Thermal and structural properties of binary mixtures of 1,3-distearoyl-2-oleoyl-glycerol (SOS) and 1,2-dioleoyl-3-stearoyl-sn-glycerol (sn-OOS)

We have conducted thermal and X-ray diffraction experiments on binary mixtures of symmetric stearic-oleic mixed-acid triacylglycerol (TAG) (1,3-distearoyl-2-oleoyl-glycerol: SOS) and asymmetric stearic-oleic mixed-acid TAG (1,2-dioleoyl-3-stearoyl-sn-glycerol: OOS), in which optically active sn-OOS was employed. We found that SOS–OOS mixtures exhibited immiscible monotectic or peritectic mixing behavior. This result was consistent with previous study on binary mixtures of 1,3-dipalmitoyl-2-oleoyl-glycerol (POP) and 1,2-dioleoyl-3-palmitoyl-rac-glycerol (OOP), in which racemic rac-OOP molecules were employed. The differences between the SOS–OOS and POP–OOP mixtures were in the polymorphic behavior of the fractions of POP and SOS. No effect was found from using an optically active (sn-OOS) or racemic mixture (rac-OOP) as an asymmetric oleic–oleic-saturated acid TAG. From the two results, we may conclude that an immiscible phase was formed in the binary mixtures of symmetric saturated-oleic-saturated TAGs and asymmetric oleic–oleic-saturated TAGs, of both racemic and optically active types. This result stands in contrast to mixtures of SOS–OSO (1,3-dioleoyl-2-stearoyl-glycerol), SOS–SSO (1,2-distearoyl-3-oleoyl-rac-glycerol), POP–OPO (1,3-dioleoyl-2-palmitoyl-glycerol), and POP–PPO (1,2-dipalmitoyl-3-oleoyl-rac-glycerol), all of which exhibited molecular-compound-forming behavior with molecular compound crystals at an equal ratio of the binary mixtures. Molecular-level mechanisms to explain this difference are discussed, based on possible roles of glycerol groups acting during the mixing processes of saturated–unsaturated mixed-acid TAGs.     

Distigmasterol-Modified Acylglycerols as New Structured Lipids—Synthesis,Identification and Cytotoxicity

Plant sterols, also referred as phytosterols, have been known as bioactive compounds which have cholesterol-lowering properties in human blood. It has been established that a diet rich in plant sterols or their esters alleviates cardiovascular diseases (CVD), and also may inhibit breast, colon and lung carcinogenesis. Phytosterols, in their free and esterified forms, are prone to thermo-oxidative degradation, where time and temperature affect the level of degradation. Looking for new derivatives of phytosterols with high thermo-oxidative stability for application in foods, our idea was to obtain novel structured acylglycerols in which two fatty acid parts are replaced by stigmasterol residues. In this work, asymmetric (1,2- and 2,3-) distigmasterol-modified acylglycerols (dStigMAs) were synthesized by the covalent attachment of stigmasterol residues to sn-1 and sn-2 or sn-2 and sn-3 positions of 3-palmitoyl-sn-glycerol or 1-oleoyl-sn-glycerol, respectively, using a succinate or carbonate linker. The chemical structures of the synthesized compounds were identified by NMR, HR-MS, and IR data. Moreover, the cytotoxicity of the obtained compounds was determined. The dStigMAs possessing a carbonate linker showed potent cytotoxicity to cells isolated from the small intestine and colon epithelium and liver, whereas the opposite results were obtained for compounds containing a succinate linker.     

Synthesis of difluoromethyl substituted lysophosphatidic acid analogues

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biology that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with nuclear hormone receptor PPARγ. We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogues from (S)-1,2,4-butanetriol to give two 3-difluoromethyl substituted analogues of 2-acyl-sn-glycerol 3-phosphate. These compounds are migration-blocked analogues of the liable sn-2 LPA species. Preliminary studies were conducted on a nuclear reporter assay in which monocytic cells were transfected with a luciferase construct activated by a PPARγ nuclear receptor response element and have shown that the 3-difluoromethyl substituted analogues are fully active as natural LPA.     

Natural anti-HIV agents. Part 3: Litseaverticillols A-H, novel sesquiterpenes from Litsea verticillata

Bioassay directed-fractionation led to the identification of litseaverticillols A-H (1-8) from the leaves and twigs of Litsea verticillata Hance. These new sesquiterpenes possess a unique skeleton that was recently designated as ‘litseane’. The structures of these compounds were determined by spectroscopic means including 1D and 2D NMR data. Structural configurations were determined by ROESY experiments. Mosher ester reactions and optical rotation measurements established the sesquiterpenes 1-8 as racemates. Isolates 1-8 inhibited HIV-1 replication in HOG.R5 cells with IC₅₀ values ranging from 2 to 15 μg/ml (8-58 μM) while affecting the growth of HOG.R5 at concentrations 2-3-fold higher. Based on this data, structure-activity relationships can be discerned, suggesting compounds of this class are good candidates for analog production.     

Synthesis of (Z)-(2′R)-1-O-(2′-methoxynonadec-10′-enyl)-sn-glycerol,a new analog of bioactive ether lipids

An unsaturated 2-methoxy-substituted 1-O-alkylglycerol, (Z)-(2′R)-1-O-(2′-methoxynonadec-10′-enyl)-sn-glycerol, a new analog of bioactive ether lipids, was synthesized from oleic acid and 2,3-isopropylidene-sn-glycerol. The two key steps of this synthesis were the conversion of oleyl aldehyde to a monounsaturated epoxide using Matteson’s method followed by hydrolytic kinetic resolution and a nucleophilic epoxide opening by 2,3-isopropylidene-sn-glycerol in the presence of potassium tert-butoxide in anhydrous DMF, which appeared to be a good reagent for this purpose. Furthermore, the diol by-product of the HKR process was also easily converted back to the starting epoxide thus almost doubling the amount of target molecule.     

Structural revision and absolute configuration of lateritin

‘Lateritin’ (1), a morpholine-2,5-dione (depsipeptide), was reinvestigated for its structure and absolute configuration. On the basis of thorough 1D and 2D NMR and mass spectrometrical analyses, the structure of 1 was revised to be identical with beauvericin (8) and confirmed that beauvericin (8) is the trimeric lactone of ‘lateritin’ (1). The absolute configuration was determined by acidic hydrolysis, followed by application of Marfey’s method, menthyl ester derivatization, and GC–MS analysis. In addition, the specific optical rotation values of the hydrolysis products were compared with those of available standards.     

25,26-Dialkoxycalix[4]arenes. Part 1: 25-Alkoxy-26,27-diacetoxy route

Acetylation of calix[4]arene 1,3-dialkyl ethers yielded the corresponding monoacetates. The ¹H NMR spectral analysis indicated that the products’ alkoxy moieties were ‘rotation restricted’. Acylation of calix[4]arene monoalkyl ethers with acetyl chloride yielded monoacetates and/or 2,3-diacetates in different reaction conditions. A simple recrystallization process was able to isolate 2,3-diacetates in good yield. The ¹H NMR spectra of the diacetylated products indicated that those compounds also possessed the ‘rotation restricted’ alkoxy moieties. In the presence of K₂CO₃ as reaction base, alkylation of 2,3-diacetates produced the acetyl-migrated 1,3-dialkyloxy derivatives. Basic hydrolysis of the acetyl-migrated compounds yielded the known 1,3-dialkoxycalix[4]arenes. In the presence of NaH as reaction base, 2,3-diacetates were alkylated with and without the acetyl-migration. For the highly reactive benzyl bromide and allyl bromide, the majority of alkylation proceeded without acetyl-migration. In the other alkyl halides, the products were the acetyl-migrated 1,3-dialkoxy derivatives along with less than one-fourth the amount of non-migrated 1,2-dialkoxy derivatives.     

Synthesis of short and long chain cardiolipins

A phosphoramidite approach using 2-cyanoethyl N,N-diisopropylchlorophosphoramidite was utilized for the first time to synthesize short chain cardiolipins. The approach was extended to synthesize long chain and their ether analogue. Optically active 1,2-di-O-acyl-sn-glycerol or 1,2-di-O-myristyl-sn-glycerol was coupled with phosphoramidite reagent and 2-benzyloxy-1,3-propanediol in presence of 1H-tetrazole, followed by in situ oxidation, to give the corresponding protected cardiolipin analogues. The above intermediates were converted into cardiolipin analogues in two steps by deprotection of cyanoethyl and benzyl groups.     

Chemoenzymatic synthesis of a focused library of enantiopure structured 1-O-alkyl-2,3-diacyl-sn-glycerol type ether lipids

A highly efficient two-step chemoenzymatic synthesis of enantiopure structured ether lipids of the 1-O-alkyl-2,3-diacyl-sn-glycerol type has been developed. Chimyl, batyl and selachyl alcohols possessing pure saturated fatty acid (SFA) attached to the sn-3 position and pure EPA and DHA attached to the sn-2 position were obtained under full regiocontrol. This was offered by mild conditions and a highly efficient lipase that operated at room temperature. High-resolution ¹H NMR spectroscopy was used to monitor the progress of the reactions and to evaluate the full regiocontrol of the reactions involved by keeping track of all prospective adducts involved in these reactions. This was extended to preparation of a focused library of eight monoacyl intermediate adducts for all even-numbered SFA ranging from C₂-C₁₆ and the corresponding EPA and DHA structured diacyl glycerol ethers (DAGE) products for chimyl, batyl and selachyl alcohols, the total of 72 compounds.     

Dispersive kinetic models for isothermal solid-state conversions and their application to the thermal decomposition of oxacillin

The authors recently published works in which the use of two novel equations for modeling the dispersive kinetics observed in various solid-state conversions are described. These equations are based on the assumptions of a ‘Maxwell-Boltzmann (M-B)-like’ distribution of activation energies and a first-order rate law. In the present work, it is shown that it may be possible to expand the approach to include mechanisms other than first-order, i.e. some of those commonly encountered in the field of thermal analysis, thus obtaining ‘dispersive versions’ of these kinetic models. The application of these dispersive kinetic models to the slightly sigmoidal, isothermal conversion-time (x-t) data of Rodante and co-workers for the degradation of the antibiotic, oxacillin, is described. This is done in an effort to test the limitations of the proposed dispersive models in describing kinetic data which is not clearly sigmoidal (i.e. as shown in previous works). Finally, it is demonstrated that, using graphical analysis, the typically sigmoidal x-t plots of first-order dispersive processes are the direct result of (asymmetric) activation energy distributions that are either ‘∩-shaped’ (for heterogeneous conversions) or ‘∪-shaped’ (for homogeneous conversions) in appearance, i.e. when the activation energy is plotted as a function of conversion. This finding lends support to the founding hypothesis of the authors’ approach for modeling dispersive kinetic processes: the existence of ‘M-B-like’ distributions of activation energies.     

Synthesis, inclusion capabilities, and electrical properties of some asymmetrical cyclophanes

For the first time, we announce the synthesis of cyclo(bis-paraquat-p-phenylene-p-phenylene-carbonyl)tetrakis(hexafluorophosphate), named ‘CETOBOX’. This compound exists in three tautomeric forms. These forms were evidenced by NMR data (¹H NMR, TOCSY, COSY, and NOESY), UV-vis spectra coupled with pH measurements, and by synthesis. As the ‘CETOBOX’ gives ‘in situ’ only the corresponding monoylide, the synthesis of a new fluorescent indolizine cyclophane has been performed by a 3+2 cycloaddition. This cycloadduct, in an amidation reaction with 6-amino-β-cyclodextrin, furnishes the final two-cavity sensor with good yields. All structures of the new compounds presented herein have been established by NMR spectroscopy. Also, theoretical methods (MM3, AM1, AM1 (COSMO), and B88LYPDFT) have been used to determine the most stable conformer structures. For the fluorescent indolizine cycloadduct, we evaluated its inclusion capabilities and for the two-cavity sensor, we measured some of its electrical properties that make it suitable for use in VOCs detection and energy conversion.     

New oxypnictide superconductors: PrOFe1−xCoxAs

Oxypnictides of the type PrOFe_1−xCo_xAs (x≤0.3) were synthesized for the first time by the sealed tube method. All the compounds were found to be monophasic and crystallize in the tetragonal ZrCuSiAs type structure (space group=P4/nmm) and the lattice parameters (a and c) decrease with increase in cobalt content. Mössbauer measurements of the compounds indicate low spin Fe²⁺ in tetrahedral coordination. Resistivity and magnetization studies reveal superconducting transitions in compounds with ‘x’=0.05, 0.10 and 0.15, with maximum transition temperature (T_c) at ∼14 K in the compound with ‘x’=0.1. The variation of resistivity with temperature under different magnetic field has been studied to estimate the upper critical field (H_c2) (∼50.2 T for the ‘x’=0.1 composition). The Seebeck and Hall coefficient (R_H) suggests electron type charge carriers in these compound and the charge carrier density increases with increase in Co-doping.     

Comparison of indices and multivariate models to non-destructively predict the fruit chlorophyll by means of visible spectrometry in apple fruit

Non-destructive, rapid, instrumental tools in fruit production are required for predicting the optimum harvest window and monitoring fruit quality during shelf life. The degree of chlorophyll degradation is a sensitive indicator for fruit maturation and ageing. Adequate indices for chlorophyll prediction by means of non-destructive spectral analysis have been studied in the fields of photosynthesis research and remote sensing developments. However, an evaluation of these indices and multivariate linear regression models does not exist so far for predicting the fruit chlorophyll content.Spectral transmittance recordings in the visible wavelength range were carried out on apple fruit Malus domestica Borkh. ‘Elstar’ (n=99) and ‘Jonagold’ (n=117). The fruit chlorophyll a content of ‘Elstar’ apples was measured wet-chemically and predicted by means of the specific indices: NDVI, Tr₆₉₈/Tr₇₆₀, red-edge, TrII on Tr′(λ), TrII, and RVSI with the correlation coefficients of determination R²=0.84, 0.81, 0.75, 0.81, 0.15, and 0.67, respectively. Partial least-squares (PLS) calibration models were built using calibrated spectra (630-730 nm), first derivative of spectra and second derivative of spectra yielding multivariate correlation coefficients of determination R²=0.81, 0.86, and 0.92, respectively. Similar results were found for ‘Jonagold’ apple fruit. Linear regression of indices and PLS calibration models were empirically tested on the chlorophyll a content of apple fruit measuring the same cultivars grown in a different seasons and growing locations. In the case of ‘Elstar’ apple fruit, correlation coefficients of fruit chlorophyll a content analysed wet-chemically as well as fruit maturation measured as calendar weeks were similar to those in the calibration experiment. Application of linear regression equations of indices and PLS models on spectra of ‘Jonagold’ apple fruit led to less accurate results for those methods, which use wavelengths above 720 nm as indicative range.     

Application of probabilistic neural networks in qualitative analysis of near infrared spectra: determination of producing area and variety of loquats

Near infrared (NIR) spectra of a sample can be treated as a signature, allowing samples to be grouped on basis of their spectral similarities. Near infrared spectroscopy (NIRS) combined with probabilistic neural networks (PNN) have been used to discriminate producing area and variety of loquats. Two varieties of loquats (‘Dahongpao’ and ‘Jiajiaozhong’) picked from two producing areas of ‘Tangxi’ and ‘Cunan’ in Zhejiang province were analyzed in this study. Principal component analysis (PCA) was applied before PNN modeling and the results indicated that the dimension of the vast spectral data can be effectively reduced. For each model, half samples were used to train the network and the remaining half were used to test the network. The results of the PCA-PNN models for discriminating the variety of samples from the same producing area or for discriminating the producing area of the same variety samples were much better than those of the PCA-PNN models for discriminating variety or producing area of all loquat samples. The results of this study show that NIRS combined with PCA-PNN is a feasible way for qualitative analysis of discriminating fruit producing areas and varieties.     

Synthesis of enantiomerically pure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol present in the liver oil of cartilaginous fish

Synthesis of enantiopure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol 1, the principal methoxylated glyceryl ether found in Nature, is described by a highly convergent five-step process taking place in 27% overall yield. The synthesis is based on an ether bond formation between the chiral synthon (R)-2,3-O-isopropylidene-sn-glycerol and (Z)-(R)-1-chlorohexadec-4-en-2-ol employing ground potassium hydroxide and tetra-n-butylammonium bromide as a catalyst under solvent free conditions.     

Phosphoramidite approach for the synthesis of cardiolipin

A phosphoramidite approach was utilized for the first time to synthesize cardiolipin. Optically active 1,2-di-O-acyl-sn-glycerol was coupled with 2-O-protected glycerols utilizing mono- and bifunctional phosphitylating agents to yield, after final removal of protecting groups, the title compound.     

Synthesis and biological evaluation of anthranilamide-based non-peptide mimetics of ω-conotoxin GVIA

Non-peptide mimetics based on an anthranilamide ‘scaffold’ possessing fragments that mimic Lys2, Tyr13 and Arg17 in ω-conotoxin GVIA have been prepared. Compounds were assayed for binding to the voltage-gated calcium channels Ca_v2.2 (‘N-type’) and Ca_v2.1 (‘P/Q-type’) in rat brain. The primary synthetic target, 2-(6-amino-hexanoylamino)-5-(3-guanidino-propoxy)-N-[4-(4-hydroxyphenoxy)-phenyl]-benzamide (2a), exhibited low μM binding to Ca_v2.2 and was more than 30-fold selective for Ca_v2.2 over Ca_v2.1.     

Membrane fluidity of tetramyristoyl cardiolipin (TMCL) liposomes studied by chronoamperometric monitoring of their adhesion and spreading at the surface of a mercury electrode

Giant unilamellar liposomes of the synthetic cardiolipin 1′,3′-bis[1,2-dimyristoyl-sn-glycero-3-phospho]-sn-glycerol give chronoamperometric current peaks at a stationary mercury electrode. The signals are due to the adhesion and spreading of the liposomes on the hydrophobic mercury surface. The potential dependence shows a minimum of the peak frequency at the point of zero charge, a large maximum of peak frequency at about ?0.2?V and a second, however, smaller maximum at ?0.8?V. The electrochemical behaviour of the liposomes indicates phase transitions of the cardiolipin which could be also observed in differential scanning calorimetry.     

Synthesis of a cytisine/epibatidine hybrid: a radical approach

With the aim of developing a new ligand of neuronal nicotinic receptors (nAChRs), ionic, and radical routes to the synthesis of a cytisine/epibatidine hybrid were studied. The key step of the convergent synthesis was an unprecedented intramolecular coupling between a primary radical and a pyridine heterocycle. The target compound ‘6,11-diaza’ was formed with its ‘4,11-diaza’ regioisomer (‘6,11″/’4,11″: 70/30). Both compounds exhibited a nanomolar affinity at the α₄β₂ nAChR subtype, slightly better for the unexpected regioisomer [K_i (nM) target compound and its regioisomer: 3.5 and 0.5 nM, respectively].     

‘Two-point’-bound supramolecular complexes from semi-rigidified dipyridine receptors and zinc porphyrins

Two linear compounds 1 and 2 have been designed and synthesized as new receptors for zinc porphyrins. Both compounds consist of two folded aromatic amide moieties, which are connected with an acetylene linker in 1 or directly in 2. The rigid conformations of their folded moieties are stabilized by intramolecular tri-centered hydrogen bonding, while the whole molecule adopts a ‘S’- or ‘C’-styled conformation depending on the relative orientation of the two rigid moieties. Two pyridine units are introduced at the ends of 1 and 2 for the complexation of zinc porphyrin guests. Although the ¹H NMR investigation indicated that both compounds can bind two zinc porphyrin guests at high concentrations (≥5 mM) in chloroform, the UV-vis studies revealed that, at low concentration of 1 and 2 (4 μM), both compounds complex one zinc porphyrin guest to form structurally unique ‘two-point’-bound 1:1 complexes. The association constants of the 1:1 complexes have been determined with the UV-vis titration experiments.