transferrin. The two Fe(III)-binding sites within conalbumin are compared by noting the strong similarities of the CD and MCD of proteins with Fe(III) in one site and Ga(III) in the other site, and vice versa, with the protein containing Fe(III) in both sites. Due to features of the amino acid sequences of the single protein chains, the four strong metal ion binding sites in conalbumin and transferrin cannot be identical in all particulars, yet CD spectra of their metal ion complexes are closely similar. From a study of model phenolate complexes and the wavelength maxima of visible absorption in the Fe(III), Cu(II), and Co(III) proteins near 465, 440, and 405 nm, respectively, these strong absorption bands are identified as ligand to metal ion electron-transfer transitions. It is suggested that tyrosyl residues are the donors in the electron transfer transitions and that they lock in the metal ions after being keyed into position by binding of bicarbonate or other anions.     

Copper(II).bleomycin, iron(III).bleomycin, and copper(II).phleomycin: comparative study of deoxyribonucleic acid binding

The kinetics and mechanism of binding of Cu-(II).bleomycin, Fe(III).bleomycin, and Cu(II).phleomycin to DNA were studied by using fluorometry, equilibrium dialysis, electric dichroism, and temperature-jump and stopped-flow spectrophotometry. The affinity of Cu(II).bleomycin for DNA was greater than that of metal-free bleomycin but less than that of Fe(III).bleomycin. Cu(II).bleomycin exhibited a two-step binding process, with the slow step indicating a lifetime of 0.1 s for the Cu(II).bleomycin.DNA complex. Fe(III).bleomycin binding kinetics indicated the presence of complexes having lifetimes of up to 22 s. DNA was lengthened by 4.6 A/molecule of bound Cu(II).bleomycin and by 3.2 A/bound Fe(III).bleomycin but not at all by Cu(II).phleomycin, suggesting that both bleomycin complexes intercalate while the phleomycin complex does not. However, phleomycin exhibited nearly the same specificity of DNA base release as bleomycin. These results suggest that the coordinated metal ion plays a major role in the binding of metal-bleomycin complexes to DNA but that intercalation is neither essential for DNA binding and degradation nor primarily responsible for the specificity of DNA base release by these drugs.     

Synthesis, structure and DNA interaction of cobalt(III) bis-complexes of 1,3-bis(2-pyridylimino)isoindoline and 1,4,7-triazacyclononane

The complex [CoL(2)](ClO(4)).MeOH (1), where HL is the tridentate 3N ligand 1,3-bis(2-pyridylimino)isoindoline, has been isolated and its X-ray crystal structure successfully determined. It possesses a distorted octahedral structure in which both the ligands are coordinated meridionally to cobalt(III) via one deprotonated isoindoline (L(-)) and two pyridine nitrogen atoms. Interestingly, the average dihedral angle between pyridine and isoindoline rings is 25.9 degrees , indicating that the ligand is twisted upon coordination to cobalt(III). The interaction of the complex with calf-thymus DNA has been studied using various spectral methods and viscosity and electrochemical measurements. For comparison, the DNA interaction of [Co(tacn)(2)]Cl(3) (2), where tacn is facially coordinating 1,4,7-triazacyclononane, has been also studied. The ligand-based electronic spectral band of 1 and the N(sigma)-->Co(III) charge transfer band of 2 exhibit moderate hypochromism with small or no blue shift on interaction with DNA. The intrinsic binding constants calculated reveal that the monopositive complex ion [CoL(2)](+) exhibits a DNA-binding affinity lower than the tripositive complex ion [Co(tacn)(2)](3+). The steric clashes with DNA exterior caused by the second L(-) ligand bound to cobalt(III), apart from the lower overall positive charge on the [CoL(2)](+) complex, dictates its DNA-binding mode to be surface binding rather than partial intercalative interaction expected of the extended aromatic chromophore of deprotonated isoindoline anion. An enhancement in relative viscosity of CT DNA on binding to 1 is consistent with its DNA surface binding. On the other hand, a slight decrease in viscosity of CT DNA was observed on binding to 2 revealing that the smaller cation leads to bending (kinking) and hence shortening of DNA chain length. The electrochemical studies indicate that the DNA-bound complexes are stabilised in the higher Co(III) rather than the lower Co(II) oxidation state, suggesting the importance of electrostatic forces of DNA interaction.     

Iron(III)-salen damages DNA and induces apoptosis in human cell via mitochondrial pathway

We synthesized a water soluble Fe(III)-salen complex and investigated its biochemical effects on DNA in vitro and on cultured human cells. We showed that Fe(III)-salen produces free radicals in the presence of reducing agent dithiothreitol (DTT) and induces DNA damage in vitro. Interestingly, upon treatment with Fe(III)-salen at concentration as low as 10microM, HEK293 human cells showed morphological changes, nuclear fragmentation, and nuclear condensation that are typical features of apoptotic cell death. The cytotoxicity measurement showed that IC(50) of Fe(III)-salen is 2.0microM for HEK293 cells. Furthermore, treatment with Fe(III)-salen resulted in translocation of cytochrome c from mitochondria to cytosol affecting mitochondrial membrane permeability. Our results demonstrated that Fe(III)-salen not only damages DNA in vitro, but also induces apoptosis in human cells via mitochondrial pathway.     

Preparation,characterization and crystal structures of manganese(II), iron(III) and copper(II) complexes of the bis[di-1,1-(2-pyridyl)ethyl]amine (BDPEA) ligand; evaluation of their DNA cleavage activities

The synthesis of a new tetrapyridyl ligand, bis[di-1,1-(2-pyridyl)ethyl]amine (BDPEA), is described. Complexation of this ligand with manganese(II), iron(III) or copper(II) chlorides afforded mononuclear complexes: Mn(BDPEA)Cl2 (1) [Fe (BDPEA)Cl2]Cl (2) and [Cu(BDPEA)Cl]Cl (3). In all cases, BDPEA is coordinated to the metal center by three pyridine nitrogen atoms and the secondary amine. The geometrical environments around the metals in Mn(BDPEA)Cl2 and [Fe(BDPEA)Cl2]Cl are best described as distorted octahedrals and in [Cu (BDPEA)Cl]Cl as a slightly distorted square pyramid. The DNA cleavage activities of manganese(II), iron (III) or copper(II) complexes of both BDPEA and another tetrapyridyl ligand, bis[di(2-pyridyl) methyl]amine (BDPMA), in the presence of an oxidant (H2O2) or a reducing agent (ascorbate) with air, are reported. The iron(III) complexes exhibited significantly enhanced efficiencies, compared to copper(II) complexes. [Fe(BDPEA)Cl2]Cl is found to be the most active DNA cleaver, in agreement with a better stability of BDPEA in oxidizing conditions.