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PubMed1998

The metalloprotease inhibitor 1,10-phenanthroline affects Schistosoma mansoni motor activity, egg laying and viability.

The Zn(2+)-chelating metalloprotease inhibitor 1,10-phenanthroline (phenanthroline, 5-150 microM) elicited dose-dependent contraction of the longitudinal and circular (transverse) musculature of adult male schistosomes. At the same concentrations, phenanthroline did not cause contraction of dispersed individual muscle fibres. The phenanthroline-induced contractions were reduced by the inclusion of 100 or 300 microM Zn2+ in the extracellular medium. Phenanthroline (0.5-150 microM) also inhibited the egg production of adult worm pairs in vitro, with a 98% reduction at 50 microM. When worm pairs were exposed to phenanthroline, the males detached from the dish and released the females, resulting in unpaired worms. At the higher concentrations (50 and 150 microM), the worms were killed in vitro. Worm burdens were reduced by over 50% in infected mice injected with phenanthroline (20 mg/kg/day for 4 days), but twice the dose resulted in only a 25% reduction. Phenanthroline injections also induced an hepatic shift and an unpairing of adult worms in infected mice, and the female worms appeared degenerate and lacked gut pigmentation. Mice fed a diet containing 0.3% phenanthroline received significant protection from infection when challenged with schistosome cercaria, where phenanthroline-fed mice had 94% fewer adult worms than control mice. The broad range of phenanthroline effects on schistosomes suggests broad and important functions for metalloproteases in these worms.

Animals↗
PubMed2003

1,10-Phenanthroline phosphorylates (activates) MAP kinase in Xenopus oocytes.

The membrane-permeable intracellular heavy metal chelator, 1,10-phenanthroline, which prevents progesterone-induced germinal vesicle breakdown (GVBD), would be expected to regulate phosphorylation (activation) of the MAP kinase (MAPK) cascade in Xenopus oocytes. Here, our experiments show that 1,10-phenanthroline itself results in the phosphorylation of MAPK in both oocytes and a cell-free system. In contrast, 1,7-phenanthroline, the nonchelating analogue, had no effect. A supplement of zinc (as a heavy metal) given to 1,10-phenanthroline-loaded oocytes suppressed the stimulatory effects of 1,10-phenanthroline, while 1,10-phenanthroline withdrawal caused dephosphorylation of activated MAPK. Further, treatment with a MEK (a MAPK kinase) inhibitor, PD 098059 or U0126, suppressed 1,10-phenanthroline-stimulated MAPK phosphorylation, indicating that 1,10-phenanthroline can phosphorylate MAPK in a MEK-dependent fashion. Our results suggest that phosphorylation of MAPK by 1,10-phenanthroline depends on the interaction of MEK. Thus, the intracellular heavy metal (zinc) regulates MAPK phosphorylation and 1,10-phenanthroline can serve as a unique tool for investigating MAPK phosphorylation mechanism.

Animals↗
PubMed1991

Noncovalent DNA binding of bis(1,10-phenanthroline)copper(I) and related compounds.

The noncovalent DNA binding of the bis(1,10-phenanthroline)copper(I) complex [(Phen)2CuI] was examined under anaerobic conditions by absorption and circular dichroism spectroscopy, and viscometry, as a function of phenanthroline concentration. Analyses according to the McGhee-von Hippel method indicated that binding exhibited both neighbor-exclusion and positive cooperativity effects, with a neighbor-exclusion parameter n approximately 2 and a cooperativity parameter omega approximately 4. The association constant for (Phen)2CuI binding decreased with increasing concentration of phenanthroline in excess over that required to stoichiometrically generate (Phen)2CuI, indicating that free phenanthroline was a weak competitive inhibitor of (Phen)2CuI binding. The maximal association constant for DNA binding of (Phen)2CuI in 0.2 M NaCl and 9.8% ethanol, extrapolated to zero concentration of excess phenanthroline, was 4.7 x 10(4) M-1 (DNA base pairs). The magnitude of the neighbor-exclusion parameter, the changes in spectral properties of (Phen)2CuI induced by DNA binding, and the increase in DNA solution viscosity upon (Phen)2CuI addition are consistent with a model for DNA binding by (Phen)2CuI involving partial intercalation of one phenanthroline ring of the complex between DNA base pairs in the minor groove as suggested previously [Veal & Rill (1989) Biochemistry 28, 3243-3250]. Viscosity measurements indicated that the mono(phenanthroline)copper(I) complex also binds to DNA by intercalation; however, no spectroscopic or viscometric evidence was found for DNA binding of free phenanthroline or the bis(2,9-dimethyl-1,10-phenanthroline)copper(I) complex. DNA binding of free phenanthroline may be cooperative and induced by prior binding of (Phen)2CuI.

3-Mercaptopropionic Acid↗
PubMed1994

1,10-Phenanthroline increases nuclear accumulation of insulin in response to inhibiting insulin degradation but has a biphasic effect on insulin's ability to increase mRNA levels.

Previous reports demonstrated that insulin is translocated through the cytoplasm to the nucleus of H35 hepatoma cells and suggested that nuclear insulin may be involved in stimulating transcription of immediate-early genes. In a recent study, inhibition of insulin-degrading enzyme with 1,10-phenanthroline, a Zn2+ chelator, caused a significant increase in the nuclear accumulation of insulin. The present study characterized the effects of 1,10-phenanthroline and its nonchelating isomer, 1,7-phenanthroline, on insulin degradation, nuclear accumulation, and stimulation of immediate-early gene expression. 1,10- but not 1,7-phenanthroline inhibited insulin degradation and increased nuclear accumulation of insulin in a dose-dependent manner. 1,7-phenanthroline caused a dose-dependent decrease in the expression of insulin-stimulated immediate-early genes, but had no significant effect on alpha-tubulin mRNA levels. In the presence of insulin, Northern analysis revealed that 1,10-phenanthroline at all concentrations tested increased alpha-tubulin mRNA levels, but had a biphasic effect on insulin-stimulated immediate-early gene expression. At low concentrations (5-200 microM), 1,10-phenanthroline increased the expression of insulin-stimulated g33, c-fos, and Egr-1 mRNA. At concentrations greater than 1 mM, insulin-stimulated immediate-early gene expression was decreased similar to the effect seen with 1,7-phenanthroline. Nuclear run-on analysis demonstrated that high concentrations of 1,10-phenanthroline decreased insulin-stimulated immediate-early gene transcription but had no effect on transcription of alpha-tubulin. However, low concentrations of 1,10-phenanthroline did not increase transcription of any genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Synthesis and spectroelectrochemical studies of mixed heteroleptic chelate complexes of ruthenium(II) with 1,8-bis(2-pyridyl)-3,6-dithiaoctane (pdto) and substituted 1,10-phenanthrolines.

Reaction of dichlorotris(triphenylphosphine) ruthenium(II) [RuCl(2)(PPh(3))(3)] with 1,8-bis(2-pyridyl)-3,6-dithiaoctane (pdto), a (N(2)S(2)) tetradentate donor, yields a new compound [Ru(pdto)(PPh(3))Cl]Cl (1), which has been fully characterized. (1)H and (31)P NMR studies of 1 in acetonitrile at several temperatures show the substitution of both coordinated chloride and triphenylphosphine with two molecules of acetonitrile, as confirmed by the isolation of the complex [Ru(pdto)(CH(3)CN)(2)]Cl(2) (2). Cyclic voltammetric and spectroelectrochemical techniques allowed us to determine the electrochemical behavior of compound 1. The substitution of the chloride and triphenylphosphine by acetonitrile molecules in the Ru(II) coordination sphere of compound 1 was also established by electrochemical studies. The easy substitution of this complex led us to use it as starting material to synthesize the substituted phenanthroline coordination compounds with (pdto) and ruthenium(II), [Ru(pdto)(4,7-diphenyl-1,10-phenanthroline)]Cl(2).4H(2)O (3), [Ru(pdto)(1,10-phenanthroline)]Cl(2).5H(2)O (4), [Ru(pdto)(5,6-dimethyl-1,10-phenanthroline)]Cl(2).5H(2)O (5), [Ru(pdto)(4,7-dimethyl-1,10-phenanthroline)]Cl(2).3H(2)O (6), and [Ru(pdto)(3,4,7,8-tetramethyl-1,10-phenanthroline)]Cl(2).4H(2)O (7). These compounds were fully characterized, and the crystal structure of 4 was obtained. Cyclic voltammetric and spectroelectrochemical techniques allowed us to determine their electrochemical behavior. The electrochemical oxidation processes in these compounds are related to the oxidation of ionic chlorides, and to the reversible transformation from Ru(II) to Ru(III). On the other hand, a single reduction process is associated to the reduction of the substituted phenanthroline in the coordination compound. The E(1/2) (phen/phen(-)) and E(1/2) (Ru(II)/Ru(III)) for the compounds (3-7) were evaluated, and, as expected, the modification of the substituted 1,10-phenanthrolines in the complexes also modifies the redox potentials. Correlations of both electrochemical potentials with pK(a) of the free 1,10-phenathrolines, lambda(max) MLCT transition band, and chemical shifts of phenanthrolines in these complexes were found, possibly as a consequence of the change in the electron density of the Ru(II) and the coordinated phenanthroline.

Journal Article↗
PubMed1996

Ortho-phenanthroline modulates enzymes of cellular energy metabolism.

The lipophilic iron chelator 1,10-phenanthroline has been used in mechanistic studies on intracellular oxidant damage because iron is assumed to play a role in the endogenous formation of highly reactive oxygen species. This study shows that 1,10-phenanthroline has enzyme-modulatory properties in addition to its antioxidant activity. In rat hepatocytes, 1,10-phenanthroline caused inhibition of respiration and enhancement of cellular ATP content, pyruvate release and CO2 formation from glycerol resulting from a modulatory action of 1,10-phenanthroline on various enzymes involved in cellular energy metabolism. In intact mitochondria and in submitochondrial particles, oxygen consumption, complex I activity, and ATPase degradation are inhibited by 1,10-phenanthroline. In submitochondrial particles, complex II activity can also be suppressed by 1,10-phenanthroline. The purified cytosolic enzymes lactate dehydrogenase and glycerol-3-phosphate dehydrogenase are inhibited while purified glyceraldehyde-3-phosphate dehydrogenase is activated by 1,10-phenanthroline. The results suggest that 1,10-phenanthroline modulates various enzyme activities linked to cellular energy metabolism and that this property must be taken into account when using 1,10-phenanthroline as a tool in experiments on oxidant effects in cells.

Adenosine Triphosphatases↗
PubMed1977

Stimulation of the activity of prolyl hydroxylase in 3T3 fibroblasts by 1,10-phenanthroline.

In confluent cultures of 3T3 fibroblasts, incubated for 24 h with 1,10-phenanthroline at 10(-5)--10(-9) M, the activity of prolyl hydroxylase was significantly increased. 1,10-Phenanthroline was inhibitory at concentrations greater than 10(-4) M. The stimulatory effect of 1,10-phenanthroline manifests itself after 6 h incubation and increased with time up to 48 h. 2,2'-dipyridyl and 5,6-dimethyl-1,10-phenanthroline were also stimulatory; a nonchelating analog, 1,7-phenanthroline had no effect. Cycloheximide did not modify the 1,10-phenanthroline effect. The stimulatory effect does not seem to depend on the shift of an inactive precursor of prolyl hydroxylase to an active form because 1,10-phenanthroline was shown to be ineffective in logarithmically growing cells. While dialysis of washed and homogenized cells significantly increased prolyl hydroxylase activity in cell extracts, undialyzed 1,10-phenanthroline treated samples exhibited higher prolyl hydroxylase activity than dialyzed controls. These data suggested to us that 1,10-phenanthroline and other chelating agents may be forming complexes with certain metal ions or protein-metal ions which are inhibitory towards prolyl hydroxylase.

2,2'-Dipyridyl↗
PubMed2005

Investigation on the interactions between diperoxovanadate and substituted phenanthroline.

Detailed investigations were carried out to explore the interaction systems of NH4VO3/H2O2/5,6-dimethyl-1,10-phenanthroline and NH4VO3/H2O2/5-methyl-1,10-phenanthroline in aqueous solution under physiological conditions by NMR spectroscopy, such as 1D 1H, 13C, 51V variable temperature, and 2D COSY, NOESY, HETCOR, COLOC techniques as well as density functional calculations. New species [OV(O2)2(5,6-dimethyl-1,10-phenanthroline)]- and [OV(O2)2(5-methyl-1,10-phenanthroline)]- including isomers were formed in a bidentate coordination fashion which were stable under the experimental conditions. The solution structures of these new species were proposed based on the direct NMR experimental information and confirmed by the theoretical calculations. All the 1H and 13C NMR peaks were assigned. The calculated 1H and 13C chemical shifts on the whole are in fair agreement with the experimental values. The methyl groups on the aromatic ring of the three new complexes were found to have a steric hindrance effect on the coordination process. Experimental results show that the order of coordination capability of phenanthroline and its derivants was: 1,10-phenanthroline>5-methyl-1,10-phenanthroline>5,6-dimethyl-1,10-phenanthroline.

Magnetic Resonance Spectroscopy↗
PubMed2001

Phenanthrolines--a new class of CFTR chloride channel openers.

1. A number of phenanthrolines and benzoquinolines were examined for their ability to activate epithelial chloride secretion by measuring short circuit current (SCC) using the mouse colon epithelium. 1,10 phenanthroline stimulated electrogenic chloride secretion with an EC(50) of 612+/-10 microM and a Hill slope of 4.9+/-0.3. A similar pharmacology was demonstrated by both 1,7 and 4,7 phenanthrolines, 7,8 benzoquinoline and phenanthridine. 2. Evidence that the increase in SCC caused by 1,10 phenanthroline was due to chloride secretion is based upon (a) inhibition of the current by furosemide, (b) failure of cystic fibrosis (CF) colons to respond and (c) an associated net flux of (36)Cl(-). 3. 1,10 Phenanthroline affected neither the generation of cyclic AMP or the concentration of intracellular Ca(2+) in colonic epithelial cells. 4. 1,10 phenanthroline affected the chloride conductance of the apical membrane, as shown by an increase in chloride current in 'apical membrane only' preparations in the presence of an apical to basolateral chloride gradient. The increase in chloride current was inhibited by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and was not present in CF colons. 5. Additionally, 1,10 phenanthroline activated basolateral K(+) channels, both Ca(2+)- and cyclic AMP-sensitive channels, as shown by inhibitor studies with charybdotoxin (ChTX) and XE991, and after the apical membrane was permeabilized with nystatin. 6. The phenanthrolines and benzoquinolines described here, with dual actions affecting CFTR and basolateral K(+) channels, may constitute useful lead compounds for adjunct therapy in CF.

1-Methyl-3-isobutylxanthine↗
PubMed2000

A combination of iontophoresis and the chelating agent 1,10 phenanthroline act synergistically as penetration enhancers.

The peroxovanadium compound VO(O2)2 1,10 phenanthroline (bpV(phen)) is capable of lowering blood glucose levels. It is not available in oral form, but it is effective when delivered transdermally. Iontophoresis can significantly reduce the lag time of this response in vivo when compared with passive penetration. To better mimic in vivo insulin release, we explored the effects of various iontophoretic current durations on dermal penetration of bpV(phen). Iontophoretic transport was not related to total applied charge, as steady-state flux was equivalent for current durations ranging from 15 minutes to 9 hours. We hypothesized that the unexpectedly large transport after just 15 minutes of current was caused by an increase in passive penetration of bpV(phen) induced by iontophoresis. Iontophoretic pretreatment with the chelating agent 1,10 phenanthroline increased passive penetration of bpV(phen), whereas neither the nonchelating isomer 1,7 phenanthroline nor the less potent chelator EDTA were effective. The use of 1,10 phenanthroline as a penetration enhancer for other chemicals was examined with the amino acids alanine and leucine. Fifteen minutes of 1,10 phenanthroline iontophoresis enhances alanine transport 11.4-fold over passive, whereas the 1,7 phenanthroline increased transport by a factor of 4.6 and the iontophoretic control of ethanol by 1.9. Surprisingly, phenanthroline did not enhance 3H leucine penetration. The reasons for this selectivity are not clear and warrant further investigation. Overall, the data suggest that chelating agents, specifically 1,10 phenanthroline, may be used as penetration enhancers for the delivery of certain compounds.

Alanine↗
PubMed2006

A simple method for estimating activation energies using the fragmentation yield: collision-induced dissociation of iron(II)-phenanthroline complexes in an electrospray ionization mass spectrometer.

The gas-phase stabilities of Fe(Phi)3(2+) complexes, where Phi represents the 1,10-phenanthroline, 5-chloro-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, and 4,7-diphenyl-1,10-phenanthroline ligands were investigated by collision-induced dissociation (CID) in the capillary-first skimmer region upon changing the voltage difference between the capillary and the skimmer. The loss of only one ligand from the Fe(Phi)3(2+) complexes was observed with each of the phenanthroline ligands studied. An increase in the voltage difference between the capillary and the skimmer resulted in a higher fragmentation yield as calculated from the intensity of the precursor and the fragment ion. The fragmentation yield versus capillary-skimmer voltage difference plots were evaluated by means of the Arrhenius and the Rice-Ramsperger-Kassel (RRK) model by fitting the model parameters to the experimental data. Both models yielded practically the same results. In addition, if the internal energy gained through the capillary-skimmer region is estimated correctly, the approximate value of the critical energy (activation energy) for fragmentation can be extracted from the fragmentation yield versus capillary-skimmer voltage difference plots. It was found that the gas-phase stabilities of the Fe(Phi)3(2+) complexes are nearly identical except for the more stable Fe(II)-4,7-diphenyl-1,10-phenanthroline complex. The critical energy for fragmentation was estimated to be approximately 1.2 and 0.9 eV for the Fe(II)- 4,7-diphenyl-1,10-phenanthroline, and the other complexes, respectively.

Journal Article↗
PubMedDate not supplied

Structural and photophysical studies of Cu(NN)2+ systems in the solid state. Emission at last from complexes with simple 1,10-phenanthroline ligands.

For a variety of reasons, relating the photophysical properties of a copper phenanthroline to a structure in solution is problematic. To elucidate some of the issues involved, in this paper we describe the crystal and molecular structures of a series of Cu(NN)2(+)-containing systems along with spectral data obtained from the solids themselves. The NN ligands investigated are tmp (3,4,7,8-tetramethyl-1,10-phenanthroline), dpdmp (2,9-diphenyl-4,7-dimethyl-1,10-phenanthroline), dptmp (2,9-diphenyl-3,4,7,8-tetramethyl-1,10-phenanthroline), and dipp (2,9-diisopropyl-1,10-phenanthroline). The results show that a flattening distortion can have a large impact on the spectroscopic properties of a Cu(NN)2+ system, whereas a typical rocking distortion has comparatively little effect. The reflectance spectra of orange or orange-red salts that have approximately perpendicular phenanthroline ligands exhibit absorption bands in the neighborhood of 460 nm along with a shoulder at longer wavelength. In the other limit, when a pronounced flattening distortion occurs and the dihedral angle between ligands is 20 degrees or more off perpendicular, the reflectance spectrum exhibits two distinct visible bands with intense absorption occurring at 525 nm or even longer wavelength. If the phenanthroline ligand lacks bulky substituents in the 2,9 positions, the compound may even be purple, depending on the counterion. Cu(NN)2+ complexes that contain phenyl substituents in the 2,9 positions and exhibit long-wavelength absorption in solution probably adopt a flattened structure in the ground electronic state. In most other systems ground-state flattening is a solid-state effect induced by lattice forces. However, a flattening distortion is an intrinsic attribute of the emissive excited state, although intra- or intermolecular forces can inhibit the effect. In the case of the Cu(dptmp)2+ system, intramolecular steric interactions oppose flattening because the methyl groups in the 3,8 positions control the torsion angles of the neighboring phenyl groups. In the case of [Cu(tmp)2]BPh4, packing interactions induce a small flattening in the crystal, but they also constrain the degree of distortion that can occur in the excited state. As a consequence [Cu(tmp)2]BPh4 exhibits a weak photoluminescence in the solid phase (tau = 15 ns). This is the first report of emission from a bis(phenanthroline)copper(I) system that does not have bulky substituents in the 2 and/or 9 positions of the ligand. The [Cu(tmp)2]BPh4 system crystallizes in space group P2(1)/n with a = 17.4883(4) A, b = 9.86860(10) A, c = 26.3747(6) A, alpha = 90 degrees, beta = 97.7021(8) degrees, gamma = 90 degrees, V = 4510.8(3) A3, and Z = 4. For 12,948 unique data with Fo2 > 2 sigma(Fo2), R = 6.5%. The [Cu(dpdmp)2]PF6 system crystallizes in space group P2/n with a = 16.0722(13) A, b = 8.1100(7) A, c = 16.8937(10) A, alpha = 90 degrees, beta = 93.947(5) degrees, gamma = 90 degrees, V = 2196.8(5) A3, and Z = 2. For 2833 unique data with Fo2 > 2 sigma(Fo2), R = 6.0%. The [Cu(dptmp)2]PF6.THF system crystallizes in space group P1 with a = 12.8486(4) A, b = 13.7341(1) A, c = 15.1678(3) A, alpha = 99.5819(14) degrees, beta = 96.7263(13) degrees, gamma = 97.3311(12) degrees, V = 2591.3(2) A3, and Z = 2. For 13,753 unique data with Fo2 > 2 sigma(Fo2), R = 7.4%. Finally, the [Cu(dipp)2]TFPB system crystallizes in space group P1 with a = 14.2523(3) A, b = 16.0496(4) A, c = 17.5801(3) A, alpha = 112.4150(13) degrees, beta = 105.7480(13) degrees, gamma = 99.6078(11) degrees, V = 3408.7(3) A3, and Z = 2. For 8774 unique data with Fo2 > 2 sigma(Fo2), R = 9.3%.

Journal Article↗
PubMed2005

Synthesis and electronic properties of series of oligothiophene-[1,10]phenanthrolines.

Organic semiconductors containing metal binding sites within their molecular backbones are of a general interest in organic materials chemistry. In this paper, we describe a straightforward synthetic procedure, which gives access to a series of 2-(oligothienyl)-[1,10]phenanthrolines (nT-phen), 2,9-bis(oligothienyl)-[1,10]phenanthrolines (nT-phen-nT) and 2,2'-(oligothienyl)bis-[1,10]phenanthrolines (phen-nT-phen). By a Negishi-type cross coupling of 2-iodo-[1,10]phenanthroline or 2,9-diiodo-[1,10]phenanthroline with in situ generated alpha-zinc derivatives of different mono-, ter-, and quinquethiophenes we were able to synthesize the corresponding oligothienyl-phenanthrolines in medium to excellent yields. Furthermore, characterization of the optical properties of the new materials indicated that the two subunits, oligothiophene and phenanthroline, are in pi-conjugation. Characterization of the redox properties revealed additional evidence for the role of [1,10]phenanthroline as a pi-bridging unit in the nT-phen-nT series.

Journal Article↗
PubMedDate not supplied

Nuclease activity of 1,10-phenanthroline-copper. New conjugates with low molecular weight targeting ligands.

The chemical nuclease activity of 1,10-phenanthroline-copper depends on DNA sequence because the coordination complex has affinity for DNA. In order to target this efficient nucleolytic activity, it is essential to override its inherent specificity. The minimal size of ligands capable of redirecting the specificity has been investigated. A conjugate (HOP) prepared by alkylating Hoechst dye 33258 with 5-(iodoacetamido)-1,10-phenanthroline has a greater preference for A-T-rich regions than the unsubstituted 1,10-phenanthroline-copper complex, reflecting the specificity of this A-T-specific minor-groove binder. However, since quaternizing the dye with 5-(iodoacetamido)-1,10-phenanthroline increases its affinity for DNA, the specificity of cleavage by the conjugate is less than the binding selectivity of the dye. Linking 1,10-phenanthroline with the peptide of the helix-turn-helix domain of the Trp repressor specificity results in a conjugate with greater reactivity for the operator sequence than the unsubstituted complex. The intrinsic affinity of the 1,10-phenanthroline-Cu can only be partially overridden by the conformationally unstable peptide. Attachment of 1,10-phenanthroline to a deoxyoligonucleotide complementary to a single-stranded loop of RNA successfully targets the scission of the chemical nuclease. Cleavage sites are observed not only contiguous to the site of hybridization but also at nonadjacent sequence positions. The latter set of sites must be close in space to the 5' end of the hybridized deoxyoligonucleotide.

Alkylation↗
PubMedDate not supplied

Optimizing the targeted chemical nuclease activity of 1,10-phenanthroline-copper by ligand modification.

Our interest in improving the efficiency of targeted scission reagents has prompted us to study the influence of ring substituents on the nuclease activity of 1,10-phenanthroline-copper conjugated to oligonucleotides and DNA-binding proteins. Since methyl substitution at all but the 2 and 9 positions enhances the copper-dependent chemical nuclease activity of 1,10-phenanthroline, we have compared the activity of conjugates prepared from 5-(aminomethyl)-1,10-phenanthroline (MOP) to those of conjugates prepared from 5-amino-1,10-phenanthroline (amino-OP). Tethering MOP derivatives to the Escherichia coli Fis protein enhances DNA scission several-fold at the weaker cleavage sites initially observed with conjugates prepared from amino-OP. However, scission efficiency is not increased at the stronger cleavage sites, or when scission is targeted to single-stranded DNA by a complementary oligonucleotide. These results are consistent with a change in the rate-determining step for cleavage associated with the differential accessibility of the DNA-bound coordination complex to solvent and reductant. Although the free bis cuprous complex of 2,9-dimethyl-1,10-phenanthroline (neocuproine) is redox-inactive, an oligonucleotide tethered to neocuproine through C5 of the phenanthroline ring efficiently cleaves a complementary DNA sequence. These results establish that the nucleolytic species in targeted scission is the 1:1 cuprous complex and suggest that the oxidative reaction proceeds through a copper-oxo intermediate rather than a metal-coordinated peroxy species. However, substituents at the 2 and 9 positions of the ligand will often hinder close approach of the phenanthroline-copper moiety to the oxidatively sensitive ribose as shown by the preference of the oligonucleotide-targeted chimera for cleavage of single-stranded regions and the failure of neocuproine-DNA-binding protein chimeras and a C2-tethered chimera to cleave DNA.

Amino Acid Transport Systems, Neutral↗
PubMed1988

Inactivation of chicken liver pyruvate carboxylase by 1,10-phenanthroline.

Inactivation of chicken liver pyruvate carboxylase by the chelating agent 1,10-phenanthroline follows pseudo-first-order kinetics. The hyperbolic dependence of the apparent first-order rate constant on 1,10-phenanthroline concentration is consistent with a two-step inactivation mechanism, in which 1,10-phenanthroline binds firstly to the enzyme, and secondly to the enzyme-bound Mn(II) ion. Binding of 1,10-phenanthroline to pyruvate carboxylase results in complete loss of ATP/Pi exchange activity, but only a 61% decrease in pyruvate/oxaloacetate exchange activity. The rate of inactivation is greater at low enzyme concentrations, implying that binding of 1,10-phenanthroline to monomers and dimers is preferred relative to that of tetramers. Furthermore, in the presence of acetyl-CoA, which stabilizes the tetrameric structure, no dependence of inactivation on enzyme concentration is observed. As monitored by gel-permeation liquid chromatography, formation of the enzyme-Mn(II)-phenanthroline complex results in loss of the tetrameric structure of the enzyme. From atomic-absorption measurements, inactivation by 1,10-phenanthroline also causes some loss of Mn(II) from the enzyme. It is concluded that the Mn(II) atom does not participate directly in the reaction mechanism, but may play a structural role essential to the integrity of the enzyme's tetrameric structure.

Acetyl Coenzyme A↗
PubMed2005

Mechanistic studies on DNA damage by minor groove binding copper-phenanthroline conjugates.

Copper-phenanthroline complexes oxidatively damage and cleave nucleic acids. Copper bis-phenanthroline and copper complexes of mono- and bis-phenanthroline conjugates are used as research tools for studying nucleic acid structure and binding interactions. The mechanism of DNA oxidation and cleavage by these complexes was examined using two copper-phenanthroline conjugates of the sequence-specific binding molecule, distamycin. The complexes contained either one or two phenanthroline units that were bonded to the DNA-binding domain through a linker via the 3-position of the copper ligand. A duplex containing independently generated 2-deoxyribonolactone facilitated kinetic analysis of DNA cleavage. Oxidation rate constants were highly dependent upon the ligand environment but rate constants describing elimination of the alkali-labile 2-deoxyribonolactone intermediate were not. Rate constants describing DNA cleavage induced by each molecule were 11-54 times larger than the respective oxidation rate constants. The experiments indicate that DNA cleavage resulting from beta-elimination of 2-deoxyribonolactone by copper-phenanthroline complexes is a general mechanism utilized by this family of molecules. In addition, the experiments confirm that DNA damage mediated by mono- and bis-phenanthroline copper complexes proceeds through distinct species, albeit with similar outcomes.

Binding Sites↗
PubMed1999

Effects of Sterics and Electronic Delocalization on the Photophysical, Structural, and Electrochemical Properties of 2,9-Disubstituted 1,10-Phenanthroline Copper(I) Complexes.

The syntheses, crystal structures, electronic absorption spectra, electrochemical properties, and photophysical properties of a series of copper(I) bis(phenanthroline) complexes are reported. The phenanthroline ligands that have been prepared and investigated are the following: dop (2,9-di-(2-methylphenyl)-1,10-phenanthroline), xop (2-(2-methylphenyl)-9-(2,6-dimethylphenyl)-1,10-phenanthroline), dpep (2,9-diphenylethynyl-1,10-phenanthroline), and dmesp (2,9-dimesityl-1,10-phenanthroline). The complex [Cu(dop)(2)](PF(6)).Et(2)O crystallizes in space group P&onemacr;with a = 11.854(3) Å, b = 14.705(3) Å, c = 15.866(4) Å, alpha = 107.81(2) degrees, beta = 106.72(2) degrees, gamma = 97.56(2) degrees, V = 2447.6(10) Å(3), and Z = 2. For 5739 unique data with F > 4.0sigma(F), R = 7.52%. The complex [Cu(xop)(2)](PF(6)).(3)/(2)CH(3)OH crystallizes in space group C2/c with a = 23.096(6) Å, b = 23.387(6) Å, c = 17.873(7) Å, beta = 100.08(3) degrees, V = 9505(5) Å(3), and Z = 8. For 5631 unique data with F > 4.0sigma(F), R = 6.02%. The complex [Cu(dpep)(2)](PF(6)) crystallizes in space group P&onemacr; with a = 13.327(7) Å, b = 14.114(7) Å, c = 15.175(5) Å, alpha = 87.23(4) degrees, beta = 66.48(3) degrees, gamma = 61.84(4) degrees, V = 2273(2) Å(3), and Z = 2. For 4851 unique data with F > 4.0sigma(F), R = 5.47%. The complex [Cu(dmesp)(dpep)](PF(6)) crystallizes in space group Pbca with a = 14.547(6) Å, b = 22.868(6) Å, c = 30.659(10) Å, V = 10199(6) Å(3), and Z = 8. For 2281 unique data with F > 4.0sigma(F), R = 9.43%. The electrochemical, spectral, and structural properties of [Cu(dop)(2)](+) and [Cu(xop)(2)](+) demonstrate that the copper coordination environment is more sterically encumbered and more rigid in these two complexes than the coordination environment in the comparison molecule [Cu(dpp)(2)](+) (dpp = 2,9-diphenyl-1,10-phenanthroline). A larger energy gap is predicted for [Cu(dop)(2)](+) and [Cu(xop)(2)](+) based on these data, and consequently, a blue-shifted emission is observed relative to [Cu(dpp)(2)](+). The room-temperature excited-state lifetimes in dichloromethane and methanol of the dop and xop complexes are shown to be shorter than the dpp complex, and these results are interpreted as due to a reduction in ligand pi-electron delocalization in the former two complexes. The complexes [Cu(dpep)(2)](+) and [Cu(dmesp)(dpep)](+) are shown to have increased ligand pi-electron delocalization relative to [Cu(dpp)(2)](+); however, neither complex displays room-temperature steady-state emission in dichloromethane.

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