Synthesis, characterization and X-ray crystal structure of [Re(L4)(CO)3]Br · 2CH3OH (L4 = N,N-bis[(2-diphenylphosphino)ethyl]methoxyethylamine): A model compound for novel cationic Tc(I)-tricarbonyl radiotracers useful for heart imaging

This report describes synthesis and evaluation of cationic complexes, [^99mTc(CO)₃(L)]⁺ (L = N-methoxyethyl-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L1), N-[(15-crown-5)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L2) and N-[(18-crown-6)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L3)) as potential radiotracers for heart imaging. Preliminary results from biodistribution studies in female adult BALB-c mice indicated that the cationic ^99mTc(I)-tricarbonyl complex, [^99mTc(CO)₃(L2)]⁺, has a significant localization in the heart at 60 min post-injection. To understand the coordination chemistry of these bisphosphine ligands with the ^99mTc(I)-tricarbonyl core, we prepared [Re(CO)₃(L4)]Br (L4: N,N-bis[(2-diphenylphosphino)ethyl]methoxyethylamine) as a model compound. [Re(CO)₃(L4)]Br has been characterized by elemental analysis, IR, ESI-MS, NMR (¹H, ¹³C, ¹H-¹H COSY, and ¹H-¹³C HMQC) methods, and X-ray crystallography. In solid state, [Re(CO)₃(L4)]⁺ has a distorted octahedron coordination geometry with PNP occupying one facial plane. The chelator backbone adopts a “chair” conformation with phosphine-P atoms at equatorial positions and the amine-N at the apical site. In solution, [Re(CO)₃(L4)]⁺ is able to maintain its cationic nature with no dissociation of carbonyl ligands or any of the three PNP donors.     

Chiral tetradentate amine and tridentate aminocarbene ligands: Synthesis, reactivity and X-ray structural characterizations

(1R,2R)-diaminocyclohexane (1) and (1R,2R)-diaminodiphenylethylenediamine (2) were used as building blocks for the synthesis of chiral tetradentate diquinolyl-diamine and related diquinolyl-dihydroimidazolium salts. A neutral chiral palladium(II) complex was synthesized by reaction of palladium acetate with the tetradentate diquinolyl diamine derived from 2 and used as a homogeneous catalyst for the Heck reaction between styrene and haloarenes. A chiral tridentate aminocarbene was generated in situ by deprotonation of the dihydroimidazolium salt derived from 1 and allowed to react with CuI to give a new chiral quinolyl-carbene copper(I) complex.     

Mononuclear and dinuclear bromo bridged iridium(I) complexes with N-allyl substituted imidazolin-2-ylidene ligands

The reaction of 1-methyl-3-(2-propenyl)imidazolium bromide (1) or 1,3-bis(2-propenyl)-imidazolium bromide (2) with [Ir(μ-OMe)(cod)]₂ afforded the five coordinated iridium(I) carbene complexes [IrBr(L)(cod)] (3) (L=1-methyl-3-(2-propenyl)imidazolin-2-ylidene) and (4) (L=1,3-bis(2-propenyl)imidazolin-2-ylidene). The reaction proceeds via an in situ deprotonation of the imidazolium salt. Molecular structure determinations on 3 and 4 confirmed the coordination of the carbene ligands via the carbene carbon atom and one allyl group in both complexes. Treatment of complex 3 with an excess of AgBF₄ gave the dinuclear bromo bridged complex [(Ir(μ-Br)(L)(cod)]₂BF₄ (5) (L=1-methyl-3-(2-propenyl)imidazolin-2-ylidene). The reaction of complex 4 with an excess of AgBF₄ led to the mononuclear complex [Ir(L)(cod)]BF₄ (6) (L=1,3-bis(2-propenyl)imidazolin-2-ylidene) where both N-allyl substituents are coordinated to the iridium(I) center.     

Structural variations and spectroscopic properties of copper(I) complexes with bis(schiff base) ligands

Six copper(I) complexes {[Cu₂(L1)(PPh₃)₂I₂] · 2CH₂Cl₂}_n (1), {[Cu₂(L2)(PPh₃)₂]BF₄}_n (2), [Cu₂(L3)(PPh₃)₄I₂] · 2CH₂Cl₂ (3), [Cu₂(L4)(PPh₃)₄I₂] (4), [Cu₂(L5)(PPh₃)₂I₂] (5) and [Cu₂(L6)(PPh₃)₂I₂] (6) have been prepared by reactions of bis(schiff base) ligands: pyridine-4-carbaldehyde azine (L1), 1,2-bis(4′-pyridylmethyleneamino)ethane (L2), pyridine-3-carbaldehyde azine (L3), 1,2-bis(3′-pyridylmethyleneamino)ethane (L4), pyridine-2-carbaldehyde azine (L5), 1,2-bis(2′-pyridylmethyleneamino)ethane (L6) with PPh₃ and copper(I) salt, respectively. Ligand L1 or L2 links (PPh₃)₂Cu₂(μ-I)₂ units to form an infinite coordination polymer chain. Ligand 3 or 4 acts as a monodentate ligand to coordinate two copper(I) atoms yielding a dimer. Ligand 5 or 6 chelates two copper(I) atoms using pyridyl nitrogen and imine nitrogen to form a dimer. Complexes 1-4 exhibit photoluminescence in the solid state at room temperature. The emission has been attributed to be intraligand π-π* transition mixed with MLCT characters.     

A new tyrosinase model with 1,3-bis[(2-dimethylaminoethyl)iminomethyl]benzene: Binuclear copper(I) and phenoxo/hydroxo-bridged dicopper(II) complexes

The ligand 1,3-bis[(2-dimethylaminoethyl)iminomethyl]benzene (baib) reacts with [Cu(MeCN)₄][ClO₄] to form a binuclear copper(I) complex . Crystal structure analysis reveals that the distorted tetrahedral coordination of each copper(I) center is satisfied by one bidentate arm of each ligand. The complex undergoes ready aromatic ring hydroxylation at position 2 of the phenyl ring when reacted with molecular oxygen in MeCN/MeOH/CH₂Cl₂, producing a four-coordinate μ-phenoxo- and μ-hydroxo-bridged dicopper(II) complex, [Cu₂(baib-O)(OH)(OClO₃)₂] · 1.5H₂O (2) (baib-OH: 1,3-bis[(2-dimethylaminoethyl)iminomethyl]phenol). This reaction mimics the reactivity of the copper monooxygenase tyrosinase. A trend is observed for the extent of aromatic ring hydroxylation (25 °C): MeCN > MeOH > CH₂Cl₂. Cyclic voltammetric experiment of 1 in MeCN reveals an appreciably high redox potential (anodic peak potential, E_pa = 0.69 V versus SCE) for the redox process. Complex 2 has been characterized by single-crystal X-ray crystallography. Variable temperature (60-300 K) magnetic susceptibility measurements on 2 establish that the copper(II) centers in 2 are antiferromagnetically coupled (2J = −280 cm⁻¹).     

Leishmania donovani: differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays

Different classes of topoisomerase (TOP) inhibitors and antitrypanosomatid agents exhibited variable efficacies against Leishmania donovani parasites and human mononuclear cells both at the level of DNA topoisomerase I (TOPI) catalytic activity and in cytotoxicity assays. Bis-benzimidazoles and the diamidine diminazene aceturate exhibited uniformly high efficacies against parasite and host enzymes as well as against parasite and mononuclear cells, but pentamidine showed around 2 orders of magnitude greater specificity for Leishmania TOPI and amastigote cells (P<0.05). The protoberberine coralyne and the flavonoid quercetin were highly potent, but non-selective, inhibitors in vitro, although the latter showed slight selectivity for parasite TOPI. Camptothecin was selective for mononuclear cells at both levels (P<0.05) and sodium stibogluconate was selective only at the enzyme level displaying 30-fold greater potency against parasite TOPI (P<0.05). These data suggest that at least part of pentamidines' leishmanicidal activity may be mediated through TOPI inhibition, and support the feasibility of exploiting differences between Leishmania and human TOPs to develop modified compounds with improved selectivity.     

Theileria-induced constitutive IKK activation is independent of functional Hsp90

The intracellular parasite Theileria induces uncontrolled proliferation and host cell transformation. Parasite-induced transformation is accompanied by constitutive activation of IkappaB kinase (IKK), resulting in permanently high levels of activated nuclear factor (NF)-kappaB. IKK activation pathways normally require heat shock protein 90 (Hsp90), a chaperone that regulates the stability and activity of signalling molecules and can be blocked by the benzoquinone ansamycin compound geldanamycin (GA). In Theileria-transformed cells, IkappaBalpha and p65 phosphorylation, NF-kappaB nuclear translocation and DNA binding activity are largely resistant to GA and also NF-kappaB-dependent reporter gene expression is only partly affected. Our findings indicate that parasite-induced IKK activity does not require functional Hsp90.     

Endogenous macrophage migration inhibitory factor modulates glucocorticoid sensitivity in macrophages via effects on MAP kinase phosphatase-1 and p38 MAP kinase

The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) is induced by glucocorticoids (GCs), but it was not previously known if MIF regulates cellular sensitivity to GC. Here we show in GC and LPS-treated peritoneal macrophages derived from MIF-/- and wt mice that the absence of endogenous MIF is associated with increased sensitivity to GC of TNF release. This is associated with increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), concomitant decreased phosphorylation of p38 MAPK, but no effect of MIF on nuclear factor kappaB (NF-kappaB). These results demonstrate that MIF regulates GC sensitivity by phosphorylation of p38, and provides a cellular mechanism for this observation, indicating that MKP-1 is a central target of this regulation.     

Identification of TNF-alpha-responsive NF-kappaB p65-binding element in the distal promoter of the mouse serine protease inhibitor SerpinE2

Serine protease inhibitor SerpinE2 is known as a cytokine-inducible gene. Here, we investigated whether tumor necrosis factor alpha-(TNF-alpha)-induced expression of SerpinE2 is mediated by the nuclear factor-kappaB (NF-kappaB) p65 subunit. Both steady state and TNF-alpha-induced expression of SerpinE2 mRNA were abrogated in p65-/- murine embryonic fibroblasts (MEFs). Reconstitution with wild-type p65 rescued SerpinE2 mRNA expression in an IkappaB kinase beta-dependent manner. Electrophoresis mobility shift assay and ChIP assay demonstrated that p65 bound to the kappaB-like DNA sequence located at approximately -9 kbp in the SerpinE2 promoter. In addition, TNF-alpha stimulated luciferase gene expression driven by the kappaB-like element in the reconstituted MEFs, but not in p65-/- MEFs. These results indicated that activation of NF-kappaB p65 plays an important role in TNF-alpha-induced expression of SerpinE2.