Building Flexible Escherichia coli Modules for Bifunctionalizing n-Octanol: The Byproduct of Oleic Acid Biorefinery.

Artificial biorefinery of oleic acid into 1,10-decanedioic acid represents a revolutionizing route to the sustainable production of chemically difficult-to-make bifunctional chemicals. However, the carbon atom economy is extremely low (56%) due to the formation of unifunctional n-octanol. Here, we report a panel of recombinant Escherichia coli modules for diverse bifunctionalization, where the desired genetic parts are well distributed into different modules that can be flexibly combined in a plug-and-play manner. The designed ω-functionalizing modules could achieve ω-hydroxylation, consecutive ω-oxidation, or ω-amination of n-octanoic acid. By integrating these advanced modules with the reported oleic acid-cleaving modules, high-value C8 and C10 products, including ω-hydroxy acid, ω-amino acid, and α,ω-dicarboxylic acid, were produced with 100% carbon atom economy. These ω-functionalizing modules enabled the complete use of all of the carbon atoms from oleic acid (released from plant oil) for the green synthesis of structurally diverse bifunctional chemicals.

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia.

MGS0274 besylate is an ester-based lipophilic prodrug of a metabotropic glutamate (mGlu) 2 and mGlu3 receptor agonist MGS0008 and being developed for the treatment of schizophrenia. We investigated the disposition of these compounds in rats and monkeys and in vitro metabolism in humans to evaluate whether MGS0274 besylate could be useful as a prodrug in humans. After the oral administration of MGS0274 besylate to monkeys (2.89 mg/kg), MGS0008 was immediately found in plasma, reached a maximum concentration at 4 hours postdose, and decreased with a terminal half-life of 16.7 hours; MGS0274 was barely detectable. The oral bioavailability as MGS0008 was 83.7%, which was approximately 20-fold greater than that after oral dosing of MGS0008 (3.8%). In rats, MGS0008 penetrated the cerebrospinal fluid and was eliminated slower than from plasma. The in vitro metabolism study indicated that MGS0274 was rapidly hydrolyzed to MGS0008, which was not further metabolized. After the intravenous administration of MGS0008 to rats and monkeys, almost all the dose was excreted unchanged in urine. These results suggested that MGS0274 was, as expected, presystemically hydrolyzed to MGS0008 after gastrointestinal absorption and that MGS0008 was distributed throughout the body without further metabolism and ultimately excreted in urine in the animals. Furthermore, the hydrolytic activity against MGS0274 in the human liver S9 fraction was comparable to that in monkeys, suggesting the possibility of the rapid presystemic hydrolysis of MGS0274 to MGS0008 in humans, as it is in monkeys. Consequently, MGS0274 besylate is expected to function as a preferable prodrug in humans.

Identification of Fatty Acid Binding Protein 5 Inhibitors Through Similarity-Based Screening.

Fatty acid binding protein 5 (FABP5) is a promising target for development of inhibitors to help control pain and inflammation. In this work, computer-based docking (DOCK6 program) was employed to screen ∼2 M commercially available compounds to FABP5 based on an X-ray structure complexed with the small molecule inhibitor SBFI-26 previously identified by our group (also through virtual screening). The goal was discovery of additional chemotypes. The screen resulted in the purchase of 78 candidates, which led to the identification of a new inhibitor scaffold (STK-0) with micromolar affinity and apparent selectivity for FABP5 over FABP3. A second similarity-based screen resulted in three additional hits (STK-15, STK-21, STK-22) from which preliminary SAR could be derived. Notably, STK-15 showed comparable activity to the SBFI-26 reference under the same assay conditions (1.40 vs 0.86 µM). Additional molecular dynamics simulations, free energy calculations, and structural analysis (starting from DOCK-generated poses) revealed that R enantiomers (dihydropyrrole scaffold) of STK-15 and STK-22 have a more optimal composition of functional groups to facilitate additional H-bonds with Arg109 of FABP5. This observation suggests enantiomerically pure compounds could show enhanced activity. Overall, our study highlights the utility of using similarity-based screening methods to discover new inhibitor chemotypes, and the identified FABP5 hits provide a strong starting point for future efforts geared to improve activity.

Robust and nanoparticle-free superhydrophobic cotton fabric fabricated from all biological resources for oil/water separation.

Traditional superhydrophobic cotton fabrics (SCFs) for oil/water separation were usually fabricated by surface coating with inorganic nanoparticles combined with nonrenewable and nonbiodegradable or even toxic fossil-based chemicals, which would lead to secondary environmental pollution after their lifetime. In this study, we report robust, nanoparticle-free, fluorine-free SFC, which was prepared by acid etching followed by surface coating with epoxidized soybean oil resin (CESO) and subsequent modification with stearic acid (STA). No toxic compound and no nanoparticle were included within the SCF and all the raw materials including cotton fabric, CESO and STA are biodegradable and derived from biological resources. The SCF showed excellent mechanical stability and chemical/environmental resistances. The superhydrophobicity of the SFC survived from mechanical abrasion, tape peeling, ultrasonication, solvent erosion and low/high temperature exposure. The SCF also exhibited good acid/alkali resistance with contact angle over 150° toward different pH water droplets. Moreover, the SCF could efficiently separate oil/water mixtures with efficiency above 97.9% and the superhydrophobicity remained after reusing for at least 10 times. The fully biological-derived SCF with excellent mechanical and chemical resistances exhibit great potential for separation of oil/water mixtures.

Pyrrolizidine Alkaloids: Biosynthesis, Biological Activities and Occurrence in Crop Plants.

Pyrrolizidine alkaloids (PAs) are heterocyclic secondary metabolites with a typical pyrrolizidine motif predominantly produced by plants as defense chemicals against herbivores. They display a wide structural diversity and occur in a vast number of species with novel structures and occurrences continuously being discovered. These alkaloids exhibit strong hepatotoxic, genotoxic, cytotoxic, tumorigenic, and neurotoxic activities, and thereby pose a serious threat to the health of humans since they are known contaminants of foods including grain, milk, honey, and eggs, as well as plant derived pharmaceuticals and food supplements. Livestock and fodder can be affected due to PA-containing plants on pastures and fields. Despite their importance as toxic contaminants of agricultural products, there is limited knowledge about their biosynthesis. While the intermediates were well defined by feeding experiments, only one enzyme involved in PA biosynthesis has been characterized so far, the homospermidine synthase catalyzing the first committed step in PA biosynthesis. This review gives an overview about structural diversity of PAs, biosynthetic pathways of necine base, and necic acid formation and how PA accumulation is regulated. Furthermore, we discuss their role in plant ecology and their modes of toxicity towards humans and animals. Finally, several examples of PA-producing crop plants are discussed.

Application of novel catalytic-ceramic-filler in a coupled system for long-chain dicarboxylic acids manufacturing wastewater treatment.

To gain systematic technology for long-chain dicarboxylic acids (LDCA) manufacturing wastewater treatment, catalytic micro-electrolysis (CME) coupling with adsorption-biodegradation sludge (AB) process was studied. Firstly, novel catalytic-ceramic-filler was prepared from scrap iron, clay and copper sulfate solution and packed in the CME reactor. To remove residual n-alkane and LDCA, the CME reactor was utilized for LDCA wastewater pretreatment. The results revealed that about 94% of n-alkane, 98% of LDCA and 84% of chemical oxygen demand (COD) were removed by the aerated CME reactor at the optimum hydraulic retention time (HRT) of 3.0 h. In this process, catalysis from Cu and montmorillonites played an important role in improving the contaminants removal. Secondly, to remove residual COD in the wastewater, AB process was designed for the secondary biological treatment, about 90% of the influent COD could be removed by biosorption, bio-flocculation and biodegradation effects. Finally, the effluent COD (about 150 mg L(-1)) discharged from the coupled CME-AB system met the requirement of the national discharged standard (COD ≤ 300 mg L(-1)). All of these results suggest that the coupled CME-AB system is a promising technology due to its high-efficient performance, and has the potential to be applied for the real LDCA wastewater treatment.

Redox-responsive polyanhydride micelles for cancer therapy.

Biodegradable polyanhydrides possess unique features like those that they can predominantly undergo surface erosion, and the payloads can be released by a steady speed. However, there is little work that has been published to describe the polyanhydride micelles with redox-responsiveness as a nanocarrier for drug delivery. In this study, we develop one type of new amphiphilic polyanhydride copolymer containing disulfide bonds between the hydrophilic and hydrophobic segments. The copolymer can self-assemble into stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 69 nm. The disassembly behaviors of the micelles triggered by glutathione are evaluated from the changes of the micellar size, morphology and molecular weight. An approximate zero-order in vitro drug release mode with a fast speed can be achieved in a reducing and acid environment similar with that of tumor cells. In vitro cytotoxicity analysis demonstrate that the Cur-loaded micelles are of great efficiency in inhibiting the growth of cancer cells due to the rapidly intracellular delivery of therapeutic agent. Both the qualitative and quantitative results of the antitumor activity in 4T1 tumor-bearing BALB/c mice reveal that the redox-responsive micelles have a more significant therapeutic effect to artificial solid tumor compared to the redox-insensitive micelles. This study provides a new insight into the biomedical application of polyanhydrides in drug delivery.

Renewable non-isocyanate based thermoplastic polyurethanes via polycondensation of dimethyl carbamate monomers with diols.

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed polycondensation reactions of fatty acid derived dimethyl dicarbamates and diols are introduced as a versatile, non-isocyanate route to renewable polyurethanes. The key step for the synthesis of dimethyl carbamate monomers from plant-oil-derived dicarboxylic acids is based on a sustainable base-catalyzed Lossen rearrangement. The formed polyurethanes with molecular weights up to 25 kDa are characterized by SEC, DSC, and NMR analysis.

Series of uranyl-4,4'-biphenyldicarboxylates and an occurrence of a cation-cation interaction: hydrothermal synthesis and in situ Raman studies.

Three uranium(VI)-bearing materials were synthesized hydrothermally using the organic ligand 4,4'-biphenyldicarboxylic acid: (UO2)(C14O4H8) (1); [(UO2)2(C14O4H8)2(OH)]·(NH4)(H2O) (2); (UO2)2(C14O4H8)(OH)2 (3). Compound 1 was formed after 1 day at 180 °C in an acidic environment (pH(i) = 4.03), and compounds 2 and 3 coformed after 3 days under basic conditions (pH(i) = 7.95). Coformation of all three compounds was observed at higher pH(i) (9.00). Ex situ Raman spectra of single crystals of 1-3 were collected and analyzed for signature peaks. In situ hydrothermal Raman data were also obtained and compared to the ex situ Raman spectra of the title compounds in an effort to acquire formation mechanism details. At pH(i) = 4.00, the formation of 1 was suggested by in situ Raman spectra. At an increased pH(i) (7.90), the in situ data implied the formation of compounds 1 and 3. The most basic conditions (pH(i) = 9.00) yielded a complex mixture of phases consistent with that of increased uranyl hydrolysis.

Chiral uranyl-organic compounds assembled with achiral furandicarboxylic acid by spontaneous resolution.

Influenced by different cations in the self-assembly of chiral units, achiral (UOC-NH4, UOC-Ca) and chiral (UOC-Na) uranyl-organic compounds were obtained from achiral reactants. The photocatalytic activity of UOC-Na was also investigated.

Multistep enzymatic synthesis of long-chain α,ω-dicarboxylic and ω-hydroxycarboxylic acids from renewable fatty acids and plant oils.

A multistep enzyme catalysis was successfully implemented to produce long-chain α,ω-dicarboxylic and ω-hydroxycarboxylic acids from renewable fatty acids and plant oils. Sebacic acid as well as ω-hydroxynonanoic acid and ω-hydroxytridec-11-enoic acid were produced from oleic and ricinoleic acid.

AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism.

ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid ß-oxidation. However, the molecular mechanism(s) mediating these activities remained undefined. Studies described here show that ETC-1002 free acid activates AMP-activated protein kinase in a Ca(2+)/calmodulin-dependent kinase ß-independent and liver kinase ß 1-dependent manner, without detectable changes in adenylate energy charge. Furthermore, ETC-1002 is shown to rapidly form a CoA thioester in liver, which directly inhibits ATP-citrate lyase. These distinct molecular mechanisms are complementary in their beneficial effects on lipid and carbohydrate metabolism in vitro and in vivo. Consistent with these mechanisms, ETC-1002 treatment reduced circulating proatherogenic lipoproteins, hepatic lipids, and body weight in a hamster model of hyperlipidemia, and it reduced body weight and improved glycemic control in a mouse model of diet-induced obesity. ETC-1002 offers promise as a novel therapeutic approach to improve multiple risk factors associated with metabolic syndrome and benefit patients with cardiovascular disease.

Fragment-based discovery of novel and selective mPGES-1 inhibitors Part 1: identification of sulfonamido-1,2,3-triazole-4,5-dicarboxylic acid.

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase that catalyzes the conversion of prostaglandin PGH(2) to PGE(2) and represents a novel target for therapeutic treatment of inflammatory disorders. It is essential to identify mPGES-1 inhibitor with novel scaffold as new hit or lead compound for the purpose of the next-generation anti-inflammatory drugs. Herein we report the discovery of sulfonamido-1,2,3-triazole-4,5-dicarboxylic derivatives as a novel class of mPGES-1 inhibitors identified through fragment-based virtual screening and in vitro assays on the inhibitory activity of the actual compounds. 1-[2-(N-Phenylbenzenesulfonamido)ethyl]-1H-1,2,3-triazole-4,5-dicarboxylic acid (6f) inhibits human mPGES-1 (IC(50) of 1.1 µM) with high selectivity (ca.1000-fold) over both COX-1 and COX-2 in a cell-free assay. In addition, the activity of compound 6f was again tested at 10 µM concentration in presence of 0.1% Triton X-100 and found to be reduced to 1/4 of its original activity without this detergent. Compared to the complete loss of activity of nuisance inhibitor with the detergent, therefore, compound 6f would be regarded as a partial nuisance inhibitor of mPGES-1 with a novel scaffold for the optimal design of more potent mPGES-1 inhibitors.

A low energy electron microscopy study of the initial growth, structure, and thermal stability of 4,4'-biphenyldicarboxylic acid domains on Cu(001).

The growth of 4,4(')-biphenyldicarboxylic acid (BDA) on Cu(001) has been studied using low energy electron microscopy and selective area low energy electron diffraction. The emergence of large islands and hydrogen bonding to perpendicularly oriented, adjacent molecules is confirmed. The two benzene rings of adsorbed BDA are twisted along the molecular axis. Unconventional growth of the domains, followed by a second nucleation stage, is observed at room temperature. This unanticipated feature is attributed to the accumulation of stress in the islands. Ostwald ripening in the films and the decay of BDA domains at 448 K exhibits features that are consistent with diffusion limited behavior.

Aerosol volatility and enthalpy of sublimation of carboxylic acids.

The enthalpy of sublimation has been determined for nine carboxylic acids, two cyclic (pinonic and pinic acid) and seven straight-chain dicarboxylic acids (C(4) to C(10)). The enthalpy of sublimation was determined from volatility measurements of nano aerosol particles using a volatility tandem differential mobility analyzer (VTDMA) set-up. Compared to the previous use of a VTDMA, this novel method gives enthalpy of sublimation determined over an extended temperature range (DeltaT approximately 40 K). The determined enthalpy of sublimation for the straight-chain dicarboxylic acids ranged from 96 to 161 kJ mol(-1), and the calculated vapor pressures at 298 K are in the range of 10(-6)-10(-3) Pa. These values indicate that dicarboxylic acids can take part in gas-to-particle partitioning at ambient conditions and may contribute to atmospheric nucleation, even though homogeneous nucleation is unlikely. To obtain consistent results, some experimental complications in producing nanosized crystalline aerosol particles were addressed. It was demonstrated that pinonic acid "used as received" needed a further purification step before being suspended as a nanoparticle aerosol. Furthermore, it was noted from distinct differences in thermal properties that aerosols generated from pimelic acid solutions gave two types of particles. These two types were attributed to crystalline and amorphous configurations, and based on measured thermal properties, the enthalpy of vaporization was 127 kJ mol(-1) and that of sublimation was 161 kJ mol(-1). This paper describes a new method that is complementary to other similar methods and provides an extension of existing experimental data on physical properties of atmospherically relevant compounds.

Control of alpha-alumina surface charge with carboxylic acids.

In this work, we studied the surface charge of alpha-alumina treated with carboxylic acids with different carbon chain length. The results show the possibility of controlling surface charges of alumina by using different concentrations of carboxylic acids or changing the size of the carbon chain of the acids. We also report that part of the acid found on the surface is strongly bound, therefore making it possible to obtain pH-resistant samples of alpha-alumina with an isoelectric point (IEP) of 5.5. It is found, that IEP values obtained for modified samples have a linear correlation with the number of carbon atoms of dicarboxylic acids for up to five carbon atoms. From a practical perspective, the method presented in this work has many advantages. First, it maintains the same hydrophilicity of the alumina surface. Second, the modification of the surface is stable in a long-range of pH. Finally, the presented method is easy-to-use and cheap, as the modification consists of only two simple steps carried out at low temperatures with inexpensive and nontoxic reagents.

Expedient synthesis of pyrrolo[1,2-a]indoles: preparation of the core of yuremamine.

Pyrrolo[1,2- a]indoles are conveniently prepared from tetrahydro-1,2-oxazines, which in turn are generated through the reaction of nitrones with 1,1-cyclopropanediesters. The synthetic route proves to be highly diastereoselective and provides access to the core of the recently discovered pyrrolo[1,2- a]indole natural product yuremamine.

Sequestering ability of polycarboxylic ligands towards dioxouranium(VI).

In this paper we report a comparison on the sequestering ability of some polycarboxylic ligands towards dioxouranium(VI) (UO(2)(2+), uranyl). Ligands taken into account are mono- (acetate), di- (oxalate, malonate, succinate and azelate), tri- (1,2,3-propanetricarboxylate) and hexa-carboxylate (1,2,3,4,5,6-benzenehexacarboxylate). The sequestering ability of polycarboxylic ligands towards UO(2)(2+) was quantified by a new approach expressed by means of a sigmoid Boltzman type equation and of a empirical parameters (pL(50)) which defines the amount of ligand necessary to sequester 50% of the total UO(2)(2+) concentration. A fairly linear correlation was obtained between pL(50) or log K(110) (log K(110) refers to the equilibrium: UO(2)(2+)+L(z-)=UO(2)L((2-z)); L=generic ligand) and the polyanion charges. In order to complete the picture, a tetra-carboxylate ligand (1,2,3,4-butanetetracarboxylate) was studied in NaCl aqueous solutions at 0

[Studies on chemical constituents from Zephyranthes candida].

OBJECTIVE: To study on the chemical constituents of Zephyranthes candida. METHODS: Compounds were isolated and repeatedly purified by chromatographic techniques on silica gel column. Their structures were elucidated by chemical and spectral methods. RESULTS: Eight compounds were isolated from the whole plant of Zephyranthes candida, and identified as (2S)-3',7-dihydroxy-4'-methoxyflavan (I), beta-sitosterol (II), stigmasta-5,22-dien-3beta-ol (III), stigmasterol (IV), beta-daucosterin (V), Butylisobutyl phthalat (VI), Heptacosane (VII) and Ambrettolide (VIII). CONCLUSION: I-XIII are all isolated from this plant for the first time.

[Isolation and structure identification of chemical constituents from the skin of Bufo bufo gargarizans].

The skin of Bufo bufo gargarizans, originated from Bufo bufo gargarizans Cantor (Bufonidae), is widely used in traditional Chinese medicine for the treatment of hepatoma, lung cancer and etc. The preparation of the aqueous components has significant therapeutic effect against the digestive tract cancer. The water-soluble chemical constituents in the skin of Bufo bufo gargarizans were then investigated to make clear the active compounds. Six compounds were isolated and purified by recrystallization and column chromatography on silica gel and ODS, their structures were elucidated as 4-amido-3-hydroxymethyl-cyclooctylamidezotetra-alpha-furanone (I), bufogargarizanine C (II), bufothionine (III), dehydrobufotenine hydrobromide (IV), suberic acid (V) and succinic acid (VI) on the basis of physicochemical properties and spectral data (UV, IR, 1H NMR, 13C NMR and MS). Of the above compounds, compounds I and II are new compounds and named bufogargarizanine B and C, respectively.