Ethyl Side Chain Research Articles

Ethyl 2-[1-(4-chlorophenyl)-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1′,2′:1,2]pyrimidino[5,4-b][1]benzofuran-3-yl]acetate

The asymmetric unit of the title compound, C22H16ClN3O5, consists of two crystallographically independent mol­ecules. The fused rings of the imidazo[1,2-a]benzo[4,5]furo[3,2-d]pyrimidine system are nearly coplanar and the chlorophenyl rings are twisted with respect to the two pyrimidinone ring systems by 71.00 (2) and 62.59 (2)°. The C atoms of the ethyl side chain are disordered and were refined using a split model. In the crystal structure, the mol­ecules are connected via weak intra- and inter­molecular C—H⋯O inter­actions are present. The ethyl group in one molecule is disordered over two positions, with site occupancy factors 0.55 and 0.45; in the other molecule only the methyl group is disordered over two positions, with site occupancy factors 0.6 and 0.4.

Redetermination of tris(ethyl carbazate-κ2N,O)cobalt(II) dinitrate

The present study of the title compound, [Co(C3H8N2O2)3](NO3)2, probably represents a correction to that reported by Zhang, Song, Zhang, Ma & Yu [Z. Naturforsch. Teil B (2005), 60, 505–510] with a doubled a axis. As modelled here, there are four independent cations, each built up around a fac-CoN3O3 octa­hedron, and eight anions in the asymmetric unit. Two of the cations show disorder in one of their ethyl side chains in ratios of 0.712 (10):0.288 (10) and 0.612 (7):0.388 (8). Numerous cation-to-anion N—H⋯O hydrogen bonds, many of which are bifurcated, help to establish the crystal packing.

Synthesis and adenosine receptor binding studies of some novel triazolothienopyrimidines

A new series of 5-alkyl/aryl-8,9-dimethyl/8,9,10,11-tetrahydro[1]benzothieno[3,2- e][1,2,4]triazolo[4,3- c]pyrimidine-3(2 H)-thiones ( 4a– k) have been synthesized through a facile cyclization reaction of 4-hydrazino-2-alkyl/aryl-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3- d]pyrimidines ( 3a– k) using carbon disulphide under basic conditions. 4-Hydrazino-2-alkyl/aryl-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3- d]pyrimidines ( 3a– k) were prepared by replacing the chloro group of 4-chloro-2-substituted-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3- d]pyrimidines ( 2a– k) with hydrazine hydrate which were obtained by a known one-pot synthesis. The affinities of these compounds for adenosine A 1/A 2A receptors were determined at 1 μM concentration. The test compounds which exhibited more than 20% inhibition were selected and further screened at six different concentration levels to estimate their EC 50/ K i values. The most potent compounds in the series were 4c and 4d having an ethyl side chain at C 5 position with dimethyl and cyclohexyl substitution at the C 8–C 9 positions, exhibiting K i values of 2.1 and 1.1 μM, respectively, at A 1ARs. The SAR indicates that by increasing or decreasing the alkyl chain length at C 5 led to reduced affinity. The remaining aryl/arylalkyl derivatives of the series were inactive showing that a simple alkyl side chain at C 5 is necessary for these ligands to bind at A 1ARs. However, none of the compounds showed inhibition on A 2A receptors at 1 μM concentration indicating their selectivity. This communication describes the design, synthesis and evaluation of these new molecules.

Surface free energies of isotactic polybutene-1 tetragonal and trigonal crystals: the role of conformational entropy of side chains

Lateral and end surface free energies of melt-crystallized isotactic polybutene-1 (it-PB1) trigonal and tetragonal crystals have been determined by small-angle X-ray scattering and in situ observation of the crystal growth kinetics. The lateral surface free energy σ of the trigonal phase is about seven times as large as the value σHoff calculated according to Hoffman's equation [Hoffman (1992). Polymer, 33, 2643–2644], while that of the tetragonal phase is roughly in agreement with the estimation. The discrepancy between the values of σ and σHoff for the trigonal phase can be attributed to the loss of conformational entropy of the ethyl side chains of it-PB1.

Synthesis and biological evaluation of ( R)- N-(diarylmethylthio/sulfinyl)ethyl/propyl-piperidine-3-carboxylic acid hydrochlorides as novel GABA uptake inhibitors

A series of new ( R)-1-(2-diarylmethylthio/sulfinyl)ethyl-piperidine-3-carboxylic acid hydrochlorides 5a– d/ 6a– d and ( R)-1-(3-diarylmethylthio)propyl-piperidine-3-carboxylic acid hydrochlorides 5′ a– d were synthesized and evaluated as γ-aminobutyric acid uptake inhibitors through cultured cell lines expressing mouse GAT1. Biological screening results demonstrated that the compounds 6a– d with diarylmethylsulfinyl ethyl side chain show more potent GAT1 inhibitory activities than 5a– d/ 5′ a– d with diarylmethylthio ethyl/propyl moieties. Some of them, such as 6a, exhibited excellent inhibitions of [ 3H]-GABA uptake in cultured cells, which is 496-fold higher than ( R)-nipecotic acid and 11.5 times less than tiagabine. The synthesis and structure–activity relationships are discussed.

DNA Adduct Formation in the Livers of Female Sprague−Dawley Rats Treated with Toremifene or α-Hydroxytoremifene

Toremifene, an analogue of tamoxifen in which the ethyl side chain has been replaced with a 2-chloroethyl substituent, is used as a chemotherapeutic agent in postmenopausal women with advanced breast cancer. Toremifene is metabolized in a manner similar to that of tamoxifen, with alpha-hydroxytoremifene being a predominant metabolite in incubations in vitro. DNA adducts have been detected previously in liver DNA upon the administration of toremifene to rats; however, the identity of these adducts is unknown. In the present study, we have characterized the DNA adducts produced by alpha-hydroxytoremifene and have compared the extent of hepatic DNA adduct formation in rats administered toremifene, alpha-hydroxytoremifene, or tamoxifen. alpha-Hydroxytoremifene was synthesized, further activated by sulfation, and then reacted with salmon testis DNA. After enzymatic hydrolysis to deoxynucleosides, HPLC analysis indicated the formation of two major DNA adducts, which were characterized as (E)- and (Z)-alpha-(deoxyguanosin-N2-yl)toremifene on the basis of 1H NMR and mass spectral analyses. To assess the formation of toremifene DNA adducts in vivo, female Sprague-Dawley rats were treated intraperitoneally with toremifene, alpha-hydroxytoremifene, or tamoxifen. 32P-Postlabeling analyses of hepatic DNA from the tamoxifen-treated rats indicated three DNA adducts at a total level of 2,200 +/- 270 adducts/108 nucleotides. DNA adducts were not detected (<5 adducts/108 nucleotides) in the livers of rats treated with toremifene. Two DNA adducts, of which the major one coeluted with the 3',5'-bis-phosphate of (E)-alpha-(deoxyguanosin-N2-yl)toremifene, were present at a level of 57 +/- 12 adducts/108 nucleotides in hepatic DNA from rats administered alpha-hydroxytoremifene. The low level of hepatic DNA adduct formation observed with both toremifene and alpha-hydroxytoremifene, as compared to that with tamoxifen, may be due to the limited esterification of alpha-hydroxytoremifene and/or the poor reactivity of alpha-sulfoxytoremifene.

A Liquid Chromatographic–Mass Spectrometric Method to Evaluate the Distribution Kinetics of 1,2-Diethylbenzene and Its Metabolite 1,2-Diacetylbenzene in the F344 Male Rat

Diethylbenzene (DEB) is a moderately volatile, colorless liquid found in gasoline, kerosene, and fuel oils. Exposure to DEB has been shown to produce peripheral neuropathy in rats, and the ortho isomer of DEB (1,2-DEB) is generally believed to be the isomer responsible. 1,2-DEB is assumed to be metabolized primarily by direct oxidation of the ethyl side chain to form two enantiomers of 1-(2-ethylphenol) ethanol and their glucuroconjugates, which are the main 1,2-DEB metabolites, and 1,2-diacetylbenzene (1,2-DAB), a minor metabolite. The metabolite 1,2-DAB appears to be a chromogenic neurotoxin. A liquid chromatographic–mass spectrometric (LC-MS) method using atmospheric pressure photoionization (APPI) for quantifying 1,2-DEB and 1,2-DAB in blood, urine, and brain tissues from animals treated with an intraperitoneal injection of 1,2-DEB was developed. Calibration curves were prepared using matrix-specific standards with concentrations ranging from 0.068 to 402 μM. Results indicate that the concentration of 1,2-DEB in blood peaked at 2 h post intraperitoneal injection and rapidly declined thereafter. In contrast, 1,2-DAB levels in blood were fairly constant up to 24 h postinjection. Urine concentrations of 1,2-DEB were highest at the first collection interval (0–12 h postinjection), and dropped rapidly thereafter; concentrations at 24 h were similar to concentrations observed at 48 h postexposure. Urine concentrations of 1,2-DAB, however, showed the reverse, with peak concentrations observed at 24 h postinjection and only a slight decrease in concentration by 48 h.

Synthesis and Anti-Juvenile Hormone Activity of Alkyl 4-(2-Phenoxyalkyloxy) benzoates and Related Compounds

Since juvenile hormone (JH) is involved in a wide range of physiological processes in both developing and mature insects (Riddiford, 1994), compounds that possess anti–JH activity are potentially useful not only as biochemical probes to assist in elucidating the role of JH in insect development and reproduction, but also as insect growth regulators (Staal, 1986). Several compounds including precocenes (Bowers et al., 1976), fluoromevalonate (Quistad et al., 1981), ethyl 4–[2–(tert–butylcarbonyloxy)butyloxy]benzoate (ETB) (Staal, 1982), dichloroallyl hexanoate (Quistad et al., 1985), 1,5–disubstituted imidazoles (Pratt et al., 1990) and brevioxime (Moya et al., 1997) have so far been found to have anti–JH activity. However, none of the compounds has been developed for practical use in pest control as yet. Among them, ETB is known to be a unique anti–JH agent. It shows anti–JH activity as well as JH activity for the tobacco hornworm, Manduca sexta (Staal, 1982) and the silkworm, Bombyx mori (Kiguchi et al., 1984), depending on the dose applied; low doses of ETB induced precocious metamorphosis, a clear JH–deficiency symptom, but at higher doses only JH–like activity was observed. Riddiford et al. (1983) have reported that ETB acts as a partial JH antagonist at the target tissue of the larval epidermis. No other anti–JH agents with such action have been found to date. In our previous studies (Ishiguro et al., 2003), we found that ethyl 4–[2–(6–methyl–3–pyridyloxy)butyloxy] benzoate (1), structurally derived from ETB (Fig. 1), showed stronger activity than ETB. Modifications of the ethyl side chain of 1 revealed that the butyl (2) and isobutyl (3) groups were optimal for high activity (Fujita et al., 2005). Further structure activity relationship studies on this series of compounds indicated that the phenyl analog 4 showed activity comparable to that of 2, suggesting that the 6–methyl–3–pyridyl moiety is not significant for activity (Furuta et al., 2006). Conversion of the 4–ethoxycarbonyl group of 2 and 4 to the corresponding carboxylic acids eliminated the activity, indicating that the ester moiety is responsible for the activity. We therefore synthesized additional analogs in which the ethoxycarbonyl group of 4 was modified, and evaluated their activity to induce precocious metamorphosis in B. mori larvae. We also examined the precocious metamorphosis–inducing activity of both optical isomers of ethyl 4–(4–methyl–2–phenoxypentyloxy) benzoate. We report here the structure–activity relationships of new phenyl ether analogs derived from compound 4. Synthesis and Anti–Juvenile Hormone Activity of Alkyl 4–(2–Phenoxyalkyloxy)benzoates and Related Compounds

Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives

The aim of this work was to compare hepatocellular toxicity and pharmacological activity of amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran; B2-O-Et-N-diethyl) and of eight amiodarone derivatives. Three amiodarone metabolites were studied, namely, mono-N-desethylamiodarone (B2-O-Et-NH-ethyl), di-N-desethylamiodarone (B2-O-Et-NH(2)), and (2-butyl-benzofuran-3-yl)-(4-hydroxy-3,5-diiodophenyl)-methanone (B2) carrying an ethanol side chain [(2-butylbenzofuran-3-yl)-[4-(2-hydroxyethoxy)-3,5-diiodophenyl]-methanone; B2-O-Et-OH]. In addition, five amiodarone analogs were investigated, namely, N-dimethylamiodarone (B2-O-Et-N-dimethyl), N-dipropylamiodarone (B2-O-Et-N-dipropyl), B2-O-carrying an acetate side chain [[4-(2-butyl-benzofuran-3-carbonyl)-2,6-diiodophenyl]-acetic acid; B2-O-acetate], B2-O-Et carrying an propionamide side chain (B2-O-Et-propionamide), and B2-O carrying an ethyl side chain [(2-butylbenzofuran-3-yl)-(4-ethoxy-3,5-diiodophenyl)-methanone; B2-O-Et]. A concentration-dependent increase in lactate dehydrogenase leakage from HepG2 cells and isolated rat hepatocytes was observed in the presence of amiodarone and of most analogs, confirming their hepatocellular toxicity. Using freshly isolated rat liver mitochondria, amiodarone and most analogs showed a dose-dependent toxicity on the respiratory chain and on beta-oxidation, significantly reducing the respiratory control ratio and oxidation of palmitate, respectively. The reactive oxygen species concentration in hepatocytes increased time-dependently, and apoptotic/necrotic cell populations were identified using flow cytometry and annexin V/propidium iodide staining. The effect of the three least toxic amiodarone analogs on the human ether-a-go-go-related gene (hERG) channel was compared with amiodarone. Amiodarone, B2-O-acetate, and B2-O-Et-N-dipropyl (each 10 microM) significantly reduced the hERG tail current amplitude, whereas 10 microM B2-O-Et displayed no detectable effect on hERG outward potassium currents. In conclusion, three amiodarone analogs (B2-O-Et-N-dipropyl, B2-O-acetate, and B2-O-Et) showed a lower hepatocellular toxicity profile than amiodarone, and two of these analogs (B2-O-Et-N-dipropyl and B2-O-acetate) retained hERG channel interaction capacity, suggesting that amiodarone analogs with class III antiarrhythmic activity and lower hepatic toxicity could be developed.

Studies on the metabolism and toxicological detection of the designer drug 4-ethyl-2,5-dimethoxy-β-phenethylamine (2C-E) in rat urine using gas chromatographic–mass spectrometric techniques☆

The phenethylamine-derived designer drug 4-ethyl-2,5-dimethoxy-beta-phenethylamine (2C-E) was found to be mainly metabolized in rats by O-demethylation, N-acetylation, hydroxylation of the ethyl side chain at C2' or at C1' followed by oxidation at C1' to the corresponding ketone, by deamination followed by reduction to the corresponding alcohols or by oxidation to the corresponding acids, and finally combinations of these steps. Most of the metabolites were excreted in conjugated form. The authors' systematic toxicological analysis (STA) procedure using full-scan GC-MS allowed the detection of an intake of a dose of 2C-E in rat urine that corresponds to a common drug users' dose. Assuming similar metabolism, the described STA procedure should be suitable for proof of an intake of 2C-E in human urine.

Synthesis of a versatile multifunctional building block for the construction of polyketide natural products containing ethyl side-chains

The synthesis of a multifunctional building block for polyketide construction and several subsequent reactions are presented.

(E)-Ethyl 4-chloro-3-[2-(2-fluorophenyl)hydrazono]butanoate

The title compound, C12H12ClFN2O3, adopts a keto–hydrazo tautomeric form stabilized by an intra­molecular N—H⋯O hydrogen bond. The whole mol­ecule is roughly planar, the largest deviation from the mean plane being 0.328 (3) Å for the terminal methyl C atom of the ethyl side chain.

Syntheses and 1H, 13C, 15N, 17O, 205Tl NMR of New Ring-Functionalised Chelating Half-Sandwich Complexes of Thallium(I) Containing an N-, O- or S-Donor Atom

Novel, ring-functionalised cyclopentadienylthallium(I) complexes have been synthesised in good to moderate yields from thallium ethoxide and N-, O- and S-alkyl substituted cyclopentadienes in diethyl ether at 0 °C. The new compounds have been analysed by 1H, 13C, 15N, 17O and 205Tl NMR, which revealed that cyclopentadienyl ring and the donor atom in the side chain are coordinated to thallium; they are mononuclear complexes. Hence, these compounds can be viewed as analogues of their parent, CpTl, but their solubility is much enhanced because of the mononuclear nature due to the presence of the side chain. The thallium(I) complexes with the (dimethylamino)ethyl, methoxyethyl and (methylsulfanyl)ethyl side chain are promising reagents for transmetallation reactions.

Comparison of surface structures of poly(ethyl methacrylate) and poly(ethyl acrylate) in different chemical environments

Sum frequency generation (SFG) vibrational spectroscopy has been applied to investigate and compare the chemical structures of poly(ethyl methacrylate) (PEMA) and poly(ethyl acrylate) (PEA) in air, in water, and in a non-polar solvent, FC-75. SFG spectra from both polymer surfaces in air are dominated by vibrational modes from the ester ethyl side groups. The average orientation of these ester ethyl groups on the two polymer surfaces is slightly different. In water, the two polymers show markedly different restructuring behavior. The ester ethyl side chains on the PEMA surface in water reorient to tilt more toward the surface, yet remain ordered. Such a restructuring of the PEMA surface in water is reversible. However, no SFG signal was detected from the PEA/water interface, showing that the surface of PEA becomes disordered upon contacting water, and this process is irreversible. SFG results collected from the C=O range indicate that hydrogen bonding is observed for both polymer/water interfaces, but the order of C=O at the PEA/water interface is much lower than that at the PEMA/water interface. Supplemental experiments support our hypothesis that the PEA surface becomes rough and loses order gradually as it interacts with water. We have demonstrated, for the first time, that the loss of surface structural order is due to the interaction between soft PEA chains with water molecules followed by reorganization of the polymer backbone. This causes the polymer surface to become rough and disordered. However, the surface structures of PEMA and PEA in FC-75 are similar and are also similar to those in air. This indicates that not only T(g), but also the contacting medium plays an important role in determining the surface restructuring behavior of polymer materials.

Production of hybrid 16-membered macrolides by expressing combinations of polyketide synthase genes in engineered Streptomyces fradiae hosts.

Combinations of the five polyketide synthase (PKS) genes for biosynthesis of tylosin in Streptomyces fradiae (tylG), spiramycin in Streptomyces ambofaciens (srmG), or chalcomycin in Streptomyces bikiniensis (chmG) were expressed in engineered hosts derived from a tylosin-producing strain of S. fradiae. Surprisingly efficient synthesis of compounds predicted from the expressed hybrid PKS was obtained. The post-PKS tailoring enzymes of tylosin biosynthesis acted efficiently on the hybrid intermediates with the exception of TylH-catalyzed hydroxylation of the methyl group at C14, which was efficient if C4 bore a methyl group, but inefficient if a methoxyl was present. Moreover, for some compounds, oxidation of the C6 ethyl side chain to an unprecedented carboxylic acid was observed. By also expressing chmH, a homolog of tylH from the chalcomycin gene cluster, efficient hydroxylation of the 14-methyl group was restored.

Photo-physical and electro-optical properties of polythiophenes bearing tetrahydropyran side groups

Photo-physical and electro-optical properties of regio-regular polythiophenes functionalized with tetrahydropyran (THP) moieties tethered to the main chain by alkyl spacers are reported. Three sets of polymers were characterized. One consisted of polythiophenes in which THP groups were attached by either ethyl or undecyl side chains. The former exhibited solid state quantum yield of photoluminescence ( Φ pl) of 12%, while the undecyl analog exhibited a value of only 2.7%. Non-optimized polymer LEDs displayed orange and red emission for the ethyl and undecyl analogs, respectively. A second series of polymers investigated was based on random copolymers of 3-(2-(2-tetrahydropyranyloxy)ethyl)thiophene) and 3-hexyl, dodecyl or hexadecyl-thiophene. Polymers possessing shorter alkyl chains possessed shorter solid-state absorption and emission wavelengths but greater quantum yields of luminescence. The third series was based on random copolymers 3-(2-(2-tetrahydropyranyloxy)ethyl)thiophene) with various amounts of 3-hexylthiophene. As the 3-hexylthiophene content was reduced, the solid-state absorption and emission wavelengths decreased, while quantum yields of luminescence increased. Differences in luminescent properties are explained on the basis of extent of interchain aggregation induced by π–π intermolecular interactions and/or local ordering/disordering of alkyl chains.

Development of a psilocin immunoassay for serum and blood samples

After the immunisation of rabbits with a psilocin-specific immunogen, polyclonal antisera were obtained. With these antisera a competitive, heterogeneous radioimmunoassay for the detection of psilocin was developed. As tracer a derivative of psilocin was synthesised, which contained a tritiated CH(3) group. The antisera showed a specific reaction with psilocin. The cross-reactivity of structurally related endogenous substances like serotonin, tryptophan and tyrosine was below 0.01%. Also common drugs of abuse (Delta(9)-tetrahydrocannabinol, cocaine, morphine, amphetamine) showed negligible cross-reactivity (0.01-2%). Only tricyclic neuroleptics with a (dimethylamino)ethyl side-chain showed some cross-reactivity (20%). Spiked serum and blood samples were analysed with this new immunoassay and the results obtained were compared with the values measured with a validated GC-MS method.

4-Ammonio-5-chloro-N-[2-(N,N-diethylammonio)ethyl]-2-methoxybenzamide sulfate

The structural properties of C14H24ClN 3O22+ ·SO42-, known as metoclopramide sulfate was investigated. Single crystals for the study were grown from a methanol solution by slow evaporation at room temperature. It was observed that the compound was non-planar, both the molecular and crystal structures being stabilized by N-H···O and C-H···O hydrogen bonds. A gauche conformation was also observed in an amino ethyl side chain.

Biliverdin Binds Covalently to Agrobacterium Phytochrome Agp1 via Its Ring A Vinyl Side Chain

The widely distributed phytochrome photoreceptors carry a bilin chromophore, which is covalently attached to the protein during a lyase reaction. In plant phytochromes, the natural chromophore is coupled by a thioether bond between its ring A ethylidene side chain and a conserved cysteine residue within the so-called GAF domain of the protein. Many bacterial phytochromes carry biliverdin as natural chromophore, which is coupled in a different manner to the protein. In phytochrome Agp1 of Agrobacterium tumefaciens, biliverdin is covalently attached to a cysteine residue close to the N terminus (position 20). By testing different natural and synthetic biliverdin derivatives, it was found that the ring A vinyl side chain is used for chromophore attachment. Only those bilins that have ring A vinyl side chain were covalently attached, whereas bilins with an ethylidene or ethyl side chain were bound in a noncovalent manner. Phycocyanobilin, which belongs to the latter group, was however covalently attached to a mutant in which a cysteine was introduced into the GAF domain of Agp1 (position 249). It is proposed that the regions around positions 20 and 249 are in close contact and contribute both to the chromophore pocket. In competition experiments it was found that phycocyanobilin and biliverdin bind with similar strength to the wild type protein. However, in the V249C mutant, phycocyanobilin bound much more strongly than biliverdin. This finding could explain why during phytochrome evolution in cyanobacteria, the chromophore-binding site swapped from the N terminus into the GAF domain.

Engineering anthracycline biosynthesis toward angucyclines.

The biosynthesis pathways of two anthracyclines, nogalamycin and aclacinomycin, were directed toward angucyclines by using an angucycline-specific cyclase, pgaF, isolated from a silent antibiotic biosynthesis gene cluster. Addition of pgaF to a gene cassette that harbored the early biosynthesis genes of nogalamycin resulted in the production of two known angucyclinone metabolites, rabelomycin and its precursor, UWM6. Substrate flexibility of pgaF was demonstrated by replacement of the nogalamycin minimal polyketide synthase genes in the gene cassette with the equivalent aclacinomycin genes together with aknE2 and aknF, which specify the unusual propionate starter unit in aclacinomycin biosynthesis. This modification led to the production of a novel angucyclinone, MM2002, in which the expected ethyl side chain was incorporated into the fourth ring.