Synthesis of N-substituted 9-azabicyclo[3.3.1]nonan-3alpha-yl carbamate analogs as sigma2 receptor ligands

A series of N-substituted 9-azabicyclo[3.3.1]nonan-3alpha-yl phenylcarbamate analogs was prepared and their affinities for sigma (sigma(1) and sigma(2)) receptors were measured in vitro. The results of their structure-activity relationship study identified two new compounds, N-(9-(4-aminobutyl)-9-azabicyclo[3.3.1]nonan-3alpha-yl)-N'-(2-methoxy-5-methylphenyl)carbamate and N-(9-(6-aminohexyl)-9-azabicyclo[3.3.1]nonan-3alpha-yl)-N'-(2-methoxy-5-methylphenyl)carbamate, having a high affinity and selectivity for sigma(2) versus sigma(1) receptors. These compounds were also used in the preparation of biotinylated and fluorescent probes of the sigma(2) receptor.     

Kappa-receptor selective binding of opioid ligands with a heterocyclic bicyclo[3.3.1]nonan-9-one structure

Previous pharmacological results have suggested that members of the heterocyclic bicyclo[3.3.1]nonan-9-one-like compounds are potent kappa-opioid receptor specific agonists. One lead molecule of this series. called compound 1 (dimethyl 7-methyl-2,4-di-2-pyridyl-3.7-diazabicyclo[3.3.1]nonan-9-one-1,5-dicarboxylate) exhibited high affinity for [3H]ethylketocyclazocine and [3H]U-69.593 binding sites in guinea pig cerebellar membranes which known to be a good source for kappa1 receptors. It was shown by molecular modelling that heterocyclic bicyclo[3.3.1]nonan-9-ones fit very well with the structure of ketazocine, a prototypic kappa-selective benzomorphan compound; when compared to the arylacetamide structure of U-69.593, a specific kappa1-receptor agonist, a similar geometry was found with a slightly different distribution of the charges. It is postulated, that the essential structural skeleton involved in the opioid activity is an aryl-propyl-amine element distributed along the N7-C6-C5-C4-aryl bonds.     

Design, synthesis, stereochemistry and antioxidant properties of various 7-alkylated 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones

We used the modified Mannich condensation to synthesize three closely-related series of 7-alkylated 3-ABNs 1-5 viz., 7-methylated 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (7-Me ABNs 1-5), 7-ethylated 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (7-Et ABNs 1-5) and 7-tert-pentylated 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (7-tert-pentyl ABNs 1-5). All compounds yielded good as single isomers by the use of PPA·SiO(2) as a heterogeneous Bronsted acidic catalyst. The 1D, 2D NMR, and single-crystal XRD interpretations unambiguously characterized the stereochemistry of the synthesized compounds. In solution as well as solid-state, all compounds exist in the twin-chair conformation with equatorial orientations of all substitutions, despite their nature and positions. The chemical methods viz., DPPH, reducing power, and phospho-molybdenum methods identified some of the target curcumin analogs as active compounds. Among them, 7-Me ABN 4 (7-methyl-2,4-bis(3-methoxy-4-hydroxyphenyl)-3-azabicyclo[3.3.1]nonan-9)-one exerted the best antioxidant profile that comparable to standard l-ascorbic acid, α-tocopherol and curcumin. Hence, we evaluated further for its intracellular ROS inhibition potency on RAW 264.7 macrophage cells, and found to be effective as well as non-toxic at 100μM.     

Synthesis and antitumor activity of bicyclo[3.3.1]nonenol derivatives

Various novel bicyclo[3.3.1.]nonenol derivatives were synthesized in an efficient one-pot procedure in a remarkably stereoselective reaction. The title compounds show significant antitumor activity against human cancer cell lines. A variety of cinnamic acid derivatives were linked to the title compounds as side chains in order to enhance the antitumor activity. These compounds were subjected to the in vitro antitumor screening, and the results are discussed. It seems important with respect to antitumor activity to locate an aromatic ring at the C-7 position of the bicyclo[3.3.1]nonane framework.     

Determination of the absolute configuration of bicyclo[3.3.1]nonane-2,7-dione by circular dichroism spectroscopy and chemical correlation.

A study of the enantiomers of bicyclo[3.3.1]nonane-2,7-dione, a chiral molecule containing two carbonyl chromophores, was performed. Enantiomers of this structure were obtained by HPLC resolution and the (+)-(1R,5S)-enantiomer by enantiospecific synthesis from(+)-(1S,5S)-bicyclo[3.3.1]nonane-2,6-dione. The title structure is an interesting molecule to demonstrate the validity of the octant rule. The location of the major chair-chair conformer into octants placing each chromophore into the origin of the octants led to the opposite configuration assignments. In order to prove unequivocally absolute configuration, enantiospecific synthesis of the title compound was carried out. The kinetic resolution of racemic bicyclo[3.3.1]nonane-2,6-dione using baker's yeast afforded (+)-(1S,5S)-2,6-dione. Employing a reaction sequence analogous to one developed earlier by us with racemic substrates led to carbonyl group shift giving enantiomerically pure (+)-(1R,5S)-bicyclo[3.3.1]nonane-2,7-dione. The absolute configuration of the investigated compound was established by combined use of the octant rule and chemical correlation.     

C(8)-substituted 1-azabicyclo[3.3.1]non-3-enes: a novel scaffold for muscarinic receptor ligands

The [3.3.1]-bicyclic amine, exo-8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene (1), has been shown to be a potent competitive antagonist against the hM(1)-hM(5) muscarinic receptors. This heterocyclic system has not been extensively evaluated despite the notable activities reported for other bicyclic amines. Synthetic strategies permitted the selective alteration of five structural sites in 1. Pharmacological evaluation demonstrated that modification of either the C(3) alkoxycarbonyl or the C(4) enol units in 1 gave compounds with high affinity for the hM(1)-hM(5) muscarinic receptors with selectivity for the hM(2) receptor.     

Synthesis,Molecular Structure,and Chiroptical Properties of Dibenzylidene Derivatives of Bicyclo[3.3.1]nonane and Brexane

Synthesis of several enantiomerically pure unsaturated bicyclo[3.3.1]nonane and related brexane (tricyclo[4.3.0.0^3,7]nonane) derivatives bearing exocyclic benzylidene substituents from readily available (+)‐(1S,5S)‐bicyclo[3.3.1]nonane‐2,6‐dione was accomplished. Molecular geometry and chiroptical properties of compounds with enone and styrene chromophores were studied by X‐ray diffraction analysis, molecular modeling, and circular dichroism (CD) spectroscopy. Difunctional 3,7‐dibenzylidenebicyclo[3.3.1]nonanes, such as 2 and 7 , 8 , 9 , exhibited intense CD couplets, arising from the exciton coupling between the two unsaturated chromophores. The observed negative sign of the exciton couplets is congruent with the negative twist (negative chirality) defined by the two interacting transition dipoles. The sign of the Cotton effect corresponding to the π→π* transitions in the CD spectra of monoenone 4 and tricyclic brexane acetate 11 was correlated with the intrinsic dissymmetry (helicity) of the styrene chromophore. Chirality 27:728–737, 2015. © 2015 Wiley Periodicals, Inc.     

Influence of Acetyl and Bromine Substitutions on Stacking. Crystal and Molecular Structures of 8-Bromo 2′,3′,5′-Triacetyl Adenosine and 8-Bromo 2′,3′,5′-Triacetyl Guanosine

Abstract

The three dimensional structures of 8-bromo 2′,3′,5′-triacetyl adenosine (8-Br Tri A) and 8-bromo 2′,3′,5′-triacetyl guanosine (8-Br Tri G) have been determined by single crystal X-ray diffraction methods to study the combined effect of bromine and acetyl substitutions on molecular conformation and interactions. The ribose puckers differ from those found in unbrominated Tri A and Tri G and unacetylated 8-Br A and 8-Br G analogues. The adenine bases in 8-Br Tri A form A.A.A base triplets using both Watson-Crick and Hoogsteen sites. Br atoms are not involved in stacking unlike most halogenated structures. The ‘scorpion tail’ positioning of acetyl over base in 8-Br Tri G is different from Tri G and is an interesting consequence of bromine substitution.     

Synthesis, stereochemistry and in vitro antimicrobial evaluation of novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-4-phenyl-2,3-dihydrothiazoles

2-[(2,4-Diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-4-phenyl-2,3-dihydrothiazoles (3a-3k) have been synthesized by the cyclization of 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one thiosemicarbazones with phenacyl bromide and characterized by analytical (melting point and elemental analysis) and spectral (IR, (1)H NMR, (13)C NMR, D(2)O exchange, NOESY and mass) techniques. The novel Hantzsch products (3a-3k) were screened for their in vitro antibacterial and antifungal activities against some selected microorganisms. Structure activity relationship (SAR) for the reported compounds was studied by comparing their MIC values with standard drugs (Streptomycin and Amphotericin B). The results show that 3e against Escherichia coli and Cryptococcus neoformans3i against Bacillus Subtilis, 3b against Aspergillus flavus, and 3k against Rhizopus sp. were found to show significant growth inhibition.     

Synthesis and antimicrobial studies of novel 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one 4'-phenylthiosemicarbazones

New series of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one 4'-phenylthiosemicarbazones (compounds 9-16) was obtained from the corresponding 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones. The synthesized compounds have been characterized by their elemental, analytical, and spectral studies. Besides, these reported compounds were screened for their antibacterial and antifungal activities against a spectrum of microbial organisms. These studies proved that against bacteria, compounds 10 and 11 against Bacillus subtilis, compound 13 against Salmonella typhi, show maximum inhibition potency at low concentration (6.25 μg/mL), whereas against fungal, compounds 11, 13, and 16 against Candida albicans and compounds 12 and 13 against Cryptococcus neoformans, showed beneficial antifungal activity at minimum concentration (6.25 μg/mL).     

Reactions of hybrid organotellurium ligands 1-(4-methoxyphenyl telluro)-2-[3-(6-methyl-2-pyridyl)propoxy]ethane (L) and 1-ethylthio-2-[2-thienyltelluro]ethane (L) with mercury (II) bromide: formation of complexes and their decomposition

Two tellurium ligands 1-(4-methoxyphenyltelluro)-2-[3-(6-methyl-2-pyridyl)propoxy]ethane (L¹) and 1-ethylthio-2-[2-thienyltelluro]ethane (L²) have been synthesized by reacting nucleophiles [4-MeO-C₆H₄Te⁻] and [C₄H₃S-2-Te⁻] with 2-[3-(6-methyl-2-pyridyl)propoxy]ethylchloride and chloroethyl ethyl sulfide, respectively. Both the ligands react with HgBr₂ resulting in complexes of stoichiometry [HgBr₂ · L¹/L²] (1/4), which show characteristic NMR (¹H and ¹³C{¹H}). On crystallization of 1 from acetone-hexane (2:1) mixture, the cleavage of L¹ occurs resulting in 4-MeOC₆H₄HgBr (2) and [RTe⁺→HgBr₂]Br⁻ (3) (where R = -CH₂CH₂OCH₂CH₂CH₂-(2-(6-CH₃-C₅H₃N))). The 2 is characterized by X-ray diffraction on its single crystal. It is a linear molecule and is the first such system which is fully characterized structurally. The Hg-C and Hg-Br bond lengths are 2.085(6) and2.4700(7) Å. The distance of four bromine atoms (3.4041(7)-3.546(7) Å) around Hg (cis to C) is greater than the sum of van der Waal’s radii 3.30 Å. This mercury promoted cleavage is observed for an acyclic ligand of RArTe type for the first time and is unique, as there appears to be no strong intramolecular interaction to stabilize the cleavage products. The 4 on crystallization shows the cleavage of organotellurium ligand L² and formation of a unique complex [(EtS(CH₂)₂SEt)HgBr(μ-Br)Hg(Br)(μ-Br)₂Hg(Br)(μ-Br)BrHg(EtS(CH₂)₂SEt)] · 2HgBr₂ (5), which has been characterized by single crystal structure determination and ¹H and ¹³C{¹H} NMR spectra. The elemental tellurium and [C₄H₃SCH₂]₂ are the other products of dissociation as identified by NMR (proton and carbon-13). The cleavage appears to be without any transmetalation and probably first of its kind. The centrosymmetric structure of 5 is unique as it has [HgBr₃]⁻ unit, one Hg in distorted tetrahedral geometry and one in pseudo-trigonal bipyramidal one. The molecule of 5 may also be described as having [(EtSCH₂CH₂SEt)HgBr]⁺ [HgBr₃]⁻ units, which dimerize and co-crystallize with two HgBr₂ moieties. There are very weak Hg?Br interactions between co-crystallized HgBr₂ units and rest of the molecule. [Hg(3)-Br(1)/Hg(3)-Br(4) = 3.148(1)/3.216(1) Å]. The bridging Hg?Br distances, Hg(2)-Br(4)′, Hg(2)′-Br(4) and Hg(1)-Br(2), are from 2.914(1) to 3.008(1) Å.     

In vivo anticancer, anti-inflammatory, and toxicity studies of mixed-ligand Cu(II) complexes of dien and its Schiff dibases with heterocyclic aldehydes and 2-amino-2-thiazoline. Crystal structure of [Cu(dien)(Br)(2a-2tzn)](Br)(H(2)O)

A new series of complexes of the type [Cu(dien)(2a-2tzn)Y(2)] and [Cu(dienXX)(2a-2tzn)Y(2)], where dien=diethylenetriamine and dienXX=Schiff dibase of diethylenetriamine formed with 2-furaldehyde (dienOO), 2-thiophenecarboxaldehyde (dienSS), or pyrrol-2-carboxaldehyde (dienNN); Y=Cl, Br or NO(3); and 2a-2tzn=2-amino-2-thiazoline, were synthesized and their structure established by C, H, N and Cu analysis; IR and electronic spectra; magnetic susceptibility; and molar conductivity. The isolated complexes are monomers, paramagnetic, and electrolytes of types 1:1 or 1:2. In both types of solid state complexes, [Cu(dien)(2a-2tzn)Y(2)] and [Cu(dienXX)(2a-2tzn)Y(2)], dien and its Schiff dibases are bonded to Cu(II) in a tridentate fashion through 3N atoms. The coordination sphere is completed by the endocyclic nitrogen of the thiazoline moiety and by two Cl, Br, or NO(3) groups with distorted octahedral geometry. The proposed structure of these compounds was supported by X-ray analysis of [Cu(dien)(Br)(2a-2tzn)](Br)(H(2)O). The coordination polyhedron around the copper atom can be described as a distorted square pyramid [Cu(dien)(Br)(2a-2tzn)](+). Its basal plane is occupied by the four nitrogen atoms of the dien and thiazoline ligands with Cu-N distances ranging between 1.996(6) and 2.032(3)A, and the axial position is occupied by one of the two bromine atoms (Br1) with a Cu1-Br1 bond distance of 2.782(1)A. The second bromine atom (Br2) is 4.694(2)A from the copper atom, which exists as a discrete anion and is responsible for the cationic nature of the complex. Results regarding toxicity, antitumor, and anti-inflammatory activities of the investigated compounds are promising and allow the selection of a lead compound for further biological studies.     

N-3(9)-arylpropenyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes as mu-opioid receptor agonists. Effects on mu-affinity of arylalkenyl chain modifications

Two series of N-3-arylpropenyl-N-9-propionyl-3,9-diazabicyclo[3.3.1]nonanes (1b-j) and of the reverted N-3-propionyl-N-9-arylpropenyl isomers (2b-j) as analogues of the previously reported analgesic N-3(9)-cinnamyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes (DBN) (1a, 2a) were synthesised and their affinity and selectivity towards opioid mu-, delta- and kappa-receptors were evaluated. Several compounds (1e,i,j-2d,e,f,g,j) exhibited a mu-affinity in the low nanomolar range with moderate or negligible affinity towards delta- and kappa-receptors. The representative term N-9-(3,3-diphenylprop-2-enyl)-N-3-propionyl-DBN (2d) displayed in vivo (mouse) a potent analgesic effect (ED(50) 3.88 mg/kg ip) which favourably compared with that of morphine (ED(50) 5 mg/kg ip). In addition, 2d produced in mice tolerance after a period twice as long with morphine.     

The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor (nAChR) ligands. Part 1: The influence of different hydrogen bond acceptor systems on alkyl and (hetero)aryl substituents

3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4β2¹ were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4β2¹ possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents.     

Cobalt(II) and nickel(II) complexes with nitrogen-sulfur tripod ligands. Crystal and molecular structure of the five-coordinate complex bromotris(2-tert-butylthioethyl)aminecobalt(II) hexafluorophosphate (NS3Br donor set)

The tripod ligands tris(2-alkylthioethyl)amine, with alkyl = ethyl, iso-propyl, and tert-butyl, give with cobalt(II) and nickel(II) halides high-spin complexes with formulae [MLX₂], [MLX]Y, and [MLX]₂[MX₄] (where X = Cl, Br, I; Y = BPh₄, PF₆). The nickel complexes are either six- or five-coordinate: the coordination number decreases as the bulkiness of the alkyl group bound to the sulfur is increased. All the cobalt complexes contain the five-coordinate cation [CoLX]⁺. The crystal and molecular structure of the [Co(NS₃-t-Bu)Br]PF₆ complex has been determined by standard X-ray methods, and refined to R = 0.061. The crystals are monoclinic, space group P2¹/n. The unit cell dimensions are: a = 27.420 (2), b = 11.923 (4), c = 17.082 (1) Å, β = 102.40 (1)°, Z = 8. The complex cation has a trigonal bipyramidal geometry with the nitrogen and bromine atoms at the apexes, and the three sulfur atoms in the equatorial plane. The tetrahedral distortion is relatively small (mean BrCoS angle = 98.5°), and similar to that found for the [Co (Me₆tren)Br]Br complex [Me₆tren = tris(2-dimethylaminoethyl)amine).     

Synthesis and reactions of [M(CO)4(Ph2PSiMe3)X] complexes (M = Mn,Re; X = Halogen)

The silylphosphine ligand Ph₂PSiMe₃ reacts readily with a slurry of [Re(CO)₅X] (X  Cl, Br) in polar and in non-polar solvents to yield soluble cis-[Re(CO)₄- (Ph₂PSiMe₃)X] (Ia, X  Cl;Ib, X  Br) via CO substitution. Compound I is readily hydrolyzed by water or silica gel to cis-[Re(CO)₄(Ph₂PH)X]. Compound Ib reacts with [Re(CO)₅Br] to yield [Re₂(CO)₈(μ-PPh₂)- (μ-Br)] (II), and with [Mn(CO)₅Br] to yield [MnRe- (CO)₈(μ-PPh₂)(μ-Br)] (III).The reaction of Ph₂PSiMe₃ with [Mn(CO)₅X] (X=Cl,Br,I) is highly dependent upon reaction conditions.In polar and in non-polar solvents, an excess of ligand gives mainly cis-[Mn(CO)₄(Ph₂PSiMe₃)X] (IVa, X  Cl;IVb, X  Br;IVc, X I). With ligand: [Mn(CO)₅X] reacting ratios in the range 0.5–1.0:1, the products from the three respective halomanganese complexes in THF were: (a) mainly [Mn₂(CO)₈(μ- PPh₂)(μ-Cl) (Va); (b) both [Mn(CO)₄(Ph₂PSiMe₃)Br] and [Mn₂(CO)₈(μ-PPh₂)(μ-Br)] (Vb); and (c) exclusively [Mn(CO)₄(Ph₂PSiMe₃)I]. The compounds IVa-c are stable in solution at ambient temperatures and are readily hydrolyzed by water or methanol to [Mn(CO)₄(Ph₂PH)X]. Compound IVb reacts at room temperature with [Mn(CO)₅Cl] to yield only [Mn₂- (CO)₈(μ-PPh₂)(μ-Br)] (Vb); compound IVc reacts in hot toluene with [Mn(CO)₅Cl] to yield mainly [Mn₂(CO)₈(μ-PPh₂)(μ-I)] (Vc), together with a small amount of the chloro-bridged analog.The dinuclear species II, III and Va-c appear to be formed mainly via an intermolecular elimination of Me₃SiX from the appropriate [M(CO)₄(Ph₂PSiMe₃)X] and metalpentacarbonylhalide (chloride or bromide) complexes.     

Design,synthesis and biological evaluation of novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-1,3-thiazolidin-4-ones as a new class of antimicrobial agents

New series of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one thiosemicarbazones (9–16) obtained from the corresponding 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (1–8) upon cyclization with ethylbromoacetate in the presence of sodium acetate–acetic acid buffer afforded novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-1,3-thiazolidin-4-ones (17–24). The synthesized compounds have been characterized by their elemental, analytical and spectral studies. Besides, the reported compounds were screened for their antibacterial and antifungal activities against a spectrum of microbial organisms. These studies proved that compounds 11/18/20/23 against Staphylococcus aureus, 19/20/24 against Salmonella typhi show maximum inhibition potency at low concentration (6.25 μg/ml) whereas 18/19 against Candida albicans and 19/20/21 against Rhizopus sp. showed beneficial antifungal activity at minimum concentration.     

Synthesis of Diastereomeric Bicyclo[3.3.1]nonane Dibenzoyl Esters and Study of Their Chiroptical Properties

A synthesis of diastereomeric bicyclic dibenzoyl esters derived from enantiomerically pure (1S,5S)‐bicyclo[3.3.1]nonane‐2,6‐dione was accomplished. Molecules containing two benzoyl chromophores with different configuration in the bicyclic framework were obtained. Chiroptical properties of the synthesized enantiomerically pure molecules were studied. Diastereomeric esters exhibited exciton couplets in the circular dichroism (CD) spectra because of transannular interaction between non‐conjugated benzoate chromophores. The conformational effects and solvent impact on the exciton coupling were examined by CD spectroscopy. Theoretical computation of the CD spectra of diastereomers correctly reproduced the sign of the exciton couplets in the studied molecules, however, no major solvent dielectric constant influence and conformational effects per se on the exciton coupling was observed. Chirality 24:810–816, 2012. © 2012 Wiley Periodicals, Inc.     

Production of brominating intermediates by myeloperoxidase. A transhalogenation pathway for generating mutagenic nucleobases during inflammation

The existence of interhalogen compounds was proposed more than a century ago, but no biological roles have been attributed to these highly oxidizing intermediates. In this study, we determined whether the peroxidases of white blood cells can generate the interhalogen gas bromine chloride (BrCl). Myeloperoxidase, the heme enzyme secreted by activated neutrophils and monocytes, uses H2O2 and Cl(-) to produce HOCl, a chlorinating intermediate. In contrast, eosinophil peroxidase preferentially converts Br(-) to HOBr. Remarkably, both myeloperoxidase and eosinophil peroxidase were able to brominate deoxycytidine, a nucleoside, and uracil, a nucleobase, at plasma concentrations of Br(-) (100 microM) and Cl(-) (100 mM). The two enzymes used different reaction pathways, however. When HOCl brominated deoxycytidine, the reaction required Br(-) and was inhibited by taurine. In contrast, bromination by HOBr was independent of Br(-) and unaffected by taurine. Moreover, taurine inhibited 5-bromodeoxycytidine production by the myeloperoxidase-H2O2-Cl(-)- Br(-) system but not by the eosinophil peroxidase-H2O2-Cl(-)-Br(-) system, indicating that bromination by myeloperoxidase involves the initial production of HOCl. Both HOCl-Br(-) and the myeloperoxidase-H2O2-Cl(-)-Br(-) system generated a gas that converted cyclohexene into 1-bromo-2-chlorocyclohexane, implicating BrCl in the reaction. Moreover, human neutrophils used myeloperoxidase, H2O2, and Br(-) to brominate deoxycytidine by a taurine-sensitive pathway, suggesting that transhalogenation reactions may be physiologically relevant. 5-Bromouracil incorporated into nuclear DNA is a well known mutagen. Our observations therefore raise the possibility that transhalogenation reactions initiated by phagocytes provide one pathway for mutagenesis and cytotoxicity at sites of inflammation.     

Polynuclear complexes of copper(II) with the tetra-aza ligand 3,6-bis(2′-pyridyl)pyridazine(L). Crystal structure of the bromine derivative [Cu2L(OH)Br3]n

The tetra-aza ligand 3,6-bis(2′-pyridyl)pyridazine (L), when reacting in appropriate conditions with Cu(II) halides, gives rise to polynuclear complexes of general formula [Cu₂L(OH)X₃]_n (X = Cl or Br). The bromine derivative has been studied by X-ray analysis. The crystals are twins by merohedry of class I, space group Pn (P2₁/n apparent space group), with the following cell constants: a = 13.691(5), b = 6.245(3), c = 10.298(4) Å, β = 103.92(5)°. The structure was refined by least-squares techniques to a final R factor of 0.066. The structure consists of binuclear units joined to each other through bridging bromine atoms to form a polymeric array. The two independent copper atoms of the dinuclear moiety are five-coordinated with a geometry which is intermediate between a square-pyramid and a trigonal-bipyramid.