Synthesis and characterization of alkynes β-diketonate copper(I) complexes

The reactions of 1,3,5-tris-(trimethylsilylethynyl)benzene (1) with Cu₂O and 1,1,1,5,5,5,-hexafluoroacetylacetone in alkyne to Cu ratios 1:0.5, 1:1 and 1:3 in CH₂Cl₂ at room temperature give copper complexes (η²-1,3,5-tris(trimethylsilylethynyl)benzene)(Cu(hfac)) (2), (η²:η²-1,3,5-tris(trimethylsilylethynyl)benzene)(Cu(hfac))₂ (3) and (η²:η²:η²-(1,3,5- tris(trimethylsilylethynyl)benzene))₂(Cu(hfac))₃(4), respectively. In the same conditions, 2,5-bis-(trimethylsilylethynyl)thiophene (5) reacts with 0.5 or 1 equiv. of Cu₂O to give (η²:η²-2,5-bis(trimethylsilylethynyl)thiophene)(Cu(hfac)) (6) and (η²:η²-2,5-bis(trimethylsilylethynyl)thiophene)(Cu(hfac))₂ (7), respectively, and 1,4-bis(trimethylsilyl)-1,3-butadiyne (8) with 0.5 equiv. of Cu₂O give (η²:η²-1,4-bis(trimethylsilyl)-1,3-butadiyne)(Cu(hfac))₂(9). All the new compounds have been characterized by analytical and spectroscopic methods and their thermal properties were examined by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC).     

Synthesis, crystal structures and spectroscopic properties of copper(I) complexes containing β-dialdiminato supporting ligands

Two mononuclear neutral copper(I) complexes, Cu(L¹)PPh₃ (1), Cu(L²)(PPh₃)₂ (2) ([L¹]⁻ = [{N(C₆H₃ⁱPr₂-2,6)C(H)}₂CPh]⁻; [L²]⁻ = [{N(C₆H₅)C(H)}₂CPh]⁻) have been synthesized and structurally characterized by X-ray crystallography. In complex 1, the copper(I) atom is in a distorted three-coordinate trigonal planar environment, whereas in complex 2 with the less sterically hindered β-dialdiminato ligand, the copper(I) atom is the centre of a four-coordinate distorted tetrahedron. At room temperature complexes 1 and 2 in a film of PMMA exhibit green emission at 543 and 549 nm with lifetimes of 5.28 and 5.32 ns, respectively.     

Synthesis and antimicrobial activity of copper(II) and manganese(II) α,ω-dicarboxylate complexes

Copper(II) ,-dicarboxylate complexes of general formulae, [Cu(O₂C(CH₂)_nCO₂)]·xH₂O, [Cu(O₂C(CH₂)_nCO₂) (phen)₂]·xH₂O and [Cu(O₂C(CH₂)_nCO₂)(bipy)_y]·xH₂O (n=1–8; y=1, 2; phen = 1,10-phenanthroline; bipy = 2,2-bipyridine) were synthesised. These copper complexes, some related manganese(II) complexes and the metal-free ligands were screened in vitro for their ability to inhibit the growth of Candida albicans. Metal-free 1,10-phenanthroline and all of the copper(II) and manganese(II) phenanthroline complexes were potent growth inhibitors, with only one bipyridine complex, [Cu(O₂C(CH₂)CO₂)(bipy)₂]·2H₂O, having moderate activity. The remaining substances were effectively inactive. Complexes which were active against C. albicans also proved effective against C. glabrata, C. tropicalis and C. kreusi with the manganese complexes retaining superior activity. For the phenanthroline complexes the active drug species is thought to be the dication [M(phen)₂(H₂O)_n]²⁺ (M = Cu, Mn). Escherichia coli and Staphylococcus aureus were resistant to all of the metal complexes and also to metal-free 1,10-phenanthroline. Only the copper phenanthroline complexes showed intermediate activity against Pseudomonas aeruginosa.     

Synthesis and structure–activity relationships of N-substituted spiropiperidines as nociceptin receptor ligands: Part 2

A series of N-8 substituted analogs based upon the spiropiperidine core of the original lead compound 1 was synthesized. This lead has been elaborated to compounds to give compounds 2 and 3 (R = H) that exhibited high NOP binding affinity as well as selectivity against other known opioid receptors. These two series have been further functionalized at the amido nitrogen. The synthesis and structure–activity relationship (SAR) of these and related compounds are discussed.     

Rectangular tetranuclear silver(I) and μ8-selenide-centered octanuclear copper(I) complexes containing bis(diphenylphosphino)amide ligands

Interaction of Ag(CF₃CO₂) with bis(diphenylphosphino)amide (dppa) in THF gave a tetranuclear Ag₄-coplanar silver(I) complex [Ag₄(μ-dppa)₂(μ₄-O₂PPh₂)₂(μ-CF₃CO₂)₂] (1). The trinuclear trigonal-bipyramid copper(I) complex [Cu₃(μ₃-Cl)₂(μ-dppa)₃][CuCl₂] (2) was obtained from the reaction of [CuCl] powder with bis(diphenylphosphino)amide (dppa) in THF. Treatment of 2 with (Me₃Si)₂Se in THF afforded a μ₈-selenide-centered octanuclear copper(I) complex [Cu₈(μ₈-Se)(μ₄-Se)(μ₄-SeH)₃(μ-dppa)₄][(Ph₂PO)₂N] (3). The structures of 1-3 were determined by single-crystal X-ray diffraction analyses. Complex 1 comprises a rectangular Ag₄ array with each edge bridged with a pair of μ-dppa, μ₄-O₂PPh₂ and μ-CF₃CO₂ ligands that are approximately perpendicular to each other. Complex 2 contains a trigonal-bipyramid [Cu₃(μ₃-Cl)₂]⁺ core surrounded by three μ-dppa ligands. The cationic complex in 3 consists of four [Cu₂(μ-dppa)] fragments side-capped by one μ₄-Se and three μ₄-SeH ligands and center-connected by a μ₈-Se atom.     

A new insulin-mimetic bis(allixinato)zinc(II) complex: structure–activity relationship of zinc(II) complexes

During the investigation of the development of insulin-mimetic zinc(II) complexes with a blood glucose-lowering effect in experimental diabetic animals, we found a potent bis(maltolato)zinc(II) complex, Zn(ma)₂, exhibiting significant insulin-mimetic effects in a type 2 diabetic animal model. By using this Zn(ma)₂ as the leading compound, we examined the in vitro and in vivo structure–activity relationships of Zn(ma)₂ and its related complexes. The in vitro insulin-mimetic activity of these complexes was determined by the inhibition of free fatty acid release and the enhancement of glucose uptake in isolated rat adipocytes treated with epinephrine. A new Zn(II) complex with allixin isolated from garlic, Zn(alx)₂, exhibited the highest insulin-mimetic activity among the complexes analyzed. The insulin-mimetic activity of the Zn(II) complexes examined strongly correlated (correlation coefficient=0.96) with the partition coefficient (logP) of the ligand, indicating that the activity of Zn(ma)₂-related complexes depends on the lipophilicity of the ligand. The blood glucose-lowering effects of Zn(alx)₂ and Zn(ma)₂ were then compared, and both complexes were found to normalize hyperglycemia in KK-A^y mice after a 14-day course of daily intraperitoneal injections. However, Zn(alx)₂ improved glucose tolerance in KK-A^y mice much more than did Zn(ma)₂, indicating that Zn(alx)₂ possesses greater in vivo anti-diabetic activity than Zn(ma)₂. In addition, Zn(alx)₂ improved leptin resistance and suppressed the progress of obesity in type 2 diabetic KK-A^y mice. On the basis of these observations, we conclude that the Zn(alx)₂ complex is a novel potent candidate for the treatment of type 2 diabetes mellitus.Electronic Supplementary Material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00775-004-0590-8     

Magnetostructural correlations and catecholase-like activities of μ-alkoxo-μ-carboxylato double bridged dinuclear and tetranuclear copper(II) complexes

Two μ-alkoxo-μ-carboxylato bridged dinuclear copper(II) complexes, [Cu₂(L¹)(μ-HCO₂)] (1) ((H₃L¹ = 1,3-bis(5-bromosalicylideneamino)-2-propanol)), [Cu₂(L²)(μ-HCO₂)] · dmf (2) (H₃L² = 1,3-bis(3,5-chlorosalicylideneamino-2-propanol)), and two μ-alkoxo-μ-dicarboxylato doubly bridged tetranuclear copper(II) complexes, [{Cu₂(L³)}₂(μ-O₂C–C(CH₃)₂–CO₂)] · 5H₂O · 3CH₃OH (3) ((H₃L³ = 1,3-bis(salicylid-deneamino)-2-propanol)) and [{Cu₂(L³)}₂(μ- O₂CCH₂–C₆H₄–CH₂CO₂)] · 2H₂O (4) have been prepared and characterized. The single crystal X-ray analysis shows that the structures of complexes 1 and 2 are dimeric with two adjacent copper(II) atoms bridged by μ-alkoxo-μ-carboxylato ligands with the Cu⋯Cu distances and Cu–O(alkoxo)–Cu angles are 3.511 Å and 132.85° for 1, 3.517 Å and 131.7° for 2, respectively. Complexes 3 and 4 consist of μ-alkoxo-μ-dicarboxylato doubly bridged tetranuclear Cu(II) complexes with mean Cu–Cu distances and Cu–O–Cu angles of 3.158 Å and 108.05° for 3 and 3.081 Å and 104.76° for 4, respectively. Magnetic measurements reveal that 1 and 2 are strong antiferromagnetically coupled with 2J = −156 and −152 cm⁻¹, respectively, while 3 and 4 exhibit ferromagnetic coupling with 2J = 86 and 155.2 cm⁻¹, respectively. The 2J values of 1–4 are linearly correlated to the Cu–O–Cu angles. Dependence of the pH at 25 °C on the reaction rate of oxidation of 3,4-di-tert-butylcatechol (3,5-dtbc) to the corresponding quinone catalyzed by 1–4 was studied. Complexes 1–4 exhibit high catecholase-like activity at pH 9.0 and 25 °C for oxidation of 3,5-di-tert-butylcatechol.     

Inhibition of monoamine oxidase–A activity in rat brain by synthetic hydrazines: Structure-activity relationship (SAR)

A series of hydrazine derivatives was synthesized in order to evaluate their monoamine oxidase A (MAO-A) inhibitory effects. MAO-A inhibitory activity of 4-tosyl benzoic acid carbohydrazide was quite potent, similarly to that of the corresponding 4-benzyloxy-benzoic acid carbohydrazide and its N-cyanoethylated derivative. Structural variations of these compounds, such as the replacement of the 4-substitutent, of the aromatic ring on which the carbohydrazide moiety is grafted, as well as cyclization of the hydrazide moiety in five- or six-membered rings caused either significant decline or complete loss of MAO inhibitory properties. The most active compound (4-tosyl benzoic acid carbohydrazide) was also subjected to the forced swim test, an animal model of depression, eliciting a marked reduction in immobility time in rats, without affecting the locomotor activity, implying that it possesses anti-depressant properties due to inhibition of MAO type-A.     

Rational quantitative structure–activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related orphan nuclear receptor proteins that share several ligands and target overlapping sets of genes involved in homeostasis and all phases of drug metabolism. CAR and PXR are involved in the development of certain diseases, including diabetes, metabolic syndrome and obesity. Ligand screens for these receptors so far have typically focused on steroid hormone analogs with pharmacophore-based approaches, only to find relatively few new hits. Multiple CAR isoforms have been detected in human liver, with the most abundant being the constitutively active reference, CAR1, and the ligand-dependent isoform CAR3. It has been assumed that any compound that binds CAR1 should also activate CAR3, and so CAR3 can be used as a ligand-activated surrogate for CAR1 studies. The possibility of CAR3-specific ligands has not, so far, been addressed. To investigate the differences between CAR1, CAR3 and PXR, and to look for more CAR ligands that may be of use in quantitative structure–activity relationship (QSAR) studies, we performed a luciferase transactivation assay screen of 60 mostly non-steroid compounds. Known active compounds with different core chemistries were chosen as starting points and structural variants were rationally selected for screening. Distinct differences in agonist versus inverse agonist/antagonist effects were seen in 49 compounds that had some ligand effect on at least one receptor and 18 that had effects on all three receptors; eight were CAR1 ligands only, three were CAR3 only ligands and four affected PXR only. This work provides evidence for new CAR ligands, some of which have CAR3-specific effects, and provides observational data on CAR and PXR ligands with which to inform in silico strategies. Compounds that demonstrated unique activity on any one receptor are potentially valuable diagnostic tools for the investigation of in vivo molecular targets.     

Effect of anionic co-ligands on structure and magnetic coupling of bis(μ-phenoxo)-bridged dinuclear copper(II) complexes

Two phenoxo bridged dinuclear Cu(II) complexes, [Cu₂L₂(NO₂)₂] (1) and [Cu₂L₂(NO₃)₂] (2) have been synthesized using the tridentate reduced Schiff-base ligand 2-[(2-dimethylamino-ethylamino)-methyl]-phenol (HL). The complexes have been characterized by X-ray structural analyses and variable-temperature magnetic susceptibility measurements. The structures of the two compounds are very similar having the same tridentate chelating ligand (L) and mono-dentate anionic ligand nitrite for 1 and nitrate for 2. In both complexes Cu(II) is penta-coordinated but the square pyramidal geometry of the copper ions is severely distorted (Addison parameter (τ) = 0.33) in 1 while the distortion is quite small (average τ = 0.11) in 2. These differences have marked effect on the magnetic properties of two compounds. Although both are antiferromagnetically coupled, the coupling constants (J = −140.8 and −614.7 cm⁻¹ for 1 and 2, respectively) show that the coupling is much stronger in 2.     

A study of structure–activity relationship and anion-controlled quinolinyl Ag(I) complexes as antimicrobial and antioxidant agents as well as their interaction with macromolecules

BioMetals - In this communication, we feature the synthesis and in-depth characterization of a series of silver(I) complexes obtained from the complexation of quinolin-4-yl Schiff base ligands...     

Synthesis and reactivity of perchlorate bis(tetrahydrothiophen)gold(I). 197Au Mössbauer spectra of three-coordinate gold(I) complexes

The displacement of tetrahydrothiophen (tht) in [Au(tht)₂]ClO₄ by neutral ligands gives bi-, tri- or tetra-coordinated complexes of the type [Au- (py)₂]ClO₄, [(tht)AuPPh₂NHPPh₂Au(tht)] (ClO₄)₂, [LAu(LL)]ClO₄ (L=tht, PPh₃; LL=bipy, phen) or [AuL₄]ClO₄ (L=PPh₃, AsPh₃ or SbPh₃). The reaction between [Au(tht)₂]ClO₄ and (Bu₄N)[AuR₂] (R=C₆F₅, C₆Cl₅, C₆F₃H₂) yields RAu(tht). The ¹⁹⁷Au Mössbauer spectrum of [LAu(LL)]ClO₄ establishes it as a tri-coordinated species, albeit with an asymmetrically linked bidentate ligand.     

Synthesis and NMR characterization of cationic rhodium(I) complexes containing phosphorus—sulfur bidentate ligands

The reaction of [Rh(diene)(acac)] (diene=cyclooctadiene or norbornadiene; acac=acetylacetonate) with bidentate ligands of the type Ph₂P(CH₂)_nSR (n=1, 2 or 3; R=Me, Et, Ph, not all combinations) or cis-Ph₂PCHCHPPh₂ leads to [Rh(diene)(LL)]⁺ or [Rh(LL)₂]⁺, depending on the stoichiometry of the reaction. The complexes were fully characterized by ¹H and ³¹P NMR spectroscopy.     

Ruthenium complexes endowed with potent anti-Trypanosoma cruzi activity: Synthesis,biological characterization and structure–activity relationships

Although effective against epimastigotes (proliferative form) and of low cytotoxicity in mammals, the aryl-4-oxothiazolylhydrazones (ATZ) display only limited activity against trypomastigotes (bloodstream form) of Trypanosoma cruzi. Considering the metal complexation approach with bioactive ligands as one possible strategy for improving the biological efficacy of ATZ, a set of eight new ruthenium–ATZ complexes (RuCl₂ATZCOD, COD is 1,5-cyclooctadiene) were prepared, chemically and biologically characterized, including in vitro assays against epimastigotes and trypomastigote forms of the parasite and also assessment of cytotoxicity in mammals. Two of these complexes presented antitrypanosomal activity at non-cytotoxic concentrations on mammalian cells and of higher potency than its metal–free ligands, while the metallic precursor [RuCl₂COD(MeCN)₂] showed only moderate antitrypanosomal activity. Comparative analysis between the ruthenium complexes and metal–free ligands demonstrated the usefulness of this approach, with the establishment of new SAR data. Additional pharmacological tests, including a DNA bond assay, gave rise to the proposal of a single preliminary explanation for the molecular origin of the bioactivity.     

Synthesis and properties of (2-pyridyl)alkylamine- and (2-pyridyl)alkylamine–amide-coordinated copper(II) complexes: Structures and non-covalent interactions

Reaction of the ligand N-methyl-N-((6-pivaloylamido-2-pyridyl)methyl)-N-(2-pyridylethyl)amine (mpppa) with equimolar amounts of [Cu(H₂O)₆][ClO₄]₂ or CuCl₂ · 2H₂O in MeCN afforded mononuclear copper(II) complexes [Cu(mpppa)][ClO₄]₂ (1) and [Cu(mpppa)Cl₂] (2). Crystal structure analysis reveals CuN₃O (two pyridyl, an aliphatic amine, and an amide oxygen) coordination in 1 and CuN₃Cl₂ (two pyridyl, an aliphatic amine, and two chlorides) coordination in 2. Crystal packing diagram of 1 reveals that one of the perchlorate counteranions provides weak coordination to copper(II) centers and in turn the copper(II) centers assume pseudo-six-coordination, generating 1D chain. Notably, one of the copper(II)-coordinated chloride ions in 2 participates in an intramolecular N–H?Cl interaction. Intermolecular C–H?Cl interactions in the solid state generate helical structure. Spectroscopic (IR, UV–Vis, and EPR) and redox properties of the two complexes have been investigated and compared.     

Some binuclear acetonitrile ‘solvated’ complexes of copper(I) chloride and bromide with triphenylarsine

Reaction of copper(I) chloride and bromide, CuX (X = Cl or Br), with triphenylarsine in acetonitrile solution has resulted in two adducts, respectively, of 2:3:1, [(Ph₃As)₂Cu(μ-Cl)₂Cu(AsPh₃)(NCMe)] (1), and 1:1:2 stoichiometry, [(Ph₃As)(MeCN)Cu(μ-Br)₂Cu(NCMe)(AsPh₃)] · 2MeCN (2), characterized by elemental analysis, IR, ESI MS and NMR spectroscopy, and room temperature single crystal X-ray structure determinations. The environments of the two four-coordinate copper(I) atoms in 1 are different, being As₂Cu(μ-Cl)₂ and As,NCu(μ-Cl)₂. (2) is also binuclear, being a centrosymmetric dimer with the two four-coordinate, symmetry-related copper atoms having As,NCu(μ-Br)₂-environments.