Electron paramagnetic resonance crystallography of spin-labeled hemoglobin-protein fine structures.

Various hemoglobin derivatives have been labeled at the Cys-β93 residue with a bulky and “strongly immobilized” nitroxide maleimide (I) and a smaller, more flexible and “weakly immobilized” nitroxide iodoacetamide (II) and crystallized. The angular dependence of the paramagnetic resonance of the spin-label was measured for the ab, $\text{ac}{}^1$ and $\text{bc}{}^1$ planes at 298 K and 77 K for spin-labeled crystals of Oxyhemoglobin, methemoglobin fluoride, and methemoglobin azide. In the case of the methemoglobin crystals, the angular variation of the heme resonance was also monitored at 77 K. From the hyperfine splitting data, the spin-label I was found to assume specific orientations at both temperatures with some motional narrowing at 298 K. Spin-label II is specifically oriented only at room temperature but is frozen at 77 K in random orientations. Oxyhemoglobin labeled with I (I-HbO₂²) has the most prominent spin-label orientation (z∥b, x∥a) and the less abundant spin-labels with (z∥b ± 15 °) (Ohnishi et al., 1966). The corresponding spin-label orientations for I-Hb⁺ F^? are ($\text{z∥a, x∥c}{}^1$) and ($\text{z∥c}{}^1\text{, x∥a}$). Crystals of I-Hb⁺ N^?₃ have spin-labels oriented along angular directions similar, but not identical to those of I-Hb⁺F^?. Therefore, there are probably significant peptide segmental displacements when HbO₂ is oxidized to methemoglobins. At 25 °C II-Hb⁺ N^?₃ has spin-label orientations not too different from those in I-Hb⁺ N^?₃, whereas in HbO₂ the two spin-labels show significant differences in their orientations.     

m6A Regulates Liver Metabolic Disorders and Hepatogenous Diabetes

N⁶-methyladenosine (m⁶A) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of m⁶A is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m⁶A modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and m⁶A level increased in the livers of mice with high fat diet (HFD)-induced metabolic disorders. Overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. In contrast, hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation, and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m⁶A loss caused extended RNA half-lives of metabolism-related genes, which consequently protected mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m⁶A in HFD-induced metabolic disorders and hepatogenous diabetes.     

Spectroscopic and structural investigations on [(DD18C6)H2]I8 formed in the reaction of N,N-dibenzylated diazacrown ether (DD18C6) with iodine

Photometric titration measurements indicated in the reaction of diazacrown ether N,N^′-dibenzyl-1,4,10,13-tetraoxo-7,16-diazacyclooctadecane (DD18C6, 2) with iodine in chloroform that a complex was formed in the molar ratio DD18C6:I₂=1:4. This complex was also prepared on a preparative scale as dark brown compound and characterized by microanalysis, UV-Vis, IR, and Raman spectroscopy. By X-ray diffraction analysis the solid-state structure of the complex was shown to be [(DD18C6)H₂]I₈ ([3]I₈) consisting of a doubly protonated macrocycle and an octaiodide dianion (I₈ ²⁻) in the typical (nearly planar) Z-shaped geometry. The macrocycle is C_i symmetric and the protonated nitrogen atoms adopt an endo-endo orientation that is stabilized by the three-center hydrogen bonds N-H(?O)₂, where the oxygen atoms of the macrocycle act as hydrogen acceptors. The orientation of the phenyl groups of the benzyl sidearms are turned above and below the macrocycle. Quantum chemical calculations on the DFT level of theory of the non-protonated and the doubly protonated macrocycle (DD18C6, 2c) and [(DD18C6)H₂]²⁺ (3c), respectively, were performed and discussed for 3c in terms of conformational strain of the macrocycle, the strength of the intramolecular N-H?O hydrogen bonds and cation-π interactions.     

Chloroethylating and methylating dual function antineoplastic agents display superior cytotoxicity against repair proficient tumor cells

Two new agents based upon the structure of the clinically active prodrug laromustine were synthesized. These agents, 2-(2-chloroethyl)-N-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide (1) and N-(2-chloroethyl)-2-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide (2), were designed to retain the potent chloroethylating and DNA cross-linking functions of laromustine, and gain the ability to methylate DNA at the O-6 position of guanine, while lacking the carbamoylating activity of laromustine. The methylating arm was introduced with the intent of depleting the DNA repair protein O⁶-alkylguanine-DNA alkyltransferase (AGT). Compound 1 is markedly more cytotoxic than laromustine in both AGT minus EMT6 mouse mammary carcinoma cells and high AGT expressing DU145 human prostate carcinoma cells. DNA cross-linking studies indicated that its cross-linking efficiency is nearly identical to its predicted active decomposition product, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE), which is also produced by laromustine. AGT ablation studies in DU145 cells demonstrated that 1 can efficiently deplete AGT. Studies assaying methanol and 2-chloroethanol production as a consequence of the methylation and chloroethylation of water by 1 and 2 confirmed their ability to function as methylating and chloroethylating agents and provided insights into the superior activity of 1.     

Structural diversity in thallium chemistry, IV. Further examples of solid state bromothallate(III) derivatives obtained by employing certain classes of alkyl diammonium cations

Six new bromothallate(III)-containing salts with different alkyl diammonium cations have been prepared from bromide containing solutions and studied by single-crystal X-ray crystallographic analyses. The N,N′-diethyl-N,N,N′,N′-tetramethyl-1,2-ethylenediammonium, N-methyl-1,3-propanediammonium, N,N,N′,N′-tetramethyl-1,3-propanediammonium and N,N,N′,N′-tetraethyl-1,2-ethylenediammonium cations yield complexes (I, II, III and IV, respectively) with the [TlBr₅]²⁻ anionic stoichiometry. For I and II, both complexes contain the [TlBr₅]²⁻ anion. In complex II, this appears as a distorted octahedron with one long Tl?Br2′ contact of 3.632(4) Å from an adjacent anion, thus completing the hexacoordination about an otherwise distorted square pyramid. On the other hand, for III and IV, both complexes contain a tetrahedral [TlBr₄]⁻ anion together with an isolated, but hydrogen-bonded, Br⁻ anion. The 1,5-hexanediammonium complex (V) contains tetrahedral [TlBr₄]⁻, slightly distorted octahedral [TlBr₆]³⁻ and Br⁻ anions. The asymmetric unit of the N,N-diethyl-1,3-propanediammonium salt (VI) contains one cation and half of each of a [TlBr₄]⁻ and an axially compressed octahedral [TlBr₆]³⁻ anion. Extensive hydrogen-bonded networks exist in complexes II-VI. NH?Br hydrogen bonds generally have a significant influence on the nature of the anions present in species with the formal [TlBr₅] stoichiometry.     

Anion binding studies of tris(2-aminoethyl)amine based amide receptors with nitro functionalized aryl substitutions: A positional isomeric effect

Syntheses and crystal structures of tren-based amide, L¹, N,N′,N″-tris[(2-amino-ethyl)-4-nitro-benzamide] and L², N,N′,N″-tris[(2-amino-ethyl)-2-nitro-benzamide] are reported and compared with previously published tripodal amide receptor L³, N,N′,N″-tris[(2-amino-ethyl)-3-nitro-benzamide]. The crystallographic results show intramolecular and intermolecular hydrogen-bonding interactions between two arms of the tripodal receptor and two other adjacent molecules in cases of L¹ and L² whereas in addition to the above interactions an aromatic π···π stacking among tripodal arms is also observed in L³. Receptors L¹, L² and L³ having electron withdrawing -NO₂ substituted (para, ortho and meta, respectively) phenyl moieties are explored toward their solution state anion binding properties and selectivity studies. The substantial changes in chemical shifts are observed for the amide protons (-NH) and aromatic protons (-CH) with F⁻ and Cl⁻ in cases of L¹ and L³, and only with F⁻ for L², indicating the participation of -NH and -CH protons in the solution state binding events. Binding constants for the above cases are calculated by ¹H NMR titration upon monitoring the -NH signal. Receptor L² shows exclusive selectivity toward F⁻ in dimethyl sulfoxide (DMSO). The structural aspects of binding I⁻, ClO₄⁻ and SiF₆²⁻ with the monoprotonated L¹, L¹H⁺·I⁻·DMF (1), L¹H⁺·ClO₄⁻·DMF (2) and L¹H⁺·0.5SiF₆²⁻·H₂O (3), respectively are examined crystallographically. Anion binding with multiple receptor units is observed via amide N-H···anion as well as aryl C-H···anion hydrogen-bonding interactions in all the complexes as observed in cases of previously reported crystal structures of anionic complexes of protonated L³. The aryl group having nitro functionality that contributes to solution state anion binding with the neutral receptor and solid state coordination in complexes 1-3 through CH···anion interactions is noteworthy.     

Regulation of Ca2+ signaling by acute hypoxia and acidosis in cardiomyocytes derived from human induced pluripotent stem cells

AimsThe effects of acute (100 s) hypoxia and/or acidosis on Ca²⁺ signaling parameters of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are explored here for the first time.Methods and results1) hiPSC-CMs express two cell populations: rapidly-inactivating I_Ca myocytes (τ_i<40 ms, in 4–5 day cultures) and slowly-inactivating I_Ca (τ_i ≥ 40 ms, in 6–8 day cultures). 2) Hypoxia suppressed I_Ca by 10–20% in rapidly- and 40–55% in slowly-inactivating I_Ca cells. 3) Isoproterenol enhanced I_Ca in hiPSC-CMs, but either enhanced or did not alter the hypoxic suppression. 4) Hypoxia had no differential suppressive effects in the two cell-types when Ba²⁺ was the charge carrier through the calcium channels, implicating Ca²⁺-dependent inactivation in O₂ sensing. 5) Acidosis suppressed I_Ca by ∼35% and ∼25% in rapidly and slowly inactivating I_Ca cells, respectively. 6) Hypoxia and acidosis suppressive effects on Ca-transients depended on whether global or RyR2-microdomain were measured: with acidosis suppression was ∼25% in global and ∼37% in RyR2 Ca²⁺-microdomains in either cell type, whereas with hypoxia suppression was ∼20% and ∼25% respectively in global and RyR2-microdomaine in rapidly and ∼35% and ∼45% respectively in global and RyR2-microdomaine in slowly-inactivating cells.ConclusionsVariability in I_Ca inactivation kinetics rather than cellular ancestry seems to underlie the action potential morphology differences generally attributed to mixed atrial and ventricular cell populations in hiPSC-CMs cultures. The differential hypoxic regulation of Ca²⁺-signaling in the two-cell types arises from differential Ca²⁺-dependent inactivation of the Ca²⁺-channel caused by proximity of Ca²⁺-release stores to the Ca²⁺ channels.     

Tautomerization of 2-nitroso-N-arylanilines by coordination as N,N′-chelate ligands to rhenium(i) complexes and the anticancer activity of newly synthesized oximine rhenium(i) complexes against human melanoma and leukemia cells in vitro

The synthesis, structural characterization and biological activity of eight ortho-quinone(N-aryl)-oximine rhenium(i) complexes are described. The reaction of the halogenido complexes (CO)₅ReX (X=Cl (4), Br (5)) with 2-nitroso-N-arylanilines {(C₆H₃ClNO)NH(C₆H₄R)} (R = p-Cl, p-Me, o-Cl, H) (3a–d) in tetrahydrofurane (THF) yields the complexes fac-(CO)₃XRe{(C₆H₃ClNO)NH(C₆H₄R)} (6a–d, 7a–d) with the tautomerized ligand acting as a N,N′-chelate. The substitution of two carbonyl ligands leads to the formation of a nearly planar 5-membered metallacycle. During coordination the amino-proton is shifted to the oxygen of the nitroso group which can be observed in solution for 6 and 7 by ¹H NMR spectroscopy and in solid state by crystal structure analysis. After purification, all compounds have been fully characterized by their ¹H and ¹³C NMR, IR, UV/visible (UV/Vis) and mass spectra. The X-ray structure analyses revealed a distorted octahedral coordination of the CO, X and N,N′-chelating ligands for all Re(i) complexes. Biological activity of four oximine rhenium(i) complexes was assessed in vitro in two highly aggressive cancer cell lines: human metastatic melanoma A375 and human chronic myelogenous leukemia K562. Chlorido complexes (6a and 6c) were more efficient than bromido compounds (7d and 7b) in inducing apoptotic cell death of both types of cancer cells. Melanoma cells were more susceptible to tested rhenium(i) complexes than leukemia cells. None of the ligands (3a–d) showed any significant anticancer activity.     

Chemical analysis of the female sex pheromone in Palpita nigropunctalis (Lepidoptera: Crambidae)

The lilac pyralid, Palpita nigropunctalis Bremer (Lepidoptera: Crambidae), is a common pest of Oleaceae plants. A crude extract of the female sex pheromone glands was examined by gas chromatography-electroantennogram detection (GC-EAD) and GC coupled to a mass spectrometer (GC/MS). The GC-EAD analysis revealed three EAG-active components (I–III) in a ratio of 1:0.2:0.01 (I: II: III). GC/MS analysis successfully recorded the mass spectra of I and II. For I, ions at m/z 238 (M⁺) and 220 ([M-18]⁺) indicated the structure of a monoenyl aldehyde with a 16-carbon chain. For II, M⁺ was not detected, but ions at m/z 222 ([M-60]⁺) and 61 ([AcOH+1]⁺) suggested that II was a monoenyl acetate with a 16-carbon chain. Further GC/MS analysis of the extract treated with dimethyl disulfide revealed that the double bonds in both I and II are located at the same position of 11th-carbon. In addition, the pheromone extract was examined by GC/Fourier transform-infrared spectrophotometer (GC/FT-IR). An IR spectrum of I showed characteristic absorption at 1716 and 966?cm^?1, indicating a formyl group and E configuration of the double bond, respectively. In the case of II, absorption at 1745 and 968?cm^?1 indicated an ester carbonyl and E configuration, respectively. Taken together and by comparison with authentic standards, I and II were confirmed as (E)-11-hexadecenal and (E)-11-hexadecenyl acetate, respectively; while III was speculated as (E)-11-hexadecen-1-ol. The synthetic I, II and III all coincided well with those of the natural components in chemical data, and elicited strong electroantennographic activity in male P. nigropunctalis.     

Regionally diverse mitochondrial calcium signaling regulates spontaneous pacing in developing cardiomyocytes

The quintessential property of developing cardiomyocytes is their ability to beat spontaneously. The mechanisms underlying spontaneous beating in developing cardiomyocytes are thought to resemble those of adult heart, but have not been directly tested. Contributions of sarcoplasmic and mitochondrial Ca²⁺-signaling vs. I_f-channel in initiating spontaneous beating were tested in human induced Pluripotent Stem cell-derived cardiomyocytes (hiPS-CM) and rat Neonatal cardiomyocytes (rN-CM). Whole-cell and perforated-patch voltage-clamping and 2-D confocal imaging showed: (1) both cell types beat spontaneously (60–140/min, at 24 °C); (2) holding potentials between −70 and 0 mV had no significant effects on spontaneous pacing, but suppressed action potential formation; (3) spontaneous pacing at −50 mV activated cytosolic Ca²⁺-transients, accompanied by in-phase inward current oscillations that were suppressed by Na⁺-Ca²⁺-exchanger (NCX)- and ryanodine receptor (RyR2)-blockers, but not by Ca²⁺- and I_f-channels blockers; (4) spreading fluorescence images of cytosolic Ca²⁺-transients emanated repeatedly from preferred central cellular locations during spontaneous beating; (5) mitochondrial un-coupler, FCCP at non-depolarizing concentrations (∼50 nM), reversibly suppressed spontaneous pacing; (6) genetically encoded mitochondrial Ca²⁺-biosensor (mitycam-E31Q) detected regionally diverse, and FCCP-sensitive mitochondrial Ca²⁺-uptake and release signals activating during I_NCX oscillations; (7) I_f-channel was absent in rN-CM, but activated only negative to −80 mV in hiPS-CM; nevertheless blockers of I_f-channel failed to alter spontaneous pacing.     

Synthesis and an angiolytic role of novel piperazine–benzothiazole analogues on neovascularization,a chief tumoral parameter in neoplastic development

A novel series of benzoic acid N′-[2-(4-benzothiazol-2-yl-piperazin-1-yl)-acetyl]-hydrazides 6a–j were synthesized and characterized by IR, ¹H, ¹³C NMR, elemental and mass spectral analyses. The in-vitro cytotoxicity and cell viability assay of the synthesized compounds 6a–j were evaluated against Dalton’s lymphoma ascites (DLA) cells. Our results showed that compound 6c with a bromo group on phenyl ring has showed promising antiproliferative efficacy. Further investigation of compound 6c on in-vivo treatment model depicts the increased tumor suppression through inhibition of angiogenesis.     

The kinetics of ligand substitution in bis(N-alkylsalicylaldiminato)nickel(II) Complexes: a study on the reactivity of square-planar versus octahedral coordination

The bis(N-alkylsalicylaldiminato)nickel(II) complexes Ni(R-sal)₂ with R = CH(CH₂OH)CH(OH)Ph (I), R = CH(CH₃)CH(OH)Ph (II) and R = CH₂CH₂Ph (III; Ph = phenyl) were prepared and characterized. In the solid state I and II are paramagnetic (μ = 3.2 and 3.3 BM at 20 °C, respectively), whereas III is diamagnetic. It follows from the UV-Vis spectra that in acetone solution I is six-coordinate octahedral and III is four-coordinate planar, the spectrum of II showing characteristics of both modes of coordination. Vis spectrophotometry and stopped-flow spectrophotometry were applied to study the kinetics of ligand substitution in I–III by H₂salen (= N,N′-disalicylidene-ethylenediamine) in the solvent acetone at different temperatures. The kinetics follow a second-order rate law, rate = k[H₂-salen] [complex]. At 20 °C the sequence of rate constants is k(III):k(II):k(I) = 11 850:40.6:1. The activation parameters are ΔH^≠(I) = 112, ΔH^≠(II) = 40.7, ΔH^≠(III) = 35.7 kJ mol⁻¹ and ΔS^≠(I) = 92, ΔS^≠(II) = −103, ΔS^≠(III) = −89 J K⁻¹ mol⁻¹. The enormous difference in rate between complexes I, II and III, which is less pronounced in methanol, is attributed to the existence of a fast equilibrium planar ⇌ octahedral, which is established in the case of I and II by intramolecular octahedral coordination through the hydroxyl groups present in the organic group R. An A-mechanism is suggested to control the substitution in the sense that the entering ligand attacks the four-coordinate planar complex, the octahedral complex being kinetically inert.     

Synthesis and reactivity of mixed pentafluorophenyl platinum(I)-palladium(I) derivatives

XPd(μ-dppm)₂Pt(C₆F₅) (X = Cl (I), Br (II)) have been prepared by reacting Pd₂(dba)₃·CHCl₃ and PtX- (C₆F₅)(η¹-dppm)₂. Reaction of complex I with SnCl₂ gives the SnCl₃⁻ derivative, whilst ligands L (PPh₃, P(OPh)₃, SbPh₃) render the cationic complexes. The species R₂N⁺, SO₂ or MeOOC)CCCOOMe insert into the PdPt bond of I to give A-frame Pd(II)- Pt(II) complexes. The reactions of CIPd(μ-dppm)₂- Pt(C6F₅) with isonitriles CNR (R = p-Tol, Cy) lead to products containing either terminal or inserted isocyanide or both.     

Luminescence properties of cyclopalladated complexes with Schiff base ligands

Direct reaction between the hydroxo-complexes [{Pd(μ-OH)(C^N)}₂] (C^N = 2-(2-pyridyl)phenyl (Phpy) I; C^N = 7,8-benzoquinolyl (Bzq) II) and N-naphtylsalycilaldimine (N-naphsal) 1 yields new mononuclear cyclometallated palladium(II) complexes [Pd(N-naphsal)(C^N)] (I1, II1). Photophysical properties were investigated together with those of complexes with related ligands N-phenylsalycilaldiminate (N-Phsal) 2, N-p-chlorophenylsalycilaldiminate (N-pClPhsal) 3. All the compounds absorb intensely below 300 nm via¹LC transitions located in Bzq or Phpy ligands, and display additional low energy absorptions of mixed ¹MLCT-¹LC character. The complexes under study are quite unusual in terms of luminescence behavior, since some of them are emissive in solution at room temperature and all display intense emissions in frozen CHCl₃ solution, but also in solid state at 298 and 77 K. Structural characterization by X-ray diffraction of complexes I2, I3 and II2 confirmed the proposed formulae.     

Synthesis of N4-(substituted phenyl)-N4-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells

A series of fourteen N⁴-(substituted phenyl)-N⁴-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines was synthesized as potential microtubule targeting agents. The synthesis involved a Fisher indole cyclization of 2-amino-6-hydrazinylpyrimidin-4(3H)-one with cyclohexanone, followed by oxidation, chlorination and displacement with appropriate anilines. Compounds 6, 14 and 15 had low nanomolar potency against MDA-MB-435 tumor cells and depolymerized microtubules. Compound 6 additionally had nanomolar GI₅₀ values against 57 of the NCI 60-tumor panel cell lines. Mechanistic studies showed that 6 inhibited tubulin polymerization and [³H]colchicine binding to tubulin. The most potent compounds were all effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, which have been associated with clinical drug resistance. Modeling studies provided the potential interactions of 6, 14 and 15 within the colchicine site.     

The copper-molybdenum antagonism in ruminants. III. Reaction of copper(II) with tetrathiomolybdate(VI)

The stoichiometry of the reaction between Cu(II) and MoS₄²⁻ in neutral aqueous solution was observed to proceed with a 1.5:1 Cu:Mo ratio. The reaction results in the reduction of Cu(II) and the quantitative formation of an insoluble solid. The results contrast with an earlier report of a 1:1 stoichiometric ratio, this latter ratio was, however, observed with Cu^II(albumin) as reactant, in this case no precipitate was observed. The insoluble products were examined by a number of spectroscopic techniques and by X-ray power diffraction and elemental analysis. Two products were identified. Solid A is isostructural with the known (NH₄)Cu^IMoV^VIS₄, i.e. has the composition M^ICuMoS₄, M^I= NH₄⁺, Na⁺ or Et₄N⁺. Solid B has the approximate composition CuMoS₄O_x, x=2−3 and contains Cu(I) and Mo(V) centres. Formation of compound B therefore involves an unusual internal two-electron redox process. The reaction and products are of particular biological significance.     

Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Structural chemistry of lanthanidedicyclopentadienidehalides. Part 1. Two modifications of gadoliniumdicyclopentadienidebromide, [Gd(C5H5)2Br]2 and 1∞[Gd(C5H5)2Br]

The crystal structures of two modifications of gadoliniumdicyclopentadienidebromide, [Gd(C₅H₅)₂Br]₂ (I) and ¹_∞[Gd(C₅H₅)₂Br] (II) have been determined from X-ray diffraction data. I crystallizes in the [Sc(C₅H₅)₂Cl]₂-type structure, space group P2₁/c, with a=14.110(3), b=16.488(3), c= 13.765(3) Å, β=93.25(2)°, V=3197(2) ų, and D_c= 2.289 g cm⁻³ for Z=6 molecules. II crystallizes in space group P2₁/c with a=5.946(7), b=8.447(5), c=20.239(9) Å, β=90.11(4)°, V=1020(2) ų, D_c=2.392 g cm⁻³ for Z=4 formula units. The structures have been refined by full matrix least-squares techniques to conventional R factors of 0.034 for 3014 (I) and 1964 (II) reflections (with I>2σ(I)). I consists of dimers with two bromine bridges (mean GdBr 2.872 Å). II has a double chain structure with alternating juxtaposition of gadolinium and bromine atoms (GdBr 2.912 Å (once) and 3.133 Å (twice)). The arrangement of the C₅H₅ groups with regard to the metal η⁵ fashion) is nearly identical in I and II (mean GdC 2.63(1) Å (I) and 2.62(1) Å (II)). Single crystals of I and II are obtained by sublimation at different temperatures. The formation of both modifications is discussed as to its dependence on the state of the gaseous phase equilibrium [Gd(C₅H₅)₂Br]₂ ⇄ 2Gd(C₅H₅)₂Br. Obviously, I crystallizes from gaseous phase dimers while II forms from the monomers.     

Preparation,structure and spectroscopic studies of the palladium mercaptides Pd8(S-nPr)16 and Pd6(S-nPr)12

Various palladium salts react with n-propane thiol to form a mixture of the cyclic mercaptides Pd₈(S-nPr)₁₆ (I) and the known Pd₆(S-nPr)₁₂ (II). I is described as an octagonal toroid, containing a planar ring of palladium atoms, each being bridged by four mercapto groups in approximately square planar geometry. The pendant n-propyl groups radiate outward in approximately axial and equatorial orientations with respect to the ring, which was also observed in solution by ¹H and ¹³C NMR. Crystal data: space group C2/c, a=22.251(15), b=27.623(6), c=14.621(17) Å, β=116.35°(4), V=8053(4) ų. Least-squares refinement based on 3103 observed reflections led to an R value of 0.078. I and II failed to complex any appropriate guest species, as evidenced by the UV-Vis spectra. I was found to have a reversible oxidation wave at E/2= 0.77 V, and a irreversible oxidation wave of 1.09 V. II displayed two irreversible peak potentials at 0.77 and 1.09 V. In each case, the waves were one electron processes, in which the reversibility was not enhanced at low temperatures.     

Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide,a potent pyridazinoindole ligand for PET imaging of TSPO in cancer

A novel synthesis of the translocator protein (TSPO) ligand 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575, 3) was achieved in four steps from commercially available starting materials. Focused structure–activity relationship development about the pyridazinoindole ring at the N3 position led to the discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (14), a novel ligand of comparable affinity. Radiolabeling with fluorine-18 (¹⁸F) yielded 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[¹⁸F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide ([¹⁸F]-14) in high radiochemical yield and specific activity. In vivo studies of [¹⁸F]-14 revealed this agent as a promising probe for molecular imaging of glioma.