Inhibition of prostaglandin biosynthesis by c−5, c−8, c−11-eicosatrienoic acid

The enzyme prostaglandin H → E-isomerase (EC 5.3.99.3), which is present in sheep vesicular gland and needs glutathione as cofactor, is inhibited by c−5, c−8, c−11-eicosatrienoic acid, the fatty acid accumulating during essential fatty acid deficiency. The EFA-deficiency syndrome can partly be explained from a prostaglandin deficiency caused by lack of precursors. The present finding indicates that 5,8,11-eicosatrienoic acid could well be an additional factor in modifying the symptoms of EFA-deficiency.     

(−)-di-de-o-methylgrandisin, a lignan from Virola pavonis leaves

Leaves of Virola pavonis yielded a (7,7′β,8β,8′)-4,4′-dihydroxy-3,3′5,5′-tetramethoxy-7,7′-epoxyligna (−)-di-de-O-methylgrandisin.     

Development of a reaction system for the selective conversion of (−)-trans-carveol to (−)-carvone with whole cells of Rhodococcus erythropolis DCL14

The present article addresses the development of a microbial reaction system for the transformation of carveol to carvone, using whole cells of Rhodococcus erythropolis DCL14. This strain contains a NAD-dependent carveol dehydrogenase (CDH) when grown on limonene or on cyclohexanol. When a mixture of (−)-cis and (−)-trans-carveol is supplied, only (−)-trans-carveol is converted. Thus, besides (−)-carvone, pure (−)-cis-carveol can be obtained as product.

Initial experiments were performed batchwise using an aqueous system. (−)-Trans-carveol conversion rate gradually decreased during successive reutilisation batches. After the third reutilisation, activity was completely lost. Cells grown on cyclohexanol showed a slightly higher activity as compared to cells grown on (+)-limonene. A production of 4.3 μmol (−)-carvone formed per mg protein was achieved. A significant improvement with respect to initial reaction rate and productivity was obtained with aqueous–organic two-phase systems. Using a 5 to 1 buffer/iso-octane system, a 40% increase in the initial rate and a 16-fold increase of the production was observed. A further improvement resulted from increasing the volume of solvent (1 to 1 buffer/dodecane ratio). An initial reaction rate of 26 nmol/(min*mg protein) was observed, while production increased to 208 μmol (−)-carvone formed per mg protein. As in the single-phase system, reaction rate gradually decreased along the successive cell reutilisation batches. Addition of co-substrates for the regeneration of NAD did not prevent this decay. A simple downstream process was developed for the recovery of carvone and cis-carveol.     

Aerosol OT/Water System Coupled with Triiodide/Iodide (I3−/I−) Redox Electrolytes for Highly Efficient Dye‐Sensitized Solar Cells

Dye‐sensitized solar cells (DSCs) are considered to be a promising alternative to Si‐based photovoltaic cells. The electrolyte of the DSC primarily uses triiodide/iodide (I₃^?/I^?) as a redox couple. Therefore, it is essential to understand the regeneration and recombination kinetics of the I₃^?/I^? redox couples in the device. In this context, controlling the total and local concentrations of the I₃^?/I^? redox couples is an important parameter that can influence the DSC performance. Here, we propose that the introduction of a sodium bis (2‐ethylhexyl) sulfosuccinate (AOT)/water system to the I₃^?/I^? electrolyte enables the control of the concentration of the redox couples, which consequently achieves a high power conversion efficiency of ～11% for ～1000 h (under 1 sun illumination) owing to the enhanced dye‐regeneration efficiency and the reduced recombination rate. This novel concept assists in the comprehension of the regeneration and recombination kinetics and develops highly efficient DSCs.     

Assessing the absolute configuration of (7S,8R)-(−)-epoxyjasmone

The absolute configuration of cis-epoxyjasmone (−)-2, isolated from Trichosporum cutaneum CCT 1903 whole cells, has been unambiguously established as (7S,8R), [α]_D²⁰ −29.0° (c 1.3, CHCl₃), by a new two step method, using a regioselective epoxide opening as the key step followed by Mosher acid derivatization.     

Overexpressing STAMP2 attenuates adipose tissue angiogenesis and insulin resistance in diabetic ApoE−/−/LDLR−/− mouse via a PPARγ/CD36 pathway

The aim of this study was to investigate whether overexpression of STAMP2 improves insulin resistance by regulating angiogenesis in adipose tissues. The characteristics of diabetic mice were measured by serial metabolite and pathology tests. Samples were obtained from epididymal, subcutaneous and brown adipose tissues. Histological and morphological analysis demonstrated that STAMP2 gene overexpression reduced adipocyte size, angiogenesis in epididymal and brown adipose tissues. On aortic ring assay, microvessels sprouting from aortas were significantly inhibited after STAMP2 gene overexpression. The cellular effect of STAMP2 on angiogenesis was explored in human umbilical vein endothelial cells (HUVECs) model. Correlation of STAMP2 and angiogenesis was validated by Ad‐STAMP2 transfection and STAMP2 siRNA inhibition. In vitro, overexpression of STAMP2 significantly inhibited endothelial cell migration, tube formation. The effects of Ad‐STAMP2 transfection on HUVECs were abolished by treatment with PPARγ antagonist GW9662 (2.5 μM), and the roles of STAMP2 siRNA on HUVECs were also reversed by treatment with PPARγ agonist rosiglitazone (RSG) (0.1 mM). RT‐PCR indicated that STAMP2 could regulate levels of adhesion molecules, vascular endothelial growth factor A and CD36. The expression of PPARγ and CD36 was decreased when STAMP2 was inhibited by siRNA, while PPARγ and CD36 were highly expressed after overexpression of STAMP2. Our results suggested that STAMP2 gene overexpression may improve insulin resistance via attenuating angiogenesis in epididymal and brown adipose tissues through the PPARγ/CD36 signalling pathway.     

Different attentional dysfunctions in eEF2K−/−, IL1RAPL1−/− and SHANK3Δ11−/− mice

A common feature of several psychiatric disorders is the attentional impairment. eEF2K ^?/?, IL1RAPL1 ^?/? and SHANK3Δ11 ^?/? mice were used as animal models consistently linked to changes in synaptic plasticity, learning and memory. All knockout (KO) mice and their corresponding littermates were submitted to the novel object recognition (NOR) and visual object recognition (VOR) tasks. In the NOR, eEF2K^?/? mice exhibited a normal performance in terms of mean discrimination index, while SHANK3Δ11^?/? and IL1RAPL1 ^?/? mice were impaired when a delay of 2 and 24 hours was introduced. Surprisingly, when submitted to VOR, where the two objects were replaced with two shapes delivered from two iPods, all the mutant mice performed worse than those in the NOR. In VOR, the application of motion to different shapes, to increase attention, improved performance in eEF2K ^?/? and IL1RAPL1 ^?/? but not in SHANK3Δ11 ^?/? mice. In SHANK3Δ11 ^?/? mice, attentional deficit was also present even if different motions were applied to the same shapes or when these mice were repeatedly exposed for 5 days to the context. Behavioral analysis showed that eEF2K^?/? and IL1RAPL1 ^?/? mice had a good flexibility tested in the T‐maze. eEF2K^?/? showed normal self‐grooming. On the basis of previous literature data indicating that SHANK3Δ11 ^?/? showed impaired flexibility and reduced sociability, we identified in this genotype the most exhaustive model showing all the core symptoms of autism spectrum disorder including a heavy visual attention deficit. These findings show the importance of VOR to identify mouse models of autism.     

Pharmacokinetic behaviour of R-(+)- and S-(−)-amlodipine after single enantiomer administration

Amlodipine, 3-ethyl 5-methyl-2-[(2-aminoethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, is a chiral calcium antagonist, currently on the market and in therapeutic use as a racemate. The pharmacokinetic behaviour of R-(+)- and S-(−)-amlodipine after single enantiomer administration to healthy male human volunteers together with comparative administration of the racemic mixture of both enantiomers were studied. Plasma levels were studied as a function of time and assayed using an enantioselective chromatographic method (coupled chiral and achiral HPLC) with on-line solid-phase extraction and UV absorbance detection. The method was validated separately for the R-(+)- and S-(−)-enantiomer, respectively. Results of the study indicate that the pharmacokinetic behaviour of R-(+)- and S-(−)-amlodipine after single enantiomer administration is comparable to that of each enantiomer after administration of the racemate. No racemization occurs in vivo in human plasma after single enantiomer administration.     

Transition metal complexes with sulfur ligands. XXVIII. Ruthenium complexes of the pentadentate thioether thiolate ligands dpttd (2,3,11,12-dibenzo-1,4,7,10,13-pentathiatridecane(−2)) and the sterically demanding derivative bu4-dpttd (14,16,18,20-tetra (t-butyl)-2,3,11,12-dibenzo-1,4,7,10,13-pentathiatridecane(−2))

The template alkylation of Li₂[Ru(CO)₂(S₂C₆H₄)₂] (S₂C₆H₄²⁻ = 1,2-benzenedithiolate(−2)) by S(C₂H₄Br)₂ yields [Ru(CO)₂(dpttd)] (dpttd²⁻ = 3,11,12-dibenzo-1,4,7,10,13-pentathiatridecane(−2)) which is thermally converted into the monocarbonyl complex [Ru(CO)(dpttd)]. The reactions of dpttd-H₂ or dpttd²⁻ with [RuCl₂(PPh₃)₃], [RuCl₂(DMSO)₄], [RuCl₃(PhSCH₃)₃] and RuCl₃(NO)·xH₂O lead to [Ru(L)(dpttd)] and [Ru(L)(dpttd)]Cl (L = PPh₃, DMSO, PhSCH₃, NO), respectively, which are practically insoluble in all common solvents. Better soluble complexes are obtained with the new sterically demanding ligand ^tbu₄-dpttd²⁻ = 14,16,18,20-tetra(t-butyl)-2,3,11,12-dibenzo-1,4,7, 10,13-pentathiatridecane(−2); it is obtained in isomerically pure form by the reaction of tetrabuthylammonium-3,5-di (t-butyl)-1,2-benzenethiolthiolate, NBu₄[^tbu₂-C₆H₂S(SH), with S(C₂H₄Br)₂ and yields on reaction with [RuCl₂(PPh₃)₃] the very soluble [Ru(PPh₃)₂(^tbu₄-dpttd)] as well as [Ru(PPh₃(^tbu₄-dpttd)]. The ¹H NMR and ³¹P NMR spectra indicate that in solution [Ru(PPh₃)₂(^tbu₄-dpttd)] exists as a mixture of diastereomers, whereas [Ru(PPh₃)(^tbu₄-dpttd)] forms one pair of enantiomers only. This was confirmed by an X-ray structure determination of a single crystal. [Ru(PPh₃)(^tbu₄-dpttd)] crystallizes in space group P2₁/n with a = 10.496(4), b = 14.888(6), c = 32.382(12) Å, β = 98.04(3)°, Z = 4 and D_calc. = 1.27 g/cm³, R = 4.84; R_W = 5.06%; the ruthenium center is coordinated pseudooctahedrally by one phosphorus, two thiolate and three thiother S atoms.     

Studies on the continuous production of (R)-(−)-phenylacetylcarbinol in an enzyme-membrane reactor

The optimization of a continuous enzymatic reaction yielding (R)-(−)-phenylacetylcarbinol ((R)-PAC), a key intermediate of the (1R,2S)-(−)-ephedrine synthesis, is presented. We compare the suitability of different mutants of the pyruvate decarboxylase (PDC) from Zymomonas mobilis with respect to their application in biotransformation using pyruvate or acetaldehyde and benzaldehyde as substrates, respectively. Starting from 90 mM pyruvate and 30 mM benzaldehyde, (R)-PAC was obtained with a space time yield of 27.4 g/(L·day) using purified PDCW392I in an enzyme-membrane reactor. Due to the high stability of the mutant enzymes PDCW392I and PDCW392M towards acetaldehyde, a continuous procedure using acetaldehyde instead of pyruvate was developed. The kinetic results of the enzymatic synthesis starting from acetaldehyde and benzaldehyde demonstrate that the carboligation to (R)-PAC is most efficiently performed using a continuous reaction system and feeding both aldehydes in equimolar concentration. Starting from an inlet concentration of 50 mM of both aldehydes, (R)-PAC was obtained with a space-time yield of 81 g/(L·day) using the mutant enzyme PDCW392M. The new reaction strategy allows the enzymatic synthesis of (R)-PAC from cheap substrates free of unwanted by-products with potent mutants of PDC from Z. mobilis in an aqueous reaction system.     

The interaction of Lewis acidic boron derivatives with Re(CO)5−nH(PMe3)n complexes

Lewis acid adducts of the hydrides cis- and trans-Re(CO)(PMe₃)₄H (1) and (2), mer-Re(CO)₂(PMe₃)₃H (3), fac-Re(CO)₂(PMe₃)₃H (4) and trans-Re(CO)₃(PMe₃)₂H (5) were studied with BH₃ and 9-borabicyclo[3,3,1] norbonane (BBNH). Using BH₃·THF and (BBNH)₂ 1 and 2 afforded Re(CO)(PMe₃)₃(η²-BH₄) (6) and Re(CO)(PMe₃)₃(η²-BBNH₂) (7) as stable and isolable products. VT IR studies established for the reaction to 7 that BBNH first attaches in a pre-equilibrium to the O_CO atom of 1 or 2. At higher temperatures ReH adduct formation occurs with instantaneous transformation to 7 and elimination of PMe₃·BBNH. In a similar way, the hydrides 3 and 4 were converted with BH₃·THF and (BBNH)₂ to yield the stable complexes Re(CO)₂(PMe₃)₂(η²-BH₄) (8) and Re(CO)₂(PMe₃)₂(η²-BBNH₂) (9). The intermediacy of the η¹-BH₄ adducts mer-/fac-Re(CO)₂(PMe₃)₃(η¹-BH₄) was confirmed by VT ¹H, ³¹P NMR and VT IR experiments. The conversion of 5 with BH₃·THF led to equilibria with adducts at the O_CO terminus in trans position to H and with H_Re as revealed by VT IR studies. Temperature dependent ³¹P equilibrium studies allowed to calculate ΔH=−4.9 kcal mol⁻¹ and ΔS=+0.034 e.u. for this reaction. These adducts could not be isolated. Compound 5 does not react with (BBNH)₂ even at elevated temperatures. DFT calculations were carried out to support the structures of the BH₃ adducts of 5. In addition a vibrational analysis helped to unravel the IR band assignments of the involved compounds. DFT calculations on 8 confirmed its C_2v structure. X-ray diffraction studies were carried out on single crystals of 6 and 7.     

Unusual intramolecular N→O acyl group migration occurring during conjugation of (−)-DHMEQ with cysteine

Previously we found that (−)-DHMEQ, a specific NF-κB inhibitor, covalently bound to a specific cysteine of NF-κB component proteins. In the course of formation of the (−)-DHMEQ and protected cysteine conjugate, we observed an unusual intramolecular N→O acyl group migration.     

Fungal hydroxylation of (−)-santonin and its analogues

Santonin (1) was incubated with separate growing cultures of Aspergillus niger ATCC 9142, Mucor plumbeus ATCC 4740, Whetzelinia sclerotiorum ATCC 18687, Cunninghamella echinulata var. elegans ATCC 8688a and Phanerochaete chrysosporium ATCC 24725. Three novel metabolites were isolated: 11β,13-dihydroxysantonin (3), 6,7-dehydosantonin (5) and 3,6-dihydroxy-9-keto-9,10-seco-selina-1,3,5(10)-trien-12-oic acid-12,6-lactone (7). 11β-Hydroxysantonin (2), 14-hydroxysantonin (4) and 3,6,9-trihydroxy-9,10-seco-selina-1,3,5(10)-trien-12-oic acid-12,6-lactone (6) were also isolated. Hydroxylation at C-9 followed by a retro-aldol reaction was postulated to have produced 6 and 7. Through the synthesis and fermentation of the santonin analogues: tetrahydrosantonin (8) and α-desmotroposantonin (12), several new compounds were obtained; the most significant being 9-keto-desmotroposantonin (14), which was indicative of C-9 monohydroxylation.     

Hetero-polynuclear complexes containing bridging diphenylphosphino-alkenes and -alkynes. The crystal structure of an Rh2{μ−ν:ν−P(Ph2) (CH2)3C≡CR}Co2 complex

The phosphinoalkenes Ph₂P(CH₂)_nCH=CH₂ (n= 1, 2, 3) and phosphinoalkynes Ph₂P(CH₂)_n C≡CR (R = H, N = 2, 3; R = CH₃, N = 1) have been prepared and reacted with the dirhodium complex (η−C₅H₅)₂Rh₂(μ−CO) (μ−η²−CF₃C₂CF₃). Six new complexes of the type (ν−C₅H₅)₂(Rh₂(CO) (μ−η¹:η¹−CF₃C₂CF₃)L, where L is a P-coordinated phosphinoalkene, or phosphinoalkyne have been isolated and fully characterized; the carbonyl and phosphine ligands are predominantly trans on the Rh---Rh bond, but there is spectroscopic evidence that a small amount of the cis-isomer is formed also. Treatment of the dirhodium-phosphinoalkene complexes with (η−CH₃C₅H₄)Mn(CO)₂thf resulted in coordination of the manganese to the alkene function. The Rh₂---Mn complex [(η−C₅H₅)₂Rh₂(CO) (μ−η¹:η¹−CF₃C₂CF₃) {Ph₂P(CH₂)₃CH=CH₂} (η−CH₃C₅H₄)Mn(CO)₂] was fully characterized. Simi treatment of the dirhodium-phosphinoalkyne complexes with Co₂(CO)₈ resulted in the coordination of Co₂(CO)₆ to the alkyne function. The Rh₂---Co₂ complex [(η−C₅H₅)₂Rh₂(CO) (μ−η¹:η¹−CF₃C₂CF₃) {Ph₂PCH₂C≡CCH₃}Co₂(CO)₂], C₃₇H₂₅Co₂F₆O₇PRh₂, was fully characteriz spectroscopically, and the molecular structure of this complex was determined by a single crystal X-ray diffraction study. It is triclinic, space group (C_i¹, No. 2) with a = 18.454(6), B = 11.418(3), C = 10.124(3) Å, = 112.16(2), β = 102.34(3), γ = 91.62(3)°, Z = 2. Conventional R on |F| was 0.052 fo observed (I > 3σ(I)) reflections. The Rh₂ and Co₂ parts of the molecule are distinct, the carbonyl and phosphine are mutually trans on the Rh---Rh bond, and the orientations of the alkynes are parallel for Rh₂ and perpendicular for Co₂. Attempts to induce Rh₂Co₂ cluster formation were unsuccessful.     

Biotransformation of monoterpenoids, (−)- and menthols, terpinolene and carvotanacetone by Aspergillus species

Four monoterpenoids, (−)- and (+)-menthols, terpinolene and carvotanacetone were biotransformed by Aspergillus niger and several related species. Aspergillus niger converted (−)-menthol to 1-, 2-, 6-, 7-, and 9-hydroxymenthols and the mosquito repellent-active 8-hydroxymenthol. On the other hand, (+)-menthol was smoothly biotransformed by A. niger to give 7-hydroxymenthol. Aspergillus cellulosae biotransformed (−)-menthol specifically to 4-hydroxymenthol. Terpinolene and (−)-carvotanacetone were converted by A. niger to two , β-unsaturated ketones, a fenchane-type compound and diastereoisomeric p-menthane-2,9-diols and 8-hydroxycarvomenthol, respectively.