13‐Oxo‐9(Z),11(E),15(Z)‐octadecatrienoic Acid Activates Peroxisome Proliferator‐Activated Receptor γ in Adipocytes

Peroxisome proliferator‐activated receptor (PPAR)γ is expressed in adipose tissue and plays a key role in the regulation of adipogenesis. PPARγ activators are known to have potent antihyperglycemic activity and are used to treat insulin resistance associated with diabetes. Therefore, many natural and synthetic agonists of PPARγ are used in the treatment of glucose disorders. In the present study, we found that 13‐oxo‐9(Z),11(E),15(Z)‐octadecatrienoic acid (13‐oxo‐OTA), a linolenic acid derivative, is present in the extract of tomato (Solanum lycopersicum), Mandarin orange (Citrus reticulata), and bitter gourd (Momordica charantia). We also found that 13‐oxo‐OTA activated PPARγ and induced the mRNA expression of PPARγ target genes in adipocytes, thereby promoting differentiation. Furthermore, 13‐oxo‐OTA induced secretion of adiponectin and stimulated glucose uptake in adipocytes. To our knowledge, this is the first study to report that 13‐oxo‐OTA induces adipogenesis through PPARγ activation and to present 13‐oxo‐OTA as a valuable food‐derived compound that may be applied in the management of glucose metabolism disorders.     

Design and Synthesis of Highly Active Peroxisome Proliferator‐Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity

Based on 3‐(((4‐(hexylamino)‐2‐methoxyphenyl)amino)sulfonyl)‐2‐thiophenecarboxylic acid methyl ester (ST247, compound 2 ), a recently described peroxisome proliferator‐activated receptor (PPAR)β/δ‐selective inverse agonist, we designed and synthesized a series of structurally related ligands. The structural modifications presented herein ultimately resulted in a series of ligands that display increased cellular activity relative to 2 . Moreover, with methyl 3‐(N‐(2‐(2‐ethoxyethoxy)‐4‐(hexylamino)phenyl)sulfamoyl)thiophene‐2‐carboxylate (PT‐S264, compound 9 u ), biologically relevant plasma concentrations in mice were achieved. The compounds presented in this study will provide useful novel tools for future investigations addressing the role of PPARβ/δ in physiological and pathophysiological processes.     

5,8‐Dihydroxy‐9,12,15(Z,Z,Z)‐Octadecatrienoic Acid Production by Recombinant Cells Expressing Aspergillus nidulans Diol Synthase

Whole cells of recombinant Escherichia coli expressing diol synthase from Aspergillus nidulans produced 5,8‐dihydroxy‐9,12,15(Z,Z,Z)‐octadecatrienoic acid from α‐linolenic acid via 8‐hydroperoxy‐9,12,15(Z,Z,Z)‐octadecatrienoic acid as an intermediate. The optimal conditions for 5,8‐dihydroxy‐9,12,15(Z,Z,Z)‐octadecatrienoic acid production using whole recombinant cells were exhibited at pH 7.0, 40 °C, and 250 rpm with 40 g/L cells, 12 g/L, α‐linolenic acid, and 5 % (v/v) dimethyl sulfoxide in a 250‐mL baffled flask containing 50 mL reaction solution. Under these conditions, whole recombinant cells produced 9.1 g/L 5,8‐dihydroxy‐9,12,15(Z,Z,Z)‐octadecatrienoic acid for 100 min, with a conversion yield of 75 % (w/w), a volumetric productivity of 5.5 g/L/h, and specific productivity of 137 mg/g‐cells/h. As an intermediate, 8‐hydroperoxy‐9,12,15(Z,Z,Z)‐octadecatrienoic acid was observed at approximately 1.4 g/L after 100 min. With regard to dihydroxy fatty acid production, this is the highest reported volumetric and specific productivities thus far. This is the first report on the biotechnological production of 5,8‐dihydroxy‐9,12,15(Z,Z,Z)‐octadecatrienoic acid.     

Efficient Synthesis of β,γ‐Alkynyl α‐Amino Acid Derivatives by Ag(I)‐Catalyzed Alkynylation of α‐Imino Esters

The first catalytic synthesis of β,γ‐alkynyl α‐amino acid derivatives was achieved by direct addition of terminal alkynes to α‐imino esters in the presence of an Ag(I) salt under mild reaction conditions.     

Cationic copolymers of α,β‐poly‐(N‐2‐hydroxyethyl)‐DL‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy): synthesis and characterization

In the present study the derivatization of two water‐soluble synthetic polymers, α,β‐poly(N‐2‐hydroxyethyl)‐DL ‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy), with glycidyltrimethylammonium chloride (GTA) is described. This reaction permits the introduction of positive charges in the macromolecular chains of PHEA and PAHy in order to make easier the electrostatic interaction with DNA. Different parameters affect the reaction of derivatization, such as GTA concentration and reaction time. PHEA reacts partially and slowly with GTA; on the contrary the reaction of PAHy with GTA is more rapid and extensive. The derivatization of PHEA and PAHy with GTA is a convenient method to introduce positive groups in their chains and it permits the preparation of interpolyelectrolyte complexes with DNA. © 2000 Society of Chemical Industry     

Palladium(II)‐Catalyzed Aerobic Intermolecular Cyclization of Acrylic Acid with Alkenes to α‐Methylene‐γ‐butyrolactones

The methodology in this article is a palladium(II)/copper(II)‐ or palladium(II)‐catalyzed intermolecular cyclization of acrylic acid with alkenes to produce α‐methylene‐γ‐butyrolactone derivatives using molecular oxygen as an environmentally benign oxidant. In this system, the carboxylato, especially trifluoroacetato, or trimethylacetato ligand, plays a quite important role to afford a high catalytic activity by suppressing the deposition of palladium(0) black.     

Ruthenium(II)‐Catalyzed Protocol for Preparation of Diverse α,β‐ and β,β‐Dihaloenones from Diazodicarbonyls

Efficient one‐step syntheses of α,β‐ and β,β‐dihaloenones were achieved by ruthenium(II)‐catalyzed reactions between cyclic or acyclic diazodicarbonyl compounds and oxalyl chloride or oxalyl bromide in moderate to good yields. This methodology offers several significant advantages, which include ease of handling, mild reaction conditions, one‐step reaction, and the use of an effective and non‐toxic catalyst. The synthesized compounds were further transformed into highly functionalized novel molecules bearing aromatic rings on the enone moiety using the Suzuki reaction.

     

Asymmetric Synthesis of 3,4‐Dihydrocoumarins Bearing an α,α‐Disubstituted Amino Acid Moiety

An organocatalytic approach for the stereoselective synthesis of 3,4‐dihydrocoumarins with an α,α‐disubstituted amino acid moiety incorporated is presented. The developed methodology is based on the cascade reaction between α‐substituted azlactones and 2‐hydroxychalcones. It is initiated by a chiral Brønsted base‐catalyzed enantio‐ and diastereoselective Michael reaction followed by the azlactone ring opening to construct a 3,4‐dihydrocoumarin framework. Products bearing two adjacent stereogenic centers, one being quaternary, were formed with high enantioselectivities and excellent diastereoselectivities. Furthermore, the complete regioselectivity of the new cascade reactivity is worthy of notice.

     

Antioxidant and prooxidant effects of α‐tocopherol in a linoleic acid‐copper(II)‐ascorbate system

The peroxidation of linoleic acid (LA) in the absence and presence of either Cu(II) ions alone or Cu(II)‐ascorbate combination was investigated in aerated and incubated emulsions at 37°C and pH 7. LA peroxidation induced by either copper(II) or copper(II)‐ascorbic acid system followed pseudo‐first order kinetics with respect to primary (hydroperoxides) and secondary (aldehydes‐ and ketones‐like) oxidation products, detected by ferric‐thiocyanate and TBARS tests, respectively. α‐Tocopherol showed both antioxidant and prooxidant effects depending on concentration and also on the simultaneous presence of Cu(II) and ascorbate. Copper(II)‐ascorbate combinations generally led to distinct antioxidant behavior at low concentrations of α‐tocopherol and slight prooxidant behavior at high concentrations of α‐tocopherol, probably associated with the recycling of tocopherol by ascorbate through reaction with tocopheroxyl radical, while the scavenging effect of α‐tocopherol on lipid peroxidation was maintained as long as ascorbate was present. On the other hand, in Cu(II) solutions without ascorbate, the antioxidant behavior of tocopherol required higher concentrations of this compound because there was no ascorbate to regenerate it. Practical applications: Linoleic acid (LA) peroxidation induced by either copper(II) or copper(II)‐ascorbic acid system followed pseudo‐first order kinetics with respect to primary (hydroperoxides) and secondary (e.g., aldehydes and ketones) oxidation products. α‐Tocopherol showed both antioxidant and prooxidant effects depending on concentration and also on the simultaneous presence of Cu(II) and ascorbate. The findings of this study are believed to be useful to better understand the actual role of α‐tocopherol in the preservation of heterogenous food samples such as lipid emulsions. Since α‐tocopherol (vitamin E) is considered to be physiologically the most important lipid‐soluble chain‐breaking antioxidant of human cell membranes, the results can be extended to in vivo protection of lipid oxidation.     

Friedel–Crafts Reaction of Indoles with Isatin‐Derived β,γ‐Unsaturated α‐Keto Esters Using a BINOL‐Derived Bisoxazoline (BOX)/Copper(II) Complex as Catalyst

Several chiral BINOL‐derived bisoxazoline (BOX)/copper(II) complexes were synthesized and evaluated as catalysts for the Friedel–Crafts reaction of indoles with isatin‐derived β,γ‐unsaturated α‐keto esters. The resulting bis‐indole products bearing a quaternary stereocenter were obtained in excellent yields and enantioselectivities. Additionally, the desired products were practically transformed to α‐amino esters, α‐hydroxy esters and α‐keto amides. It is noteworthy that this catalytic procedure was conducted with a catalyst loading of 0.5 mol% without any discernible decrease in the reactivity or enantioselectivity.

     

Discovery of α‐Substituted Imidazole‐4‐acetic Acid Analogues as a Novel Class of ρ1 γ‐Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone

The ρ‐containing γ‐aminobutyric acid type A receptors (GABA_ARs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABA_ARs are of interest. In this study, we demonstrate that the partial GABA_AR agonist imidazole‐4‐acetic acid (IAA) is able to penetrate the blood–brain barrier in vivo; we prepared a series of α‐ and N‐alkylated, as well as bicyclic analogues of IAA to explore the structure–activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l ‐histidine by an efficient minimal‐step synthesis, and their pharmacological properties were characterized at native rat GABA_ARs in a [³H]muscimol binding assay and at recombinant human α₁β₂γ_2S and ρ₁ GABA_ARs using the FLIPR? membrane potential assay. The (+)‐α‐methyl‐ and α‐cyclopropyl‐substituted IAA analogues ((+)‐ 6 a and 6 c , respectively) were identified as fairly potent antagonists of the ρ₁ GABA_AR that also displayed significant selectivity for this receptor over the α₁β₂γ_2S GABA_AR. Both 6 a and 6 c were shown to inhibit GABA‐induced relaxation of retinal arterioles from porcine eyes.     

Interface formation of Ca with poly(p-phenylene α,α′-diphenyl vinylene) and poly(p-phenylene α-phenyl vinylene)

We have investigated the interface formation of Ca with poly(p-phenylene α,α′-diphenyl vinylene) (PPV-DP) and poly(p-phenylene α-phenyl vinylene) (PPV-P) using X-ray photoemission spectroscopy (XPS). Similarly to our earlier findings in metal/PPV interface formation, the O 1s peak shifted toward a lower binding energy as soon as Ca was deposited on to the polymers. This was accompanied by the formation of Ca? O, suggesting a chemical origin for the O 1s shift. By contrast, the C 1s peak shift toward a lower binding energy was observed relatively later, after about 4 Å of Ca deposition. At the same time, a new C 1s component became noticable at about ?1.5 eV relative to the initial C 1s peak. This component signifies the possibility of polymer disruption by the Ca atoms to form Ca? C species. The C 1s peak shift is attributed to Ca induced surface band bending and barrier formation as in the case of metal/PPV interface formation. The disruption of the polymer may also induce changes in the interface electronic states and contribute to the C 1s peak shift. From the intensity attenuation analysis, we conclude that the initial 15 Å of Ca overlayer is contaminated by the Ca? O and Ca? C species and the overlayer is pure beyond 15 Å of Ca coverage.     

Derivation of a Retinoid X Receptor Scaffold from Peroxisome Proliferator‐Activated Receptor γ Ligand 1‐Di(1H‐indol‐3‐yl)methyl‐4‐trifluoromethylbenzene

PPARγ agonist DIM‐Ph‐4‐CF ₃ , a template for RXRα agonist (E)‐3‐[5‐di(1‐methyl‐1H‐indol‐3‐yl)methyl‐2‐thienyl] acrylic acid: DIM‐Ph‐CF₃ is reported to inhibit cancer growth independent of PPARγ and to interact with NR4A1. As both receptors dimerize with RXR, and natural PPARγ ligands activate RXR, DIM‐Ph‐4‐CF₃ was investigated as an RXR ligand. It displaces 9‐cis‐retinoic acid from RXRα but does not activate RXRα. Structure‐based direct design led to an RXRα agonist.

     

Infrared spectra of γ‐irradiated poly(acrylic acid)–polyacrylamide complex

Samples of polyacrylamide (PAAm), poly(acrylic acid) (PAA), and their complex were γ‐irradiated at different doses, namely 48, 96, and 144 KGy. The examination of the infrared spectra of these samples showed that there are no significant observable changes in their spectral features apart from slight changes in the intensities of the absorption bands. The analysis of the absorbances ratios (A 1700 cm^?1/A 1450 cm^?1) and (A 1650 cm^?1/A 1450 cm^?1), denoted as R₁ and R₂, respectively, showed that these ratios depend on γ‐doses. It was found that in the case of PAA, R₁ assumed linear increase with increasing the dose to 96 KGy and then showed marked decrease. For the complex, R₁ increased slightly by increasing the dose to 96 KGy and then decreased. For PAAm, although irradiation with 48 KGy increases the values of R₂, irradiation with 96 and 144 KGy decreases its value. On the other hand, for the complex, R₂ suggested slight decrease on irradiation with 48 KGy followed by continued increases with increasing the dose up to 144 KGy. The increase in R₁ and R₂ may be due to crosslinking as a result of the formation of free radicals. The decrease in these ratios after irradiation with 96 KGy may be due to degradation. It was concluded that γ‐irradiation has a lower effect on the complex (i.e., the complex has a structure which is different from those of PAA and PAAm). © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 85: 1619–1623, 2002     

Polyaniline doped with α, ω‐alkanedisulfonic acids: preparation and characterization

The use of α, ω‐alkanedisulfonic acid, HO₃S(CH₂)_nSO₃H (n = 1, 4, 6 and 12), as a dopant for polyaniline (PANi) was investigated. This series of disulfonic acids with varying chain lengths were synthesized and used in the doping of PANi. The doped polymers showed conductivity in the range 10^?2 to 10^?1 S cm^?1. Thermal studies showed that the doped polymers, depending on the chain length of α,ω‐alkanedisulfonic acid, were stable up to ca 300 °C and the thermal stability decreased with increasing dopant chain length. The thermal stability of α,ω‐alkanedisulfonic acid‐doped PANi was higher than that of alkanesulfonic acid‐doped PANi which typically degrades around 250 °C, suggesting a moderately broader processing window for α,ω‐alkanedisulfonic acid‐doped PANi for blending with other thermoplastics. Copyright © 2012 Society of Chemical Industry     

Multi‐Enzymatic Synthesis of Optically Pure β‐Hydroxy α‐Amino Acids

A novel enzymatic production system of optically pure β‐hydroxy α‐amino acids was developed. Two enzymes were used for the system: an N‐succinyl L ‐amino acid β‐hydroxylase (SadA) belonging to the iron(II)/α‐ketoglutarate‐dependent dioxygenase superfamily and an N‐succinyl L ‐amino acid desuccinylase (LasA). The genes encoding the two enzymes are part of a gene set responsible for the biosynthesis of peptidyl compounds found in the Burkholderia ambifaria AMMD genome. SadA stereoselectively hydroxylated several N‐succinyl aliphatic L ‐amino acids and produced N‐succinyl β‐hydroxy L ‐amino acids, such as N‐succinyl‐L ‐β‐hydroxyvaline, N‐succinyl‐L ‐threonine, (2S,3R)‐N‐succinyl‐L ‐β‐hydroxyisoleucine, and N‐succinyl‐L ‐threo‐β‐hydroxyleucine. LasA catalyzed the desuccinylation of various N‐succinyl‐L ‐amino acids. Surprisingly, LasA is the first amide bond‐forming enzyme belonging to the amidohydrolase superfamily, and has succinylation activity towards the amino group of L ‐leucine. By combining SadA and LasA in a preparative scale production using N‐succinyl‐L ‐leucine as substrate, 2.3 mmol of L ‐threo‐β‐hydroxyleucine were successfully produced with 93% conversion and over 99% of diastereomeric excess. Consequently, the new production system described in this study has advantages in optical purity and reaction efficiency for application in the mass production of several β‐hydroxy α‐amino acids.

     

Synthesis of (E)‐α,β‐Unsaturated Carbonyls via Silver‐Catalyzed Tandem Epoxide Rearrangement/Intermolecular Carbonyl‐ Heteroalkyne Metathesis

A regio‐ and stereoselective method for the synthesis of (E)‐α,β‐unsaturated carbonyls has been developed via a silver‐catalyzed tandem epoxide rearrangement/intermolecular carbonyl‐heteroalkyne metathesis. Various heteroalkynes including ynol ethers, ynamides, and thioalkynes work well for this transformation, leading to the production of (E)‐α,β‐unsaturated esters, amides, and thioesters in moderate to excellent yields with good functional group compatibility. It represents one of the rare examples of regio‐ and stereoselective intermolecular alkyne‐carbonyl metathesis (ACM).