Molecular transporters for peptides: delivery of a cardioprotective epsilonPKC agonist peptide into cells and intact ischemic heart using a transport system, R(7).

BACKGROUND: Recently, we reported a novel oligoguanidine transporter system, polyarginine (R(7)), which, when conjugated to spectroscopic probes (e.g., fluorescein) and drugs (e.g., cyclosporin A), results in highly water-soluble conjugates that rapidly enter cells and tissues. We report herein the preparation of the first R(7) peptide conjugates and a study of their cellular and organ uptake and functional activity. The octapeptide (psi)(epsilon)RACK was selected for this study as it is known to exhibit selective epsilon protein kinase C isozyme agonist activity and to reduce ischemia-induced damage in cardiomyocytes. However, (psi)(epsilon)RACK is not cell-permeable. RESULTS: Here we show that an R(7)-(psi)(epsilon)RACK conjugate readily enters cardiomyocytes, significantly outperforming (psi)(epsilon)RACK conjugates of the transporters derived from HIV Tat and from Antennapedia. Moreover, R(7)-(psi)(epsilon)RACK conjugate reduced ischemic damage when delivered into intact hearts either prior to or after the ischemic insult. CONCLUSIONS: Our data suggest that R(7) converts a peptide lead into a potential therapeutic agent for the ischemic heart.     

Polymerisations of -caprolactone and β-butyrolactone with Zn-, Al- and Mg-based organometallic complexes

The reaction of EtAlCl₂ with 1,2-{LiN(PMes₂)}₂C₆H₄ (Mes = 2,4,6-Me₃C₆H₂) and of butyloctylmagnesium with 1,2-{NH(PPh₂)}₂C₆H₄ gave [AlEt(1,2-{N(PMes₂)}₂C₆H₄-κ²N,N′)(THF)] (1) and [Mg(1,2-{N(PPh₂)}₂C₆H₄-κ²N,N′)(THF)₂] (2), respectively. Complexes 1 and 2 were fully characterised by NMR (¹H, ¹³C, ³¹P) and IR spectroscopy and mass spectrometry. Complexes 1 and 2 were employed as catalysts in the polymerisation of -caprolactone, which produced polymers with a narrow molecular weight distribution. For comparison the polymerisations of -caprolactone and β-butyrolactone were carried out with the Zn complex [ZnPr{1-N(PMes₂)-2-N(PHMes₂)C₆H₄-κ²N,N′}] (3) as catalyst, which produced polymers with narrow molecular weight distributions and high molecular weights.     

A new flavone glycoside from Selaginella moellendorffii Hieron.

From the ethanol extract of Selaginella moellendorffii Hieron., a new flavone O-glycoside and three known flavone C-glycosides have been isolated and identified as 5-carboxymethyl-4′-hydroxyflavone-7-O-β-D-glucopyranoside 1, 6,8-di-C-β-D-glueopyranosylapigenin 2, 6-C-[3-D-glucopyranosyl-8-C-β-D-xylopyranosyl apigenin 3, 6-C-B-D-xylopyranosyl-8-C-β-glucopyranosylapigenin 4, respectively. Their structures were elucidated by spectroscopic methods.     

Biotransformation of (−)-α-Bisabolol by Absidia coerulea

(−)-α-Bisabolol, a bioactive monocyclic sesquiterpene alcohol, has been used in pharmaceutical and cosmetic products with anti-inflammatory, antibacterial and skin-caring properties. However, the poor water solubility of (−)-α-bisabolol limits its pharmaceutical applications. It has been recognized that microbial transformation is a very useful approach to generate more polar metabolites. Fifteen microorganisms were screened for their ability to metabolize (−)-α-bisabolol in order to obtain its more polar derivatives, and the filamentous fungus Absidia coerulea was selected for scale-up fermentation. Seven new and four known metabolites were obtained from biotransformation of (−)-α-bisabolol (1), and all the metabolites exhibited higher aqueous solubility than that of the parent compound 1. The structures of newly formed metabolites were established as (1R,5R,7S)- and (1R,5S,7S)-5-hydroxy-α-bisabolol (2 and 3), (1R,5R,7S,10S)-5-hydroxybisabolol oxide B (4), (1R,7S,10S)-1-hydroxybisabolol oxide B (5), 12-hydroxy-α-bisabolol (7), (1S,3R,4S,7S)- and (1S,3S,4S,7S)-3,4-dihydroxy-α-bisabolol (8 and 10) on the basis of spectroscopic analyses. These compounds could also be used as reference standards for the detection and identification of the metabolic products of 1 in the mammalian system.     

The synthesis, structure and reactivity of aldehyde substituted η-allylic complexes of molybdenum

Reaction of cis-[Mo(NCMe)₂(CO)₂(η⁵-L)][BF₄] (L=C₅H₅ or C₅Me₅) with 1-acetoxybuta-1,3-diene gives the cationic complexes [Mo{η⁴-syn-s-cis-CH₂CHCHCH(OAc)}(CO)₂(η⁵-L)][BF₄], which, on reaction with aqueous NaHCO₃/CH₂Cl₂, afford good yields of the anti-aldehyde substituted complexes [Mo{η³-exo-anti-CH₂CHCH(CHO)}(CO)₂(η⁵-L)] 2 (L=C₅Me₅), 4 (L=C₅H₅)]. The corresponding η⁵-indenyl substituted complex 5 was prepared by protonation (HBF₄·OEt₂) of [Mo(η³-C₃H₅)(CO)₂(η⁵-C₉H₇)] followed by addition of CH₂=CHCH=CH(OAc) and hydrolysis (aq. NaHCO₃/CH₂Cl₂). An X-ray crystallographic study of complex 2 confirmed the structure and showed that there is a contribution from a zwitterionic form involving donation of electron density from the molybdenum to the aldehyde carbonyl group. Treatment of 2 and 4, in methanol solution, with NaBH₄ afforded the alcohols [Mo{η³-exo-anti-CH₂CHCHCH₂(OH)}(CO)₂(η⁵-L)] [6 (L=C₅H₅), 8 (L=C₅Me₅)]; however, prolonged (30 h) reaction with NaBH₄/MeOH surprisingly gave good yields of the methoxy-substituted complexes [Mo{η³-exo-anti-CH₂CHCHCH₂(OMe)}(CO)₂(η⁵-L)] [7 (L=C₅H₅), 9 (L=C₅Me₅)], the structure of 7 being confirmed by single crystal X-ray crystallography. This methoxylation reaction can be explained by coordination of the hydroxyl group present in 6 and 8 onto B₂H₆ to form the potential leaving group HOBH₃⁻, which on ionisation affords [Mo(η⁴-exo-buta-1-3-diene)(CO)₂(η⁵-L)]⁺ which is captured by reaction with OMe⁻. Complex 8 is also formed in good yield on reaction of 2 with HBF₄·OEt₂ followed by treatment of the resulting cation [Mo{η⁴-exo-s-cis-syn-CH₂CHCHCH(OH)}(CO)₂(η⁵-C₅Me₅)][BF₄] with Na[BH₃CN]. Reaction of 4 with the Grignard reagents MeMgI, EtMgBr or PhMgCl afforded moderate yields of the alcohols [Mo{η³-exo-anti-CH₂CHCHCH(OH)R}(CO)₂(η⁵-C₅H₅)] [11 (R=Me), 12 (R=Et), 13 (R=Ph)]. Similarly, treatment of 2 with MeLi gave the corresponding alcohol 14. An attempt to carry out the Oppenauer oxidation [Al(OPr′)₃/Me₂CO] of 11 resulted in an elimination reaction and the formation of the η³-s-pentadienyl complex [Mo{η³-exo-anti-CH₂CHCH(CHCH₂)}(CO)₂(η⁵-C₅H₅)], which was structurally identified by X-ray crystallography. Interestingly, oxidation of 6 with [Bu₄ⁿN][RuO₄]/morpholine-N-oxide affords the aldehyde complex, 4 in good yield. Finally, reaction of 11 with [NO][BF₄] followed by addition of Na₂CO₃ affords the fur-3-ene complex [Mo{η²-

(H)Me}(CO)(NO)(η⁵-C₅H₅)].     

Tetramethylammonium hydroxide (TMAH) thermochemolysis of 2-arylcoumaran lignin model compounds

Phenolic 2-arylcoumarans 1–6 were used to examine the behaviors of β-5 subunits in lignin during tetramethylammonium hydroxide (TMAH) thermochemolysis. Products were monitored by gas chromatography/mass spectrometry. The process predominantly provided dimeric products with the opened hydrofuran ring. Substituent changes at the γ-position of ring A and at the 5-position of ring B had a large effect on the product compositions. 2-Arylcoumarans 1 and 6 with the γ-CH₂OH substituent predominantly gave 2,3,3′,4′-tetramethoxystilbenes involving the elimination of the γ-CH₂OH substituent, while 2–5 with the γ-CH₃ substituent gave a mixture of 2,3,3′,4′-tetramethoxy-α-methylstilbenes and α-methoxy-α-(3′,4′-dimethoxyphenyl)-β-(2,3-dimethoxyphenyl)propanes. Substituent –CHCHCH₃ on ring B remained unaffected. Substituents –CHCHCH₂OH and –COOH on ring B produced the corresponding methyl ether and ester, respectively, by methylation. The –CHCHCHO substituent on ring B was converted to the –CHO substituent.     

Theoretical investigation on possible mechanisms on regioselective formation of (η-siloxyallyl)tungsten complexes

Selective formation of (η³-siloxyallyl)tungsten complexes by reaction of hydrido(hydrosilylene)tungsten complexes with α,β-unsaturated carbonyl compounds was reported experimentally. The mechanisms have been investigated by employing the model reaction of [Cp(CO)₂(H)WSi(H)–{C(SiH₃)₃}] (R), derived from the original experimental complex Cp′(CO)₂(H)WSi(H)–[C(SiMe₃)₃] (1a, Cp′ = Cp*; 1b, Cp′ = η⁵-C₅Me₄Et), with methyl vinyl ketone, under the aid of the density functional calculations at the b3lyp level of theory. It is theoretically predicted that the route involving migration of the hydride to silicon to afford a 16e intermediate [Cp(CO)₂W–SiH₂–{C(SiH₃)₃}] is inaccessible (route 2), supporting the proposition by experiments. Another route, via [2 + 4] cycloaddition followed by directly Si–H reductive elimination, is theoretically predicted to be accessible (route 1). In route 1, two possible paths with different attacking directions of the oxygen of methyl vinyl ketone at Si (WSi) are put forward. The attack at the Si atom from the hydride (H1) side of the plane W–Si–H1 in R is found to be preferred kinetically. The regioselectivity for formation of (η³-siloxyallyl)tungsten complexes, where only the exo-anti isomer was obtained, is discussed based on the consideration of thermodynamics and kinetics.     

Synthesis and Crystal Structure of β-Amino-α-Phenyl-α-Ferrocenylethanol

β-Amino-α-phenyl-α-ferrocenylethanol, FcC(OH)(Ph)CH₂NH₂ was prepared by the reduction of cyanohydrin trimethylsilyl ether of benzoylferrocene with lithium aluminum hydride. This new compound was characterized by elemental analysis, IR and ¹H NMR spectroscopy. The structure was also confirmed by a single crystal X-ray study. The compound crystallizes in monoclinic P2₁/c space group with unit cell dimensions: a = 12.5906(17), b = 5.9636(8), c = 19.8320(3) Å, β = 102.047(2)^∘, V = 1456.3(3) ų, Z = 4. The structure exhibits intra- and inter-molecular hydrogen bonding of the type N—H⋅ < eqid1 > ⋅O and O—H⋅ < eqid2 > ⋅N, respectively. The pattern of the inter-molecular hydrogen bonding interaction contains a 10-atom ring with two donors and two acceptors, showing a dimeric crystal packing.     

Synthetic studies towards (±)-phthalascidin 650: synthesis of a fully functionalized N-protected-α-amino-aldehyde

An efficient synthesis of fully functionalized N-protected α-amino-aldehyde (±)-13 as synthetic precursor of the tetrahydroisoquinoline alkaloid phthalascidin 650 is reported. Starting from sesamol 6, 11 steps are required to give rise to the desired N-protected α-amino-aldehyde (±)-13 in 25% overall yield. This synthetic strategy involves the elaboration of fully functionalized aromatic aldehyde 7 and its transformation into an α-amino-alcohol through a Knoevenagel condensation. The phthalimidomethyl derivative (±)-11 was then synthesised from 8 by a Bischler–Napieralski reaction, a diastereoselective hydrogenation of the resultant dihydroisoquinoline and transformed into the corresponding N-protected α-amino-aldehyde (±)-13.     

Enzymatic synthesis of iso-globotriose from partially protected lactose

6′-O-Acyl-lactose derivatives (1b-d) were prepared by selective enzymatic acylation of lactose using the protease subtilisin. These compounds were used as acceptors for enzymatic transglycosylations catalysed by an α-galactosidase from Talaromyces flavus forming (after deacylation) iso-globotriose (α-d-Galp-(1→3)-β-d-Galp-(1→4)Glc, 2a).     

A novel method for the synthesis of (Z)-α-selenyl-α,β-unsaturated ketones via acylation of (E)-α-selanylvinylstannanes

The (E)-α-selenylvinylstannanes react with acyl halides in presence of a catalytic amount of Pd(PPh₃)₄ to give the corresponding (Z)-α-selenyl-α,β-unsaturated ketones in good yield.     

Packed-Fiber Solid Phase-Extraction Coupled with HPLC-MS/MS for Rapid Determination of Lipid Oxidative Damage Biomarker 8-Iso-Prostaglandin F2α in Urine

The 8-iso-prostaglandin F_2α (8-iso-PGF_2α) biomarker is used as the gold standard for tracing lipid oxidative stress in vivo. The analysis of urinary 8-iso-PGF_2α is challenging when dealing with trace amounts of 8-iso-PGF_2α and the complexity of urine matrixes. A packed-fiber solid-phase extraction (PFSPE)–coupled with HPLC-MS/MS–method, based on polystyrene (PS)-electrospun nanofibers, was developed for the specific determination of 8-iso-PGF_2α in urine and compared with other newly developed LC-MS/MS methods. The method, which simultaneously processed 12 samples within 5 min on a self-made semi-automatic array solid-phase extraction processor, was the first to introduce PS-electrospun nanofibers as an adsorbent for the extraction of 8-iso-PGF_2α and was successfully applied to real urine samples. After optimizing the PFSPE conditions, good linearity in the range of 0.05–5 ng/mL with R² > 0.9996 and a satisfactory limit of detection of 0.015 ng/mL were obtained, with good intraday and interday precision (RSD < 10%) and recoveries of 95.3–103.8%. This feasible method is expected to be used for the batch quantitative analysis of urinary 8-iso-PGF_2α.     

Novel M(II)–Hg(II) coordination polymers generated from metal-containing building blocks M(2-pyrazinecarboxylate)2 · (H2O)2 (M=Cu, Ni, Co) and HgCl2

A new class of M(II)–Hg(II) (M=Cu(II), Co(II), Ni(II)) mixed-metal coordination polymers, Cu(2-pyrazinecarboxylate)₂HgCl₂ (4), [Co(2-pyrazinecarboxylate)₂(HgCl₂)₂] · 0.61H₂O (5) and [Ni(2-pyrazinecarboxylate)₂(HgCl₂)₂] · 0.77H₂O (6), have been prepared by self assembly of metal-containing building blocks, M(2-pyrazinecarboxylate)₂ · (H₂O)₂(M=Cu(II), Co(II), Ni(II)), with HgCl₂. Compounds 4–6 were characterized fully by IR, elemental analysis and single crystal X-ray diffraction. Compound 4 crystallized in the monoclinic space group C2/c, with a=17.916(5) Å, b=7.223(2) Å, c=13.335(4) Å, β=128.726(3)°, V=1346.2(6) ų, Z=4. It contains alternating Hg(II) and Cu(II) metal centers that are cross-linked by 2-pyrazinecarboxylate spacers and chlorine co-ligands to generate a unique three-dimensional Hg(II)–Cu(II) mixed metal framework. Compound 5 crystallized in the triclinic space group P , with a=6.3879(7) Å, b=6.6626(8) Å, c=13.2286(15) Å, α=96.339(2)°, β=91.590(2)°, γ=113.462(2)°, V=511.71(10) ų, Z=1. Compound 6 also crystallized in the triclinic space group P , with a=6.3543(8) Å, b=6.6194(8) Å, c=13.2801(16) Å, α=96.449(2)°, β=92.263(2)°, γ=113.541(2)°, V=506.67(11) ų, Z=1. Compounds 5 and 6 are isostructural and in the solid state the Hg(II)M(II)Hg(II) units are connected by Hg₂Cl₂ linkages to produce a novel M(II)–Hg(II) (M=Co(II), Ni(II)) zigzag mixed-metal chain, in which a new type of M–M′–M′–M array was observed. The metal containing building blocks, M(2-pyrazinecarboxylate)₂ · (H₂O)₂ (M=Cu(II), Co(II), Ni(II)), exhibit different connectivities to HgCl₂ depending on the metal cation contained within them.     

Solvent-dependent luminescent Cu(I) framework based on 5-(4-pyridyl)tetrazole

A new Cu(Ι) coordination compound, Cu₄(L)₄·2EtOH (1), has been obtained from the solvothermal reaction of CuBr, HL (L=5-(4-pyridyl) tetrazole), EtOH and NH₃·H₂O. The structure determination reveals that 1 has a 2D network, where each Cu(I) atom adopts a trigonal coordination mode. The 2D networks stacked in an ABAB sequence through the π–π interaction to form a 3D supramolecular framework, giving a 1D channel along the b-axis. The TGA and powder XRD measurements reveal that the framework is stable after removal of the guest molecules. Gas (N₂) adsorption measurement was carried out for the framework. Framework 1 shows II sorption profile with N₂, which indicates that N₂ molecules cannot diffuse into the micropore and only surface adsorption occurs. The photoluminescent research shows that compound 1 displays an interesting solvent-dependent luminescence.     

Linear relationships in α,β-unsaturated carbonyl compounds between the half-wave reduction potentials, the frontier orbital energies and the Hammett σp values

A linear relationship between the half-wave reduction potentials of α,β-unsaturated carbonyl compounds R–CHCH–COX and the Hammett σ_p values of R and X is proposed: E_1/2=−1.341σ_p(X)σ_p(R)+1.123σ_p(X)+1.746σ_p(R)−1.694. A linear relationship is also observed for the LUMO's energy values, the absolute chemical hardness η, the chemical potential μ, the electrophilicity power ω, or the polarisation of the ethylenic double bond with the Hammett σ_p values of R and X.     

Synthesis and structure of the unsymmetrical β-diimine precursor: The β-iminoamine

The reaction of benzoylacetone with ortho-substituted aniline derivatives gives the unsymmetrical β-iminoamine ligands (5–8) with high yields. A convenient synthesis is described. These compounds have been characterized by NMR and IR spectroscopies. The structure of the β-iminoamine 5, 3-N-(2,6-diisopropylphenylamino)-1-phenyl-1N-(2,6-diisopropylphenylimino)but-2-ene, was solved by X-ray diffraction methods.     

Reduction of α,β unsaturated carbonyl compounds by Ni–BH4

The reduction of α,β unsaturated carbonyl compounds by sodiumborohydride is catalysed by Ni(bpy)Cl₂ (bpy=2,2′-bipyridine). Various carbonyl compounds having the general formula R₁CH=CHCRO [where R₁, R=C₆H₅, H; p-MeO---C₆H₄---,C₆H₄; p-CH₃---C₆H₄, C₆H₅; (m-OMe---)(p-OMe---)C₆H₃, C₆H₅; C₆H₅, (CH₃)₂CH---; CH₃, H; m-Br---C₆H₄---, C₆H₅] are reduced to corresponding allylicalcohol [R₁CH=CHCRHOH] at 25°C within half an hour. During these reductions the double bond is partially reduced to give saturated alcohols as minor products having the molecular formula R₁CH₂CH₂CRHOH. The reduction of trans-3-phenyl-2-propenal with NaBH₄ and catalytic amounts of Ni(bpy)Cl₂ in solvents containing active deuterium (D₂O, CD₃OD), leads to the partial incorporation of deuterium at the α and γ positions to give C---D bonded alcohols.     

A manganese sulfite with extended metal–oxygen–metal bonds exhibiting hydrogen uptake

A manganese sulfite of the formula Mn₅(OH)₄(SO₃)₃·2H₂O, I{a=7.5759(7) Å, b=8.4749(8) Å, c=10.852(1) Å, β=100.732(2)°, Z=2, space group=P2₁/m (no. 11), R₁=0.0399 and wR₂=0.1121 [for R indexes I>2σ(I)]}, comprising Mn₃O₁₄ units and extended Mn–O–Mn bonds along the three dimensions has been synthesized under hydrothermal conditions. It has narrow channels along the b-axis and exhibits hydrogen storage of 2.1 wt% at 300 K and 134 bar.     

A series of novel 2,6-bis(imino)pyridyl iron catalysts: synthesis, characterization and ethylene oligomerization

A series of novel 2,6-bis(imino)pyridyl iron complexes {2,6-(2-X-4-Y-5-ZC₆H₂NCCH₃)₂C₅H₃N}FeCl₂ (X = Cl, Y = CH₃, Z = H (2); X = Br, Y = CH₃, Z = H (3); X = F, Y = H, Z = CH₃ (4); X = Cl, Y = H, Z = CH₃ (5); X = Cl, Y = F (7)) have been synthesized and characterized with elemental analysis and IR. These iron coordinative complexes, activated with methylaluminoxane (MAO), lead to highly active ethylene oligomerization (>10⁷ g/mol Fe h) and the products are mostly linear α-olefins (>90%). The catalytic activities and product properties depend on the substituents on aryl rings and the reaction conditions. As reaction temperature increases, the catalytic activities decrease rapidly and more low-molar-mass products are produced. The product distributions are almost independent of the Al/Fe molar ratio, but the catalytic activities change in different trends when the ortho-substituents on the aryl rings are different. The other three complexes have also been synthesized for comparison to investigate the steric hindrance and electronic effect on the properties of complexes. The complex with adaptable steric hindrance and electronic properties exhibits the highest catalytic activities.     

A new approach to the synthesis of α-chlorocycloalkanones

α-Chlorocycloalkanones(Ⅳ) were synthesized from cycloalkanones via potassiumα-oxocycloalkylsulfonates(Ⅱ).A two-step mechanism was proposed to explain the formation ofⅣfromⅡ.