C-diholosylflavones dans les feuilles du melon (Cucumis melo)

Four C-glucosylflavones were isolated from muskmelon leaves and shown to be 6-C-diglucosylapigenin (meloside A),6-C-diglucosyl-luteolin (meloside L) and the respective caffeyl esters of meloside A (meloside a) and meloside L (meloside I).     

Fatty acid derivatives and dammarane triterpenes from the glandular trichome exudates of Ibicella lutea and Proboscidea louisiana

Ibicella lutea and Proboscidea louisiana, both of the Martyniaceae family, are known for rich glandular trichomes on their leaves and stems. Chemical investigations of the glandular trichome exudates on leaves of the two plants furnished three types of secondary metabolites, glycosylated fatty acids, glycerides (2-O-(3,6-diacetyloxyfattyacyl)glycerols and 2-O-(3-acetyloxyfattyacyl)glycerols) and dammarane triterpenes. The glycosylated fatty acids from I. lutea were determined to be 6(S)-(6-O-acetyl-β-d-glucopyranosyloxy)-octadecanoic acid (1A), -eicosanoic acid (1B) and -docosanoic acid (1C), as well as their respective deacetyl congeners (2A, 2B and 2C), whereas P. louisiana furnished 8(S)-(6-O-acetyl-β-d-glucopyranosyloxy)-eicosanoic acid (3A) and -docosanoic acid (3B) and their respective deacetyl congeners (4A and 4B), together with 2B. Both plants contained 12 identical 2-O-[(3R,6S)-3,6-diacetyloxyfattyacyl]glycerols (5A-L), in which the fatty acyl moieties contained between 17 and 21 carbon atoms. The corresponding mono-acetyloxy compounds, 2-O-[(3R)-3-acetyloxyfattyacyl]glycerols (6A–L) were detected in both plants. Among these glycerides, ten compounds (5A, 5C, 5F, 5H, 5K, 6A, 6C, 6F, 6H and 6K) had iso-fattyacyl structures and four (5E, 5J, 6E and 6J) had anteiso-fattyacyl structures. A previously unknown dammarane triterpene, betulatriterpene C 3-acetate (7), was isolated together with three known dammarane triterpenes, 24-epi-polacandrin 1,3-diacetate (8), betulatriterpene C (9) and 24-epi-polacandrin 3-acetate (10) from I. lutea, whereas 12 dammarane triterpenes, named probosciderols A–L (12–23), and the known compound betulafolienetriol (11) were isolated from P. louisiana. The structures of these compounds were elucidated by spectroscopic analysis including 2D-NMR techniques and chemical transformations. The 6-O-acetylglucosyloxy-fatty acids 1A–C (42%) and the dammarane triterpenes 7–10 (31%) were the two most abundant constituents in the glandular trichome exudate of I. lutea, whereas the dammarane triterpenes 11–23 (47%) and the glucosyloxy-fatty acids (4A, 4B and 2B) (38%) were the most abundant constituents in the glandular trichome exudate of P. louisiana.     

Synthesis,pharmacological studies and molecular modeling of some tetracyclic 1,3-diazepinium chlorides

Seven new 1,3-diazepinium chlorides exhibiting some structural similarities to the 1,4-benzodiazepines were synthesized. In a Hippocratic screen using mice, three of these salts, 3-methoxy-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8a), 3-methoxy-9-methyl-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8c) and 3-methoxy-11-methyl-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8e) were examined for their effect on the central nervous system, and their activities compared to that of diazepam. On their own, salts 8a, 8c and 8e solicited no sedative effects on the behaviour of the animals. However, they elicited significant effects in combination with diazepam on diazepam-induced activities such as decreased motor activity, ataxia and loss of righting reflex. Compounds 8a and 8c were fitted into the pharmacophore/receptor model developed by Cook et al. with interaction at the L₁, H₁ and A₂ sites indicating that they are potential inverse agonists of the Bz receptor. The compounds displayed some affinity for the α1 isoform of the GABA_A/BzR (L_Di interaction) but are non-selective for α5 (no L₂ interaction). Results of binding affinity studies showed that compound 8a is mildly selective for the α1 receptor although not very potent (K_i = 746.5 nM). The significant potentiation of diazepam-induced ataxia and decreased motor activity by compounds 8a and 8c in the Hippocratic screen may be associated with α1 selectivity.     

Synthesis and biological evaluation of a series of benzoxazole/benzothiazole-containing 2,3-dihydrobenzo[b][1,4]dioxine derivatives as potential antidepressants

A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a–5d and 8a–8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT_1A and 5-HT_2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT_1A and 5-HT_2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT_1A (K_i = 17 nM) and 5-HT_2A (K_i = 0.71 nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice.     

Quantitative studies of the non-productive binding of lysozyme to partially N-acetylated chitosans: Binding of large ligands to a one-dimensional binary lattice studied by a modified McGhee and von Hippel model

This paper considers the non-productive (inhibitory) binding of chitosans to lysozyme from chicken egg white. Chitosans are linear, binary heteropolysaccharides consisting of 2-acetamido-2-deoxy-β-d-glucose (GlcNAc; A-unit) and 2-amino-2-deoxy-β-d-glucose (GlcN, D-unit). The active site cleft of lysozyme can bind six consecutive sugar residues in subsites named A–F, and specific binding of chitosan sequences to lysozyme occurs with A-units in subsite C. Chitosans with different fractions of A-units (F_A) induced nearly identical changes in the ¹H NMR spectrum of lysozyme upon binding, and the concentration of bound lysozyme could be determined. The data were analysed using a modified version of the McGhee and von Hippel model for binding of large ligands to one-dimensional homogeneous lattices. The average value of the dissociation constant for different sequences that may bind to lysozyme (K^ave_D) was estimated, as well as the number of chitosan units covered by lysozyme upon binding. K^ave_D decreased with increasing F_A-values at pH* 3 and 4.5, while the opposite was true at pH* 5.5. Contributions from different hexamer sequences to K^ave_D of the chitosans were considered, and the data revealed interesting features with respect to binding of lysozyme to partially N-acetylated chitosans. The relevance of the present data with respect to understanding lysozyme degradation kinetics of chitosans is discussed.     

Photosynthetic electron transport activity in heat-treated barley leaves: The role of internal alternative electron donors to photosystem II

Electron transport processes were investigated in barley leaves in which the oxygen-evolution was fully inhibited by a heat pulse (48 °C, 40 s). Under these circumstances, the K peak (∼ F_400 μs) appears in the chl a fluorescence (OJIP) transient reflecting partial Q_A reduction, which is due to a stable charge separation resulting from the donation of one electron by tyrozine Z. Following the K peak additional fluorescence increase (indicating Q_A⁻ accumulation) occurs in the 0.2-2 s time range. Using simultaneous chl a fluorescence and 820 nm transmission measurements it is demonstrated that this Q_A⁻ accumulation is due to naturally occurring alternative electron sources that donate electrons to the donor side of photosystem II. Chl a fluorescence data obtained with 5-ms light pulses (double flashes spaced 2.3-500 ms apart, and trains of several hundred flashes spaced by 100 or 200 ms) show that the electron donation occurs from a large pool with t_1/2 ∼ 30 ms. This alternative electron donor is most probably ascorbate.     

A model of photosystem II for the analysis of fast fluorescence rise in plant leaves

The polyphasic patterns of fluorescence induction rise in pea leaves in vivo and after the treatment with ionophores have been studied using a Plant Efficiency Analyzer. To analyze in detail photosystem II (PS II) electron transfer processes, an extended PS II model was applied, which included the sums of exponential functions to specify explicitly the light-driven formation of the transmembrane electric potential (ΔΨ(t)) as well as pH in the lumen (pH_L(t)) and stroma (pH_S(t)). PS II model parameters and numerical coefficients in ΔΨ(t), pH_L(t), and pH_S(t) were evaluated to fit fluorescence induction data for different experimental conditions: leaf in vivo or after ionophore treatment at low or high light intensity. The model imitated changes in the pattern of fluorescence induction rise due to the elimination of transmembrane potential in the presence of ionophores, when ΔΨ = 0 and pH_L(t), pH_S(t) changed to small extent relative to control values in vivo, with maximum ΔΨ(t) ∼ 90 mV and ΔΨ(t) ∼ 40 mV for the stationary state at ΔpH ≅ 1.8. As the light intensity was increased from 300 to 1200 μmol m⁻² s⁻¹, the heat dissipation rate constants increased threefold for nonradiative recombination of P680⁺Phe⁻ and by ∼30% for P680⁺Q_A⁻. The parameters ΔΨ, pH_S and pH_L were analyzed as factors of PS II redox state populations and fluorescence yield. The kinetic mechanism of fluorescence quenching is discussed, which is related with light-induced lumen acidification, when ⁺Q_A⁻ and P680⁺ recombination probability increases to regulate the Q_A reduction.     

Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A2B receptor

On the basis of a pyrazine core structure, three new adenosine A_2B receptor ligands (7a–c) were synthesized containing a 2-fluoropyridine moiety suitable for ¹⁸F-labeling. Compound 7a was docked into a homology model of the A_2B receptor based on X-ray structures of the related A_2A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were determined at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A₁ receptor, 7a was radiolabeled as the most suitable candidate (K_i(A_2B)?=?4.24?nM) in order to perform in vivo studies in mice with the aim to estimate fundamental pharmacokinetic characteristics of the compound class. Organ distribution studies and a single PET study demonstrated brain uptake of [¹⁸F]7a with a standardized uptake value (SUV) of ≈1 at 5?min post injection followed by a fast wash out. Metabolism studies of [¹⁸F]7a in mice revealed the formation of a blood–brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivatives with improved binding properties and metabolic stability in vivo.     

Syntheses and structures of lanthanide complexes containing a bis(imidazolin-2-imino)pyridine pincer ligand

The Lewis acid-base reaction of 2,6-bis[1,3-di-tert-butylimidazolin-2-imino)methyl]pyridine (TL^tBu) and LnCl₃ in THF leads to the corresponding neutral lanthanide complexes of type [(TL^tBu)LnCl₃], Ln = Y (1a), Er (1b), Lu (1c). The yttrium and lutetium complexes have been characterized by X-ray diffraction analysis. The solid state structures reveal that the bulky TL^tBu ligand causes steric crowding around the lanthanide atoms by coordinating to the metal center in a tridentate fashion. In addition, remote C-H?Ln interactions (H?Ln ca. 2.7 Å) involving one of the ^tBu methyl groups are observed in both cases. A DFT (density functional theory) calculation on 1a was able to reproduce this interaction, which was additionally characterized by means of an H?Y compliance constant and by employing the AIM (atoms in molecules) theory.     

4-Functionalized 1,3-diarylpyrazoles bearing 6-aminosulfonylbenzothiazole moiety as potent inhibitors of carbonic anhydrase isoforms hCA I,II, IX and XII

A series of 24 novel heterocyclic compounds—functionalized at position 4 with aldehyde (5a–5f), carboxylic acid (6a–6f), nitrile (7a–7f) and oxime (8a–8f) functional groups—bearing 6-aminosulfonybenzothiazole moiety at position 1 of pyrazole has been synthesized and investigated for the inhibition of four isoforms of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozyme hCA I, compounds 6a–6f showed medium-weak inhibitory potential with K_i values in the range of 157–690 nM with 6a showing better potential than the standard drug acetazolamide (AZA). Against hCA II, all the compounds showed excellent to moderate inhibition with K_i values of compounds 5a, 5d, 5f, 6a–6f, 8d and 8f lower than 12 nM (K_i of AZA). Against hCA IX, all the compounds showed moderate inhibition with the exception of 6e which showed nearly 9 fold a better profile compared to AZA, whereas against hCA XII, four compounds 6e, 7a, 7b and 7d showed K_i in the same order as that of AZA. Carboxylic acid 6e was found to be an excellent inhibitor of both hCA IX and XII, with K_i values of 2.8 nM and 5.5 nM, respectively.     

Acid-base properties of 4-nitro-l-histidine and related compounds

Acid-base properties of 4-nitro-l-histidine (3), N^α-acetyl-4-nitro-l-histidine (2), and N^α-acetyl-4-nitro-l-histidine methyl ester (1) are studied. Their pK_a^II values can be conveniently determined by ultraviolet spectroscopy. Potentiometric titration and ¹H-nuclear magnetic resonance (nmr) titration can also be used. Introduction of a nitro group strongly enhances the acidity of all the compounds. pK_a¹ of compound (3) has been also spectrophotometrically determined. Observed differences in acidity, in those cases where solvation does not play a major role, can be explained by assessing the influence of electrostatic charges on pK_a following Bjerrum's general theory with the aid of data from ¹H-nmr conformational analysis.     

K L a Evaluation during the course of fermentation using data reconciliation techniques

The oxygen mass transfer coefficient often serves to compare the efficiency of bioreactors and their mixing devices as well as being an important scale-up factor. In submerged fermentation, four methods are available to estimate the overall oxygen mass transfer coefficient (K_La): the dynamic method, the stationary method based on a previous determination of the oxygen uptake rate (Q_O2X), the gaseous oxygen balance and the carbon dioxide balance. Each method provides a distinct estimation of the value of K_La. Data reconciliation was used to obtain a more probable value of K_La during the production of Saccharomyces cerevisiae, performed in 22.5-l fed-batch bioreactor. The estimate of K_La is obtained by minimising an objective function that includes measurement terms and oxygen conservation models, each being weighted according to their level of confidence. Weighting factors of measurement terms were taken as their respective inverse variance whereas weighting factors of oxygen conservation models were obtained using Monte Carlo simulations. Results show that more coherent and precise estimations of K_La are obtained.     

Dithiocarbazate complexes with the [M(PPh3)] (M═Pd or Pt) moiety: Synthesis, characterization and anti-Tripanosoma cruzi activity

New neutral Pd(II) and Pt(II) complexes of the type [M(L)(PPh₃)] (M═Pd or Pt) were prepared in crystalline form in high-yield synthesis with the S-benzyldithiocarbazates and S-4-nitrobenzyldithiocarbazates derivatives from 2-hydroxyacetophenone, H₂L^1a and H₂L^1b, and benzoylacetone, H₂L^2a and H₂L^2b. The new complexes [Pt(L^1a)(PPh₃)] (1), [Pd(L^1a)(PPh₃)] (2), [Pt(L^1b)(PPh₃)] (3), [Pd(L^1b)(PPh₃)] (4), [Pt(L^2a)(PPh₃)] (5), [Pd(L^2a)(PPh₃)] (6), [Pt(L^2b)(PPh₃)] (7) and [Pd(L^2b)(PPh₃)] (8) were characterized on the basis of elemental analysis, conductivity measurements, UV-visible, IR, electrospray ionization mass spectrometry (ESI-MS), NMR (¹H and ³¹P) and by X-ray diffraction studies. The studies showed that differently from what was observed for the H₂L^1a and H₂L^1b ligands, H₂L^2a and H₂L^2b assume cyclic forms as 5-hydroxypyrazolinic. Upon coordination, H₂L^2a and H₂L^2b suffer ring-opening reaction, coordinating in the same manner as H₂L^1a and H₂L^1b, deprotonated and in O,N,S-tridentate mode to the (MPPh₃)²⁺ moiety. All complexes show a quite similar planar fourfold environment around the M(II) center. Furthermore, these complexes exhibited biological activity on extra and intracellular forms of Trypanosoma cruzi in a time- and concentration-dependent manner with IC₅₀ values ranging from 7.8 to 18.7 μM, while the ligand H₂L^2a presented a trypanocidal activity on trypomastigote form better than the standard drug benznidazole.     

Electrostatic charging of an electrically insulated metal body streamlined by a plasma flow

Electrostatic charging of an electrically insulated metal body streamlined by a plasma flow is investigated theoretically. The physical processes occurring in the vicinity of the body are considered. The electric currents resulting in the charging or discharging of the body are determined. The electric charge Q(t), electric field E(t), and potential φ(t) of a metal sphere are estimated taking into account the adopted conditions and parameters of the problem. The physical phenomena that take place in the vicinity of a charged body after Q(t) reaches a certain threshold value are discussed. The obtained values of Q(t), E(t), and φ(t) are compared with the corresponding values for a body streamlined by an atmospheric air flow.     

Gas hold-up and oxygen mass transfer in three pneumatic bioreactors operating with sugarcane bagasse suspensions

Sugarcane bagasse is a low-cost and abundant by-product generated by the bioethanol industry, and is a potential substrate for cellulolytic enzyme production. The aim of this work was to evaluate the effects of air flow rate (Q _AIR), solids loading (%_S), sugarcane bagasse type, and particle size on the gas hold-up (ε _G) and volumetric oxygen transfer coefficient (k _L a) in three different pneumatic bioreactors, using response surface methodology. Concentric tube airlift (CTA), split-cylinder airlift (SCA), and bubble column (BC) bioreactor types were tested. Q _AIR and  %_S affected oxygen mass transfer positively and negatively, respectively, while sugarcane bagasse type and particle size (within the range studied) did not influence k _L a. Using large particles of untreated sugarcane bagasse, the loop-type bioreactors (CTA and SCA) exhibited higher mass transfer, compared to the BC reactor. At higher  %_S, SCA presented a higher k _L a value (0.0448 s^?1) than CTA, and the best operational conditions in terms of oxygen mass transfer were achieved for  %_S < 10.0 g L^?1 and Q _AIR > 27.0 L min^?1. These results demonstrated that pneumatic bioreactors can provide elevated oxygen transfer in the presence of vegetal biomass, making them an excellent option for use in three-phase systems for cellulolytic enzyme production by filamentous fungi.     

Probes for narcotic receptor mediated phenomena. 47.1 Novel C4a- and N-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols

A series of N-methyl rac-cis-4a-aralkyl- and alkyl-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols have been prepared (2a–l) using a simple previously designed synthetic route, in order to find a ligand that would interact with both μ- and δ-opioid receptors. A C4a-phenethyl derivative 2a, was found to have modest receptor affinity both at μ- (K_i = 60 nM) and δ-opioid receptors (K_i = 64 nM). The N-methyl substituent of 2a and that of other ligands in the series was then modified to obtain compounds with different N-substituents that might provide higher affinity at both receptors. A number of compounds differently substituted at C4a and N were synthesized and evaluated. Binding studies and functional assays revealed a moderately selective δ-antagonist (2l), selective μ–δ antagonists (3d, 3g), and a μ–κ antagonist (3f).     

Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET

Radiolabelled piperidine derivatives such as [¹¹C]MDL 100907 and [¹⁸F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with ¹⁸F-fluorine, were synthesized to improve molecular imaging properties of [¹¹C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show K_i-values in the nanomolar range towards the 5-HT_2A receptor and insignificant binding to other 5-HT receptor subtypes or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antagonistic ¹⁸F-tracers for visualization of the 5-HT_2A receptor status. Medium affine compounds (VK-1 (32), (51), (52), (54)) were synthesized and have K_i values between 30 and 120 nM. All promising compounds show log P values between 2 and 3, that is, within the range of those for the established radiotracers altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be promising high affine and selective tracers of ¹⁸F-labelled analogues for 5-HT_2A imaging with PET.