Synthesis and biological activity of the novel indanedione anticoagulant rodenticides containing fluorine

PubMed Central

Chen, Feng; Liu, Liping; Bai, Zengguo; Zhang, Tianhua; Zhao, Keke

2017-01-01

ABSTRACT Here, 3 fluorinated intermediates of drug were synthesized: (M1), (M2), (M3). Three new anticoagulant rodenticides were designed which were based on 4-hydroxycoumarin or 1,3-indandione, added acute toxicity groups containing fluorine. The structures of synthesized compounds were analyzed and proved by FT-IR spectroscopy and 1H nuclear magnetic resonance (1H-NMR). The compounds were also evaluated for their anticoagulant and acute biologic activity. In addition, both the acute orally toxicity and the feeding indexes of R1 and R2 were tested. The result of the experiment proved that the new synthesis of 1, 3 - indan diketone for maternal new anticoagulant rodenticide can replace the current 4 - hydroxyl coumarin as the mother of the second generation anticoagulant rodenticide and 1, 3 - indan diketone for maternal new anticoagulant rodenticides will have a good development prospect. PMID:27759485

Synthesis and biological activity of the novel indanedione anticoagulant rodenticides containing fluorine.

PubMed

Chen, Feng; Liu, Liping; Bai, Zengguo; Zhang, Tianhua; Zhao, Keke

2017-01-02

Here, 3 fluorinated intermediates of drug were synthesized: (M1), (M2), (M3). Three new anticoagulant rodenticides were designed which were based on 4-hydroxycoumarin or 1,3-indandione, added acute toxicity groups containing fluorine. The structures of synthesized compounds were analyzed and proved by FT-IR spectroscopy and 1 H nuclear magnetic resonance ( 1 H-NMR). The compounds were also evaluated for their anticoagulant and acute biologic activity. In addition, both the acute orally toxicity and the feeding indexes of R 1 and R 2 were tested. The result of the experiment proved that the new synthesis of 1, 3 - indan diketone for maternal new anticoagulant rodenticide can replace the current 4 - hydroxyl coumarin as the mother of the second generation anticoagulant rodenticide and 1, 3 - indan diketone for maternal new anticoagulant rodenticides will have a good development prospect.

Catalytic enantioselective synthesis of indanes by a cation-directed 5-endo-trig cyclization.

PubMed

Johnston, Craig P; Kothari, Abhishek; Sergeieva, Tetiana; Okovytyy, Sergiy I; Jackson, Kelvin E; Paton, Robert S; Smith, Martin D

2014-02-01

5-Endo-trig cyclizations are generally considered to be kinetically unfavourable, as described by Baldwin's rules. Consequently, observation of this mode of reaction under kinetic control is rare. This is usually ascribed to challenges in achieving appropriate approach trajectories for orbital overlap in the transition state. Here, we describe a highly enantio- and diastereoselective route to complex indanes bearing all-carbon quaternary stereogenic centres via a 5-endo-trig cyclization catalysed by a chiral ammonium salt. Through computation, the preference for the formally disfavoured 5-endo-trig Michael reaction over the formally favoured 5-exo-trig Dieckmann reaction is shown to result from thermodynamic contributions to the innate selectivity of the nucleophilic group, which outweigh the importance of the approach trajectory as embodied by Baldwin's rules. Our experimental and theoretical findings demonstrate that geometric and stereoelectronic constraints may not be decisive in the observed outcome of irreversible ring-closing reactions.

21 CFR 172.215 - Coumarone-indene resin.

Code of Federal Regulations, 2011 CFR

2011-04-01

... mixture of indene, indan (hydrindene), substituted benzenes, and related compounds. (2) It contains no... additive meets the following specifications: (1) Softening point, ring and ball: 126 °C minimum as determined by ASTM method E28-67 (Reapproved 1982), “Standard Test Method for Softening Point by Ring-and...

21 CFR 172.215 - Coumarone-indene resin.

Code of Federal Regulations, 2012 CFR

2012-04-01

... mixture of indene, indan (hydrindene), substituted benzenes, and related compounds. (2) It contains no... additive meets the following specifications: (1) Softening point, ring and ball: 126 °C minimum as determined by ASTM method E28-67 (Reapproved 1982), “Standard Test Method for Softening Point by Ring-and...

21 CFR 172.215 - Coumarone-indene resin.

Code of Federal Regulations, 2013 CFR

2013-04-01

... mixture of indene, indan (hydrindene), substituted benzenes, and related compounds. (2) It contains no... additive meets the following specifications: (1) Softening point, ring and ball: 126 °C minimum as determined by ASTM method E28-67 (Reapproved 1982), “Standard Test Method for Softening Point by Ring-and...

Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation.

PubMed

Camps, Pelayo; Formosa, Xavier; Galdeano, Carles; Gómez, Tània; Muñoz-Torrero, Diego; Scarpellini, Michele; Viayna, Elisabet; Badia, Albert; Clos, M Victòria; Camins, Antoni; Pallàs, Mercè; Bartolini, Manuela; Mancini, Francesca; Andrisano, Vincenza; Estelrich, Joan; Lizondo, Mònica; Bidon-Chanal, Axel; Luque, F Javier

2008-06-26

A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.

Electrochemical Water Oxidation and Stereoselective Oxygen Atom Transfer Mediated by a Copper Complex.

PubMed

Kafentzi, Maria-Chrysanthi; Papadakis, Raffaello; Gennarini, Federica; Kochem, Amélie; Iranzo, Olga; Le Mest, Yves; Le Poul, Nicolas; Tron, Thierry; Faure, Bruno; Simaan, A Jalila; Réglier, Marius

2018-04-06

Water oxidation by copper-based complexes to form dioxygen has attracted attention in recent years, with the aim of developing efficient and cheap catalysts for chemical energy storage. In addition, high-valent metal-oxo species produced by the oxidation of metal complexes in the presence of water can be used to achieve substrate oxygenation with the use of H 2 O as an oxygen source. To date, this strategy has not been reported for copper complexes. Herein, a copper(II) complex, [(RPY2)Cu(OTf) 2 ] (RPY2=N-substituted bis[2-pyridyl(ethylamine)] ligands; R=indane; OTf=triflate), is used. This complex, which contains an oxidizable substrate moiety (indane), is used as a tool to monitor an intramolecular oxygen atom transfer reaction. Electrochemical properties were investigated and, upon electrolysis at 1.30 V versus a normal hydrogen electrode (NHE), both dioxygen production and oxygenation of the indane moiety were observed. The ligand was oxidized in a highly diastereoselective manner, which indicated that the observed reactivity was mediated by metal-centered reactive species. The pH dependence of the reactivity was monitored and correlated with speciation deduced from different techniques, ranging from potentiometric titrations to spectroscopic studies and DFT calculations. Water oxidation for dioxygen production occurs at neutral pH and is probably mediated by the oxidation of a mononuclear copper(II) precursor. It is achieved with a rather low overpotential (280 mV at pH 7), although with limited efficiency. On the other hand, oxygenation is maximum at pH 8-8.5 and is probably mediated by the electrochemical oxidation of an antiferromagnetically coupled dinuclear bis(μ-hydroxo) copper(II) precursor. This constitutes the first example of copper-centered oxidative water activation for a selective oxygenation reaction. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Central muscle relaxant activities of 2-methyl-3-aminopropiophenone derivatives].

PubMed

Kontani, H; Mano, A; Koshiura, R; Yamazaki, M; Shimada, Y; Oshita, M; Morikawa, K; Kato, H; Ito, Y

1987-02-01

In this experiment, we synthetized new 2-methyl-3-aminopropiophenone (MP) derivatives, whose structure is known to have central muscle relaxant activities, and quinolizidine and indan . tetralin derivatives derived from MP by cyclization, and we investigated the central muscle relaxant activity. Among the quinolizidine derivatives, there was a very strong central depressant agent, trans (3H, 9aH)-3-(p-chloro) benzoyl-quinolizidine (HSR-740), and among the indan . tetralin derivatives, there was an excitant agents, trans (1H, 2H)-5-methoxy-3, 3-dimethyl-2-piperidinomethyl indan-1-ol (HSR-719). From the results, these derivatives were not considered to be adequate for central muscle relaxant. Among the MP derivatives, (4'-chloro-2'-methoxy-3-piperidino) propiophenone HCl (HSR-733) and (4'-ethyl-2-methyl-3-pyrrolidino) propiophenone HCl (HSR-770) strongly inhibited the cooperative movement in the rotating rod method using mice, and it exerted almost the same depressant activity on the cross extensor reflex using alpha-chloralose anesthetized rats. However, the inhibitory effects of HSR-733 on the anemic decerebrate rigidity and the rigidity induced by intracollicular decerebration in rats were weaker than those of HSR-770 and eperisone. In spinal cats, at a low dose (5 mg/kg, i.v.), HSR-733 depressed monosynaptic and dorsal root reflex potentials as compared with polysynaptic reflex potentials, and inhibitory effects of HSR-733 on these three reflex potentials were more potent than those of eperisone and HSR-770. Although HSR-770 acts on the spinal cord and supraspinal level on which eperisone has been reported to act, HSR-733 may mainly act on the spinal cord. These results indicate that the MP derivative with a 2-methyl group may be suitable as a central muscle relaxant. HSR-770, which has equipotent muscle relaxant activity to eperisone, exerted strong inhibitory effects on oxotremorine-induced tremor and weak inhibitory effects on spontaneous motor activity in the Animex method using mice, as compared with eperisone.

Quantum chemical study on gas phase pyrolysis of p-isopropenylphenol.

PubMed

Mohan Verma, Anand; Kawale, Harshal D; Agrawal, Kushagra; Kishore, Nanda

2018-05-01

In the pyrolysis of Sphagnum moss species, p-isopropenylphenol (p-IPP) is a major product which has been considered in this density functional theory based computational study for its conversion to various products such as benzene, phenol, 4-propenylphenol, indan-5-ol, 4-propylcyclohexanone, 4-cyclopropylphenol, etc. In order to achieve these products, eight different reaction schemes are performed using B3LYP/6-311 + g (d,p) level of theory. Further, thermodynamic properties such as reaction free energies and reaction enthalpies associated with these eight reaction schemes are developed in the temperature range of 298-898 K. The reaction schemes that include partial hydrogenation of the aromatic carbon followed by elimination of functional groups are found to demand low activation energy. The production of benzene from p-IPP with isopropenylbenzene as an intermediate product requiring only 19.83 kcal/mol of activation energy is the rate limiting reaction step. Indan-5-ol produced from p-IPP is validated with the literature results and found excellent agreement between two results. Furthermore, the temperature is found to have phenomenal effect in each reaction scheme. Copyright © 2018 Elsevier Inc. All rights reserved.

Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class.

PubMed

Binda, Claudia; Hubálek, Frantisek; Li, Min; Herzig, Yaacov; Sterling, Jeffrey; Edmondson, Dale E; Mattevi, Andrea

2004-03-25

Monoamine oxidase B (MAO B) is an outer mitochondrial membrane enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters. The crystal structures of MAO B in complex with four of the N-propargylaminoindan class of MAO covalent inhibitors (rasagiline, N-propargyl-1(S)-aminoindan, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan) have been determined at a resolution of better than 2.1 A. Rasagiline, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan adopt essentially the same conformation with the extended propargyl chain covalently bound to the flavin and the indan ring located in the rear of the substrate cavity. N-Propargyl-1(S)-aminoindan binds with the indan ring in a flipped conformation with respect to the other inhibitors, which causes a slight movement of the Tyr326 side chain. Four ordered water molecules are an integral part of the active site and establish H-bond interactions to the inhibitor atoms. These structural studies may guide future drug design to improve selectivity and efficacy by introducing appropriate substituents on the rasagiline molecular scaffold.

Electrical properties of a novel 1,3-bis-(p-iminobenzoic acid) indane Langmuir-Blodgett films containing ZnS nanoparticles.

PubMed

Sari, H; Uzunoglu, T; Capan, R; Serin, N; Serin, T; Tarimci, C; Hassan, A K; Namli, H; Turhan, O

2007-08-01

ZnS nanoparticles have been formed in a newly synthesized 1,3-bis-(p-iminobenzoic acid) indane (IBI) by exposing Zn2+ doped multilayered Langmuir-Blodgett (LB) film to H2S gas after the growth. The formation of ZnS nanoparticles in the LB film structure was verified by measuring UV-Visible absorption spectra. DC electrical measurements were carried out for thin films of IBI prepared in a metal/LB films/metal sandwich structure with and without ZnS nanoparticles. It was observed that ZnS nanoparticles in the LB films cause a blue-shift in the absorption spectra as well as a decrease in both capacitance and conductivity values. By analysing I-V curves and assuming a Schottky conduction mechanism the barrier height was found to be about 1.13 eV and 1.21 eV for IBI LB films without and with ZnS nanoparticles, respectively. It is thought that the presence of ZnS nanoparticles influences the barrier height at the metal-organic film interface and causes a change in electrical conduction properties of LB films.

7-Meth­oxy­indan-1-one

PubMed Central

Chang, Yuan Jay; Chen, Kew-Yu

2012-01-01

In the title compound, C10H10O2, the 1-indanone unit is essentially planar (r.m.s. deviation = 0.028 Å). In the crystal, molecules are linked via C—H⋯O hydrogen bonds, forming layers lying parallel to the ab plane. This two-dimensional structure is stabilized by a weak C—H⋯π inter­action. A second weak C—H⋯π inter­action links the layers, forming a three-dimensional structure. PMID:23284398

Evaluation of blood-brain barrier and blood-cerebrospinal fluid barrier permeability of 2-phenoxy-indan-1-one derivatives using in vitro cell models.

PubMed

Hu, Hai-Hong; Bian, Yi-Cong; Liu, Yao; Sheng, Rong; Jiang, Hui-Di; Yu, Lu-Shan; Hu, Yong-Zhou; Zeng, Su

2014-01-02

2-Phenoxy-indan-1-one derivatives (PIOs) are a series of novel central-acting cholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The adequate distribution of PIOs to the central nervous system (CNS) is essential for its effectiveness. However, articles related with their permeability in terms of CNS penetration across the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) have not been found. This study was undertaken to evaluate the in vitro BBB and BCSFB transport of PIOs using Madin-Darby canine kidney (MDCK), MDCK-MDR1 and Z310 cell line models. As a result, the transepithelial transport of PIOs did not differ between MDCK and MDCK-MDR1, and the result suggested that PIOs were not substrates for P-gp, which means that multidrug resistance (MDR) function would not affect PIOs absorption and brain distribution. High permeability of PIOs in Z310 was found and it suggested that PIOs had high brain uptake potential. The experiment also showed that PIOs had inhibitory effects on the MDR1-mediated transport of Rhodamine123 with an IC50 value of 40-54 μM. And we suggested that 5,6-dimethoxy-1-indanone might be the pharmacophoric moiety of PIOs that interacts with the binding site of P-gp. Copyright © 2013 Elsevier B.V. All rights reserved.

A Study of the Nephrotoxicity and Metabolism of Tetralin and Indan in Fischer 344 Rats

DTIC Science & Technology

1989-05-01

5, a jet fuel composed of aliphatic and aromatic hydrocarbons with the majority of the straight-chain hydrocarbons being between C10 and C15...hydrocarbon of intermediate boiling point and volatility and is similar to the civilian jet fuel , A-1. DFM is a mixture of long chain aliphatic...to compliment earlier research on jet fuel , JP-10, cis- and trans- decalin, and tetralin, it was anticipated some enlightenment could be obtained on

A Study of the Nephrotoxicity and Metabolism of Tetralin and Indan in Fischer 344 Rats.

DTIC Science & Technology

1988-02-08

evaluated petroleum and shale-derived JP-5, a jet fuel composed of aliphatic and aromatic hydrocarbons with the majority of the straight-chain hydrocarbons...much like gasoline. JP-8 is a mixture of hydrocarbon of intermediate boiling point and volatility and is similar to the civilian jet fuel , A-1. DFM is a...conventional versus shale-derived JP-5 jet fuel : Light microscopy, hematologic, and serum chemistry studies. Toxicol Appl Pharmacol, 57, 302-317 (1981

Conformationally Constrained Analogues of N'-(4-t-Butylbenzyl)-N-(4-Methylsulfonylaminobenzyl)Thiourea as TRPV1 Antagonists

PubMed Central

Ryu, HyungChul; Lim, Ju-Ok; Kang, Dong Wook; Pearce, Larry V.; Tran, Richard; Toth, Attila; Lee, Jeewoo; Blumberg, Peter M.

2012-01-01

A series of bicyclic analogues having indan and tetrahydronaphthalene templates in the A-region were designed as conformationally constrained analogues of our previously reported potent TRPV1 antagonists (1, 3). The activities for rat TRPV1 of the conformationally restricted analogues were moderately or markedly diminished, particularly in the case of the tetrahydronaphthalene analogues. The analysis indicated that steric constraints at the benzylic position in the bicyclic analogues were an important factor for their unfavorable interaction with the receptor. PMID:18406014

A Study of the Effect of Hydrocarbon Structure on the Induction of Male Rat Nephropathy and Metabolic Structure

DTIC Science & Technology

1993-08-31

rats yield the molecules 1 - indanol and 1 -indanone from the kidney homogenate extracts [421. Tetralin, which produced more renal damage than indan, did...G.B.. 1955. The oxidation of ketones to esters. I. Am. Chem. Soc. 77, 2287-2290.I 14. Finar, I.L. 1986. In Organic Chemistry Vol 1 , sixth edition...substituted at carbon-3. The only metabolic products which show no oxidation at3 carbon-2, carbon-3 or carbon-6 of 3-MH were 1 , 2, 8, 12 and 16. However

Stereospecific oxidation of (R)- and (S)-1-indanol by naphthalene dioxygenase from Pseudomonas sp. strain NCIB 9816-4.

PubMed

Lee, K; Resnick, S M; Gibson, D T

1997-05-01

A recombinant Escherichia coli strain which expresses naphthalene dioxygenase (NDO) from Pseudomonas sp. strain NCIB 9816-4 oxidized (S)-1-indanol to trans-(1S,3S)-indan-1,3-diol (95.5%) and (R)-3-hydroxy-1-indanone (4.5%). The same cells oxidized (R)-1-indanol to cis-1,3-indandiol (71%), (R)-3-hydroxy-1-indanone (18.2%), and cis-1,2,3-indantriol (10.8%). Purified NDO oxidized (S)-1-indenol to both syn- and anti-2,3-dihydroxy-1-indanol.

[Acute renal insufficiency caused by phenyl-indane-dione. Apropos of 1 case].

PubMed

Horellou, M F; Feiss, P; Voultoury, J C; Gay, R

1978-01-01

One case of Phenindione (PID) adverse reaction is reported. The patient showed a typical picture of immunological reaction to the drug. In spite of severe bacteremia, she recovered. Only 33 cases of PID intolerance are reported in the literature. In all these patients, renal failure occurred. Superinfection is the most frequent cause of death. PID adverse reaction should be evoqued in the presence of signs such a fever, asthenia, anorexia and cutaneous reaction. The PID should be stopped immediatly but renal failure yet develops. During a PID treatment, frequent evaluation of blood azotemia, creatinine and proteinuria should be performed.

Volatile components of ethanolic extract from broccolini leaves.

PubMed

Wang, Xiaoqin; Zhang, Bochao; Wang, Bingfang; Zhang, Xuewu

2012-01-01

Broccolini (Brassica oleracea Italica × Alboglabra) is a hybrid of broccoli and kai-lan, Chinese broccoli. To date, no study has been reported on the chemical composition of the volatile fractions of this raw material. In this study, the volatile constituents from the ethanolic extract of broccolini leaves were analysed by gas chromatography-mass spectrometry (GC-MS). Sixteen compounds were identified. The major components include 5-phenyl-undecane (11%), n-hexadecanoic acid (9.34%), octadecanoic acid (6.39%), 1,1,3-trimethyl-3-phenyl-indan (4.0%), 3-(2-phenylethyl)benzonitrile (3.48%) and phytol (3.37%).

Stereospecific oxidation of (R)- and (S)-1-indanol by naphthalene dioxygenase from Pseudomonas sp. strain NCIB 9816-4.

PubMed Central

Lee, K; Resnick, S M; Gibson, D T

1997-01-01

A recombinant Escherichia coli strain which expresses naphthalene dioxygenase (NDO) from Pseudomonas sp. strain NCIB 9816-4 oxidized (S)-1-indanol to trans-(1S,3S)-indan-1,3-diol (95.5%) and (R)-3-hydroxy-1-indanone (4.5%). The same cells oxidized (R)-1-indanol to cis-1,3-indandiol (71%), (R)-3-hydroxy-1-indanone (18.2%), and cis-1,2,3-indantriol (10.8%). Purified NDO oxidized (S)-1-indenol to both syn- and anti-2,3-dihydroxy-1-indanol. PMID:9143136

Structural Amendment and Stereoselective Synthesis of Mutisianthol.

PubMed

Ho, Tse-Lok; Lee, Kwang-Yuan; Chen, Chun-Kuei

1997-05-16

cis-1-(5-Acetoxy-3,6-dimethyl-1-indanyl)-2-methyl-1-propene synthesized from 3,6-dimethyl-1-indanone was found to be different from mutisianthol by spectral comparison. The presence of a high-field signal in the NMR spectrum of the final product and various intermediates, characteristic of the cis-1,3-dialkylindanes but absent in the spectrum of the natural terpene, suggests a revision of the structure of mutisianthol to the trans isomer. The trans-indane which was subsequently obtained indeed exhibits data fully agreeable with mutisianthol. A similar stereochemical revision for jungianol is also indicated.

Incorrect installation and use of materials as the cause of a severe air pollution incident in a school building.

PubMed

Rella, Rocco; Sturaro, Alberto; Vianello, Alvise

2014-07-15

The proofing treatment of the floor slabs with a solvent based material and successive treatment with epoxy resin resulted in significant air contamination in a primary school. The contamination caused illnesses in many occupants of school. The GC/MS investigations of the air showed the presence of indane and other aromatic solvents, which was unusual as they are not correlated to outdoor pollution and derived from inner layers of the new flooring. The total concentration of these chemicals in air was in the order of several mg/m(3). Copyright © 2014 Elsevier B.V. All rights reserved.

Asymmetric synthesis of all-carbon benzylic quaternary stereocenters via Cu-catalyzed conjugate addition of dialkylzinc reagents to 5-(1-arylalkylidene) Meldrum's acids.

PubMed

Fillion, Eric; Wilsily, Ashraf

2006-03-08

The asymmetric synthesis of all-carbon benzylic quaternary stereocenters has been successfully achieved through copper-catalyzed addition of dialkylzinc reagents to 5-(1-arylalkylidene) and 5-(dihydroindenylidene) Meldrum's acids in the presence of phosphoramidite ligand. The resulting benzyl-substituted Meldrum's acids and 1,1-disubstituted indanes were obtained in good yields and up to 99% ee. The significance of substituting the position para, meta, and ortho to the electrophilic benzylic center was highlighted. A benzyl Meldrum's acid product was further transformed to a 3,3-disubstituted 1-indanone and a beta,beta-disubstituted pentanoic acid.

Structural and functional comparison of two human liver dihydrodiol dehydrogenases associated with 3 alpha-hydroxysteroid dehydrogenase activity.

PubMed Central

Deyashiki, Y; Taniguchi, H; Amano, T; Nakayama, T; Hara, A; Sawada, H

1992-01-01

Two monomeric dihydrodiol dehydrogenases with pI values of 5.4 and 7.6 were co-purified with androsterone dehydrogenase activity to homogeneity from human liver. The two enzymes differed from each other on peptide mapping and in their heat-stabilities; with respect to the latter the dihydrodiol dehydrogenase and 3 alpha-hydroxysteroid dehydrogenase activities of the respective enzymes were similarly inactivated. The pI 5.4 enzyme was equally active towards trans- and cis-benzene dihydrodiols, and towards (S)- and (R)-forms of indan-1-ol and 1,2,3,4-tetrahydronaphth-1-ol and oxidized the 3 alpha-hydroxy group of C19-, C21- and C24-steroids, whereas the pI 7.6 enzyme showed high specificity for trans-benzene dihydrodiol, (S)-forms of the alicyclic alcohols and C19- and C21-steroids. Although the two enzymes reduced various xenobiotic carbonyl compounds and the 3-oxo group of C19- and C21-steroids, and were A-specific in the hydrogen transfer from NADPH, only the pI 5.4 enzyme showed reductase activity towards 7 alpha-hydroxy-5 beta-cholestan-3-one and dehydrolithocholic acid. The affinity of the two enzymes for the steroidal substrates was higher than that for the xenobiotic substrates. The two enzymes also showed different susceptibilities to the inhibition by anti-inflammatory drugs and bile acids. Whereas the pI-5.4 enzyme was highly sensitive to anti-inflammatory steroids, showing mixed-type inhibitions with respect to indan-1-ol and androsterone, the pI 7.6 enzyme was inhibited more potently by non-steroidal anti-inflammatory drugs and bile acids than by the steroidal drugs, and the inhibitions were all competitive. These structural and functional differences suggest that the two enzymes are 3 alpha-hydroxysteroid dehydrogenase isoenzymes. Images Fig. 2. PMID:1554355

Diastereoisomers of 2-benzyl-2, 3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol: potential anti-inflammatory agents.

PubMed

Sheridan, Helen; Walsh, John J; Cogan, Carina; Jordan, Michael; McCabe, Tom; Passante, Egle; Frankish, Neil H

2009-10-15

The synthesis and biological activity of the novel diastereoisomers of 2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol is reported. The 2,2-coupled indane dimers were synthesised by coupling of the silyl enol ether of 1-indanone with the dimethyl ketal of 2-indanone. The coupled product was directly alkylated to give the racemic ketone which was reduced to the diastereoisomeric alcohols. The alcohols were separated and their relative stereochemistry was established by X-ray crystallography. These molecules demonstrate significant anti-inflammatory activity in vivo and in vitro and may represent a new class of anti-inflammatory agent.

Marine Environmental Planning Guide for the Hampton Roads/Norfolk Operating Area.

DTIC Science & Technology

1974-05-01

t~J ’SWo 10 𔃻 ..... 43303UA~ A** 00 * 1 31.9 -~f -- f., 41 Aef"G .G 3 3 -1.9’ OC ’amV. -.9v ... G "* Cft 𔃻 IAMv PPO.$ ENLARGEMENT E o Iy PERMISSION...ut DlAl’ aml I indane on qlycolyt ic andi ,J I L1 ’ 11 n<K~~ Ionic (!i~~sot thec 4pahi,; , Me rcxvn aria mercenavr-ia, 5- ,7p., Uiuted Nit tons PuxA...North Cairol imi Dtpt . ot (Con.;etVat ion .iml DlX’,󈧏Tnt , Divi!;ion oit Cimmrcixil ’~~~~I~ by .B.li;t IuX inll sst~b illa5𔃿 i Strulctlure aml

Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates.

PubMed

Camps, Pelayo; Formosa, Xavier; Galdeano, Carles; Gómez, Tània; Muñoz-Torrero, Diego; Ramírez, Lorena; Viayna, Elisabet; Gómez, Elena; Isambert, Nicolás; Lavilla, Rodolfo; Badia, Albert; Clos, M Victòria; Bartolini, Manuela; Mancini, Francesca; Andrisano, Vincenza; Bidon-Chanal, Axel; Huertas, Oscar; Dafni, Thomai; Luque, F Javier

2010-09-06

Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimer's disease progression. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Hydrocarbons identified in extracts from estuarine water accommodated no. 2 fuel oil by gas chromatography-mass spectrometry

NASA Technical Reports Server (NTRS)

Lewis, B. W.; Walker, A. L.; Bieri, R. H.

1974-01-01

Results are presented on a computerized gas chromatograph-mass spectrometer analysis of methylene chloride and n-heptane extracts of a No. 2 fuel oil accommodated estuarine water sample. The analytical method is briefly described, and the limitations on the identifications are categorized. Some attempt was made to determine major and trace constituents in the water accommodate. Altogether 66 hydrocarbon compounds were identified specifically, and 75 compounds were partially identified. Seven compounds could be recognized as major constituents of the water accommodated oil and ten were present only as traces. The aromatic compounds found were alkyl benzenes, naphthalene, tetralin, indane, biphenyl, fluorene, anthracene, and some of their alkyl substituted isomers in the range of carbon numbers C7 to C15. Four n-alkanes, C10 to C13, were found along with four other assorted hydrocarbons.

Dioxin-ähnliche Wirkungen durch Grundwasser am Industriestandort Zeitz

NASA Astrophysics Data System (ADS)

Schirmer, Kristin; Bopp, Stephanie; Russold, Sandra; Popp, Peter

Kurzfassung Im Rahmen der Etablierung des Standortes Zeitz (Sachsen-Anhalt) als Referenztestfeld zur Implementierung des Natural-Attenuation-Ansatzes, haben wir Grundwasser auf seine Fähigkeit untersucht, eine Dioxin-ähnliche Wirkung hervorzurufen. Die Dioxin-ähnliche Wirkung ist die Arylhydrocarbon Rezeptor-vermittelte Induktion des Proteinkomplexes Cytochrom CYP1A, welches als 7-Ethoxyresorufin-O-Deethylase (EROD) Enzymaktivität in einer Fischleberzelllinie gemessen wurde. Von 32 Probennahmestellen wiesen sieben eine signifikante EROD-Induktion auf, welche zu einem geringen Teil auf Polyzyklische Aromatische Kohlenwasserstoffe zurückzuführen war. Ein weiterer Teil der EROD-Induktion konnte den Substanzen Benzofuran, Indan und Inden zugesprochen werden, welche hier erstmalig als EROD-Induktoren identifiziert wurden. Alle Probennahmestellen mit signifikanter EROD-Induktion lagen im Anstrom bzw. westlich des früheren Standortes der Benzolanlage in Zeitz, was einen signifikanten Einfluss von Benzol vor allem auf den Transport und das Lösungsverhalten EROD-induzierender Grundwasserkontaminanten vermuten lässt. Insgesamt zeigen diese Untersuchungen, wie eine Kombination von chemischer und biologischer Analytik zu einer deutlich verbesserten Aussagekraft führt und somit zu einer nachhaltigen Überwachung der Qualität von Grundwasser beitragen kann. As part of setting up the test field Zeitz (Saxony-Anhalt, Germany) as a reference site for the implementation of Natural Attenuation as a remediation option, we have investigated groundwater for its ability to cause a dioxin-like response. The dioxin-like response is the aryl hydrocarbon receptor-mediated induction of the protein complex cytochrome CYP1A, which was measured as 7-Ethoxyresorufin-O-deethylase (EROD) enzyme activity in a fish liver cell line. Out of 32 sampling locations, seven showed significant EROD induction, which could be explained, to a minor extent, by the presence of polycyclic aromatic hydrocarbons. Another small portion of the EROD induction was attributed to the low molecular weight compounds, Benzofuran, Indane and Indene, which were shown for the first time to act as EROD inducers. All sampling locations showing significant EROD induction were located upstream or to the west of the former benzene production site in Zeitz. This indicates that benzene is likely to affect the transport and dissolution of EROD-inducing groundwater contaminants. In sum, this study shows how a combination of chemical and biological analysis can greatly augment knowledge about site characteristics and thus contribute to a sustainable monitoring of groundwater quality.

Origin of organic matter in the early solar system. VII - The organic polymer in carbonaceous chondrites

NASA Technical Reports Server (NTRS)

Hayatsu, R.; Matsuoka, S.; Anders, E.; Scott, R. G.; Studier, M. H.

1977-01-01

Degradation techniques, including pyrolysis, depolymerization, and oxidation, were used to study the insoluble polymer from the Murchison C2 chondrite. Oxidation with Cr2O7(2-) or O2/UV led to the identification of 15 aromatic ring systems. Of 11 aliphatic acids identified, three dicarboxylic acids presumably came from hydroaromatic portions of the polymer, whereas eight monocarboxylic acids probably derive from bridging groups or ring substituents. Depolymerization with CF3COO4 yielded some of the same ring systems, as well as alkanes (C1 through C8) and alkenes (C2 through C8), alkyl (C1 through C5) benzenes and naphthalenes, and methyl- or dimethyl -indene, -indane, -phenol, -pyrrole, and -pyridine. All these compounds were detected below 200 C, and are therefore probably indigenous constituents. The properties of the meteoritic polymer were compared with the properties of a synthetic polymer produced by the Fischer-Tropsch reaction. It is suggested that the meteoritic polymer was also produced by surface catalysis.

The toxicity of selected gasoline components to glucose methanogenesis by aquifer microorganisms

USGS Publications Warehouse

Mormile, Melanie R.; Suflita, Joseph M.

1996-01-01

Six model hydrocarbons, representing various classes of chemicals found in gasoline, and methyl ethyl ketone, were assayed for their inhibitory effect on glucose methanogenesis in slurries prepared from aquifer sediments and ground water. Biogas (CH4and CO2) production was monitored with an automated pressure transducer system. Benzene, 1-methyl naphthalene, and methyltert-butyl ether (MTBE) were found to have no inhibitory influence on biogas production rates at concentrations up to 71·7 mg/L. Similarly, octane, cyclohexane, indan, and methyl ethyl ketone (MEK) were found to have only marginal negative effects on the rate of biogas production in aquifer slurries, at concentrations ranging from 51·7 to 72·1 mg/L. Thus, gasoline components had low apparent toxicities to microorganisms responsible for glucose methanogenesis in aquifier slurries. As the concentrations of the assayed hydrocarbons are about 100 times those typically reported after an aquifer has been contaminated with gasoline, it is unlikely that individual hydrocarbons will substantially impact anaerobic metabolic processes.

Dehydrogenation of indanol by rabbit liver 3-hydroxyhexobarbital dehydrogenase.

PubMed

Takenoshita, R; Toki, S

1977-06-01

1. Among the several enzyme activities in rabbit liver cytosol able to dehydrogenate 1-indanol, only the main activity was not separable from 3-hydroxyhexobarbital dehydrogenase during purification including polyacrylamide gel disc electrophoresis. 2. Results of mixed substrate method indicated that the same enzyme catalyses the dehydrogenation of 1-indanol and 3-hydroxyhexobarbital. The ratio between the two dehydrogenation activities was almost constant as the enzyme underwent thermal inactivation. The Ki values of p-chloromercuribenzoate, the Km values for NAD+, and the Km values for NADP+ were very similar for the two dehydrogenations. These results lead to the conclusion that the same enzyme catalyses the dehydrogenation of 3-hydroxyhexobarbital and 1-indanol. 3. 1-Tetralol, 1-acenaphthenol, 9-fluorenol, thiochroman-4-ol and 4-chromanol also served as substrate of the enzyme, but 2-indanol, 2-tetralol, and trans- and cis-indan-1,2-diol were not oxidized. 4. Reversibility of the reaction was also confirmed using 1-indanone as substrate.

Teratogen metabolism: activation of thalidomide and thalidomide analogues to products that inhibit the attachment of cells to concanavalin A coated plastic surfaces.

PubMed

Braun, A G; Weinreb, S L

1984-05-01

Thalidomide metabolites inhibited the attachment of tumor cells to concanavalin A coated polyethylene surfaces. Thalidomide, itself, was non-inhibitory. Thalidomide activation to inhibitory products required hepatic microsomes, an NADPH-generating system, and molecular oxygen. Production of inhibitory metabolites was unaffected by either epoxide hydrolase or 1,2-epoxy-3,3,3-trichloropropane (TCPO), an inhibitor of epoxide hydrolase endogenous to hepatic S9 fraction. Therefore, the attachment inhibitor was probably not an arene oxide. Inhibition was not accompanied by cytotoxicity, as judged by trypan blue exclusion. Although uninduced hepatic microsomes from mice, rats and dogs had similar abilities to activate thalidomide, microsomes from Aroclor 1254 induced rats were relatively inactive in the system. Inhibitory metabolites were generated from the thalidomide analogues EM8 , EM12 , EM16 , EM87 , EM136 , EM255 , E350 , phthalimide, phthalimido-phthalimide, indan, 1- indanone and 1,3- indandione . Glutarimide , glutamic acid and phthalic acid did not activate to inhibitory products.

Design, Synthesis, Structural and Spectroscopic Studies of Push-Pull Two-Photon Absorbing Chromophores with Acceptor Groups of Varying Strength

PubMed Central

Morales, Alma R.; Frazer, Andrew; Woodward, Adam W.; Ahn-White, Hyo-Yang; Fonari, Alexandr; Tongwa, Paul; Timofeeva, Tatiana; Belfield, Kevin D.

2013-01-01

A new series of unsymmetrical diphenylaminofluorene-based chromophores with various strong π-electron acceptors were synthesized and fully characterized. The systematic alteration of the structural design facilitated the investigation of effects such as molecular symmetry and strength of electron-donating and/or withdrawing termini have on optical nonlinearity. In order to determine the electronic and geometrical properties of the novel compounds, a thorough investigation was carried out by a combination of linear and nonlinear spectroscopic techniques, single crystal X-ray diffraction, and quantum chemical calculations. Finally, on the basis of two-photon absorption (2PA) cross sections, the general trend for π -electron accepting ability, i.e., ability to accept charge transfer from diphenylamine was: 2-pyran-4-ylidene malononitrile (pyranone) > dicyanovinyl > bis(dicyanomethylidene)indane > 1-(thiophen-2-yl)propenone > dicyanoethylenyl > 3-(thiophen-2-yl)propenone. An analog with the 2-pyran-4-ylidene malononitrile acceptor group exhibited a nearly three-fold enhancement of the 2PA< δ (1650 GM at 840 nm), relative to other members of the series. PMID:23305555

Centrohexaindane: six benzene rings mutually fixed in three dimensions - solid-state structure and six-fold nitration.

PubMed

Kuck, Dietmar; Linke, Jens; Teichmann, Lisa Christin; Barth, Dieter; Tellenbröker, Jörg; Gestmann, Detlef; Neumann, Beate; Stammler, Hans-Georg; Bögge, Hartmut

2016-04-28

The solid-state molecular structure of centrohexaindane (), a unique hydrocarbon comprising six benzene rings clamped to each other in three dimensions around a neopentane core, and the molecular packing in crystals of ·CHCl3 are reported. The molecular Td-symmetry and the Cartesian orientation of the six indane wings of in the solid state have been confirmed. The course and limitation of electrophilic aromatic substitution of are demonstrated for the case of nitration. Based on nitration experiments of a lower congener of , tribenzotriquinacene , the six-fold nitrofunctionalisation of has been achieved in excellent yield, giving four constitutional isomers, two nonsymmetrical ( and ) and two C3-symmetrical ones ( and ), all of which contain one single nitro group in each of the six benzene rings. The relative yields of the four isomers (∼3 : 1 : 1 : 3) point to a random electrophilic attack of the electrophiles at the twelve formally equivalent outer positions of the aromatic periphery of , suggesting electronic independence of its six aromatic π-electron systems. In turn, the pronounced conformational rigidity of the centrohexacyclic framework of enables the unequivocal structural identification of the isomeric hexanitrocentrohexaindanes by (1)H NMR spectroscopy.

Activation of human liver 3 alpha-hydroxysteroid dehydrogenase by sulphobromophthalein.

PubMed Central

Matsuura, K; Tamada, Y; Deyashiki, Y; Miyabe, Y; Nakanishi, M; Ohya, I; Hara, A

1996-01-01

Human liver contains at least two isoenzymes (DD2 and DD4) of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase. The NADP(H)-linked oxidoreductase activities of DD4 were activated more than 4-fold by sulphobromophthalein at concentrations above 20 microM and under physiological pH conditions. Sulphobromophthalein did not stimulate the activities of DD2 and human liver aldehyde reductase, which are functionally and/or structurally related to DD4. No stimulatory effect on the activity of DD4 was observed with other organic anions such as Indocyanine Green, haematin and Rose Bengal. The binding of sulphobromophthalein to DD4 was instantaneous and reversible, and was detected by fluorescence and ultrafiltration assays. The activation by sulphobromophthalein decreased the activation energy in the dehydrogenation reaction for the enzyme, and increased both kcat, and Km values for the coenzymes and substrates. Kinetic analyses with respect to concentrations of NADP+ and (S)-(+)-indan-1-ol indicated that sulphobromophthalein was a non-essential activator of mixed type showing a dissociation constant of 2.6 microM. Thus, the human 3 alpha-hydroxysteroid dehydrogenase isoenzyme has a binding site specific to sulphobromophthalein, and the hepatic metabolism mediated by this isoenzyme may be influenced when this drug is administered. PMID:8546681

Photoinduced electron transfer (PET) versus excimer formation in supramolecular p/n-heterojunctions of perylene bisimide dyes and implications for organic photovoltaics.

PubMed

Nowak-Król, Agnieszka; Fimmel, Benjamin; Son, Minjung; Kim, Dongho; Würthner, Frank

2015-01-01

Foldamer systems comprised of two perylene bisimide (PBI) dyes attached to the conjugated backbones of 1,2-bis(phenylethynyl)benzene and phenylethynyl-bis(phenylene)indane, respectively, were synthesized and investigated with regard to their solvent-dependent properties. UV/Vis absorption and steady-state fluorescence spectra show that both foldamers exist predominantly in a folded H-aggregated state consisting of π-π-stacked PBIs in THF and in more random conformations with weaker excitonic coupling between the PBIs in chloroform. Time-resolved fluorescence spectroscopy and transient absorption spectroscopy reveal entirely different relaxation pathways for the photoexcited molecules in the given solvents, i.e. photoinduced electron transfer leading to charge separated states for the open conformations (in chloroform) and relaxation into excimer states with red-shifted emission for the stacked conformations (in THF). Supported by redox data from cyclic voltammetry and Rehm-Weller analysis we could relate the processes occurring in these solution-phase model systems to the elementary processes in organic solar cells. Accordingly, only if relaxation pathways such as excimer formation are strictly avoided in molecular semiconductor materials, excitons may diffuse over larger distances to the heterojunction interface and produce photocurrent via the formation of electron/hole pairs by photoinduced electron transfer.

The "Case of Two Compounds with Similar Configuration but Nearly Mirror Image CD Spectra" Refuted. Reassignment of the Absolute Configuration of N-Formyl-3',4'-dihydrospiro[indan-1,2'(1'H)-pyridine].

PubMed

Padula, Daniele; Di Bari, Lorenzo; Pescitelli, Gennaro

2016-09-02

In 1997, Sandström and co-workers reported the case of two chiral spiro compounds with very similar skeletons but showing almost mirror-image electronic circular dichroism (ECD) spectra for the corresponding absolute configuration. The paper has been often cited as a proof and good educational example of the pronounced sensitivity of ECD toward molecular conformation, and a clear warning against the use of ECD spectral correlations to assign absolute configurations. Although both concepts remain valid, they are not exemplified by the quoted paper. We demonstrate that the original configurational assignment of one compound was wrong and revise it by using TDDFT calculations. The main reason for the observed failure is the use of the matrix method, a popular approach to predict ECD spectra of compounds which can be treated with an independent system approximation (ISA), including proteins. Using a modern version of the matrix method, we demonstrate that the ISA is not valid for the title compound. Even in the absence of apparent conjugation between the component chromophores, the validity of the ISA should never be taken for granted and the effective extent of orbital overlap should always be verified.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bercovici, B.; Wassermann, M.; Cucos, S.

Polychlorinated biphenyls and some organochlorine insecticides (DDT isomers and their metabolites, indane (..gamma..-BHC), dieldrin, heptachlor epoxide) were assessed in the serum of 17 women with recent missed abortions, 7 women who experienced one or several missed abortions in their past, and 7 women with normal, second trimester pregnancy. Fifty-three percent of the cases of recent missed abortion had PCB serum levels higher than the mean plus two standard deviations of the control group. The mean PCB serum level in women with recent missed abortion and relatively high PCB serum levels was significantly different from that of the control group (103.04more » versus 20.69 ppb,P<0.001). The mean PCB serum level of the former missed abortions group was also significantly different from that of the control group (82.00 versus 20.69 ppb, P<0.001). The quantity of the higher chlorinated biphenyl homologues (penta- and hexachlorobiphenyls) was increased in the high PCB level, missed abortion group and in the former missed abortion group, while the lower chlorinated biphenyl homologues were decreased in these groups in comparsion with the control group. The fact that the former missed abortion group showed increased PCB serum levels similar to those found in the high PCB level, recent missed abortion group confirms the existence of an association between relatively high PCB serum levels and the occurance of missed abortion. (JMT)« less

Identification of persisten anionic surfactant-derived chemicals in sewage effluent and groundwater

USGS Publications Warehouse

Field, J.A.; Leenheer, J.A.; Thorn, K.A.; Barber, L.B.; Rostad, C.; Macalady, D.L.; Daniel, S.R.

1992-01-01

Preparative isolation and fractionation procedures coupled with spectrometric analyses were used to identify surfactant-derived contaminants in sewage effluent and sewage-contaminated groundwater from a site located on Cape Cod, Massachusetts. Anionic surfactants and their biodegradation intermediates were isolated from field samples by ion exchange and fractionated by solvent extraction and adsorption chromatography. Fractions were analyzed by 13C nuclear magnetic resonance spectrometry and gas chromatography-mass spectrometry. Carboxylated residues of alkylphenol polyethoxylate surfactants were detected in sewage effluent and contaminated groundwater. Linear alkylbenzenesulfonates (LAS) were identified in sewage effluent and groundwater. Groundwater LAS composition suggested preferential removal of select isomers and homologs due to processes of biodegradation and partitioning. Tetralin and indane sulfonates (DATS), alicyclic analogs of LAS, were also identified in field samples. Although DATS are a minor portion of LAS formulations, equivalent concentrations of LAS and DATS in groundwater suggested persistence of alicyclic contaminant structures over those of linear structure. Sulfophenyl-carboxylated (SPC) LAS biodegradation intermediates were determined in sewage effluent and groundwater. Homolog distributions suggested that SPC containing 3-10 alkyl-chain carbons persist during infiltration and groundwater transport. Surfactant-derived residues detected in well F300-50 groundwater have a minimum residence time in the range of 2.7-4.6 yr. LAS detected in groundwater at 500 m from infiltration has been stable over an estimated 50-500 half lives.

Identification of persistent anionic surfactant-derived chemicals in sewage effluent and groundwater

USGS Publications Warehouse

Field, Jennifer A.; Leenheer, Jerry A.; Thorn, Kevin A.; Barber, Larry B.; Rostad, Colleen; Macalady, Donald L.; Daniel, Stephen R.

1992-01-01

Preparative isolation and fractionation procedures coupled with spectrometric analyses were used to identify surfactant-derived contaminants in sewage effluent and sewage-contaminated groundwater from a site located on Cape Cod, Massachusetts. Anionic surfactants and their biodegradation intermediates were isolated from field samples by ion exchange and fractionated by solvent extraction and adsorption chromatography. Fractions were analyzed by 13C nuclear magnetic resonance spectrometry and gas chromatography-mass spectrometry. Carboxylated residues of alkylphenol polyethoxylate surfactants were detected in sewage effluent and contaminated groundwater. Linear alkylbenzenesulfonates (LAS) were identified in sewage effluent and groundwater. Groundwater LAS composition suggested preferential removal of select isomers and homologs due to processes of biodegradation and partitioning. Tetralin and indane sulfonates (DATS), alicyclic analogs of LAS, were also identified in field samples. Although DATS are a minor portion of LAS formulations, equivalent concentrations of LAS and DATS in groundwater suggested persistence of alicyclic contaminant structures over those of linear structure. Sulfophenyl-carboxylated (SPC) LAS biodegradation intermediates were determined in sewage effluent and groundwater. Homolog distributions suggested that SPC containing 3–10 alkyl-chain carbons persist during infiltration and groundwater transport. Surfactant-derived residues detected in well F300-50 groundwater have a minimum residence time in the range of 2.7–4.6 yr. LAS detected in groundwater at 500 m from infiltration has been stable over an estimated 50–500 half lives.

Can two-dimensional gas chromatography/mass spectrometric identification of bicyclic aromatic acids in petroleum fractions help to reveal further details of aromatic hydrocarbon biotransformation pathways?

PubMed

West, Charles E; Pureveen, Jos; Scarlett, Alan G; Lengger, Sabine K; Wilde, Michael J; Korndorffer, Frans; Tegelaar, Erik W; Rowland, Steven J

2014-05-15

The identification of key acid metabolites ('signature' metabolites) has allowed significant improvements to be made in our understanding of the biodegradation of petroleum hydrocarbons, in reservoir and in contaminated natural systems, such as aquifers and seawater. On this basis, anaerobic oxidation is now more widely accepted as one viable mechanism, for instance. However, identification of metabolites in the complex acid mixtures from petroleum degradation is challenging and would benefit from use of more highly resolving analytical methods. Comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry (GCxGC/TOFMS) with both nominal mass and accurate mass measurement was used to study the complex mixtures of aromatic acids (as methyl esters) in petroleum fractions. Numerous mono- and di-aromatic acid isomers were identified in a commercial naphthenic acids fraction from petroleum and in an acids fraction from a biodegraded petroleum. In many instances, compounds were identified by comparison of mass spectral and retention time data with those of authentic compounds. The identification of a variety of alkyl naphthalene carboxylic and alkanoic and alkyl tetralin carboxylic and alkanoic acids, plus identifications of a range of alkyl indane acids, provides further evidence for 'signature' metabolites of biodegradation of aromatic petroleum hydrocarbons. Identifications such as these now offer the prospect of better differentiation of metabolites of bacterial processes (e.g. aerobic, methanogenic, sulphate-reducing) in polar petroleum fractions. Copyright © 2014 John Wiley & Sons, Ltd.

Bent CNN bond of diazo compounds, RR'(Cdbnd N+dbnd N-)

NASA Astrophysics Data System (ADS)

Akita, Motoko; Takahashi, Mai; Kobayashi, Keiji; Hayashi, Naoto; Tukada, Hideyuki

2013-02-01

The reaction of ninhydrin with benzophenone hydrazone afforded 2-diazo-3-diphenylmethylenehydrazono-1-indanone 1 and 2-diazo-1,3-bis(diphenylmethylenehydrazono)indan 2. X-ray crystal structure analyses of these products showed that the diazo functional group Cdbnd N+dbnd N- of 1 is bent by 172.9°, while that of 2 has a linear geometry. The crystal structure data of diazo compounds have been retrieved from the Cambridge Structural Database (CSD), which hit 177 entries to indicate that the angle of 172.9° in 1 lies in one of the most bent structures. The CSD search also indicated that diazo compounds consisting of a distorted diazo carbon tend to bend the Cdbnd N+dbnd N- bond. On the basis of DFT calculations (B3LYP/6-311++G(d,p)) of model compounds, it was revealed that the bending of the CNN bond is principally induced by steric factors and that the neighboring carbonyl group also plays a role in bending toward the carbonyl side owing to an electrostatic attractive interaction. The potential surface along the path of Cdbnd N+dbnd N- bending in 2-diazopropane shows a significantly shallow profile with only 4 kcal/mol needed to bend the Cdbnd N+dbnd N- bond from 180° to 160°. Thus, the bending of the diazo group in 1 is reasonable as it is provided with all of the factors for facile bending disclosed in this investigation.

2,4-Dinitrotoluene dioxygenase from Burkholderia sp. strain DNT: similarity to naphthalene dioxygenase.

PubMed Central

Suen, W C; Haigler, B E; Spain, J C

1996-01-01

2,4-Dinitrotoluene (DNT) dioxygenase from Burkholderia sp. strain DNT catalyzes the initial oxidation of DNT to form 4-methyl-5-nitrocatechol (MNC) and nitrite. The displacement of the aromatic nitro group by dioxygenases has only recently been described, and nothing is known about the evolutionary origin of the enzyme systems that catalyze these reactions. We have shown previously that the gene encoding DNT dioxygenase is localized on a degradative plasmid within a 6.8-kb NsiI DNA fragment (W.-C. Suen and J. C. Spain, J. Bacteriol. 175:1831-1837, 1993). We describe here the sequence analysis and the substrate range of the enzyme system encoded by this fragment. Five open reading frames were identified, four of which have a high degree of similarity (59 to 78% identity) to the components of naphthalene dioxygenase (NDO) from Pseudomonas strains. The conserved amino acid residues within NDO that are involved in cofactor binding were also identified in the gene encoding DNT dioxygenase. An Escherichia coli clone that expressed DNT dioxygenase converted DNT to MNC and also converted naphthalene to (+)-cis-(1R,2S)-dihydroxy-1,2-dihydronaphthalene. In contrast, the E. coli clone that expressed NDO did not oxidize DNT. Furthermore, the enzyme systems exhibit similar broad substrate specificities and can oxidize such compounds as indole, indan, indene, phenetole, and acenaphthene. These results suggest that DNT dioxygenase and the NDO enzyme system share a common ancestor. PMID:8759857

'Legal highs'--novel and emerging psychoactive drugs: a chemical overview for the toxicologist.

PubMed

Gibbons, Simon

2012-01-01

'Legal highs' are psychoactive chemicals which are sold from 'head shops', the internet and from street suppliers and may be possessed without legal restriction. An increase in the marketing of these materials has resulted in a corresponding increase in published reports of their adverse effects. However, a lack of primary literature pertaining to their chemistry, pharmacology and toxicology, makes an evaluation of their harm difficult. This review covers the basic chemistry of these novel psychoactive compounds and relates them to endogenous neurotransmitters and existing drugs of abuse. A survey of the internet was used to identify websites that are marketing 'legal highs' in the UK. Trivial and systematic chemical compound names, for example methoxetamine, 4-methoxyphencycline, 4-fluorotropacocaine and ethyl phenidate were entered into PubMed to retrieve data on these compounds. This search elicited no citations. Other search terms which were more fruitful included desoxypipradrol, diphenylprolinol, methylenedioxy-2-amino-indane and methylenedioxy-2-amino-tetralin, alpha-methyltryptamine and 5-methoxy-N,N-diallyl-tryptamine. 'Legal highs' from the phenylethylamine, cocaine, tryptamine and phencyclidine classes are increasingly being marketed and, in the majority of cases, little is cited in the literature on their true chemical identity, pharmacology or toxicology. 'Legal highs' are gaining in popularity and present clear challenges to toxicologists and society as a whole. Whilst improved use of existing legislation and development of new legislation can be used to reduce the supply of these materials, investment in better education for young people on the harms associated with 'legal highs' is needed.

Changing the chemical and physical properties of high valent heterobimetallic bis-(μ-oxido) Cu-Ni complexes by ligand effects.

PubMed

Kafentzi, Maria-Chrysanthi; Orio, Maylis; Réglier, Marius; Yao, Shenglai; Kuhlmann, Uwe; Hildebrandt, Peter; Driess, Matthias; Simaan, A Jalila; Ray, Kallol

2016-10-12

Two new heterobimetallic [LNiO 2 Cu(RPY2)] + (RPY2 = N-substituted bis 2-pyridyl(ethylamine) ligands with R = indane, 3a or R = Me, 3b) complexes have been spectroscopically trapped at low temperatures. They were prepared by reacting the mononuclear side-on LNi II superoxo precursor bearing a β-diketiminate ligand (L = [HC-(CMeNC 6 H 3 (iPr) 2 ) 2 ]) with the Cu(i) complexes. In contrast to the oxo groups in known high-valent [M 2 (μ-O) 2 ] n+ (M = Fe, Co, Ni, Cu) cores that display electrophilic reactivities, 3a and 3b display rather nucleophilic oxo cores active in aldehyde deformylation reactions. However, the spectroscopic and reactivity properties of 3a/3b are found to be distinct relative to that of the previously reported [LNiO 2 Cu(MeAN)] + complex containing a more basic (nucleophilic) N,N,N',N',N'-pentamethyl-dipropylenetriamine (MeAN) ligand at the copper centre. The geometry and electronic properties of the copper ligands affect the electron density of the oxygen atoms of the heterodinuclear {Ni(μ-O) 2 } core and 3a/3b undergo slower nucleophilic and faster electrophilic reactions than the previously reported [LNiO 2 Cu(MeAN)] + intermediate. The present study therefore demonstrates the tuning of the electrophilicity/nucleophilicity of the oxygen atoms of the heterobimetallic [Ni(μ-O) 2 Cu] 2+ cores by controlling the electron donation from the ancillary ligands, and underlines the significance of subtle electronic changes in the physical and chemical properties of the biologically relevant heterobimetallic metal-dioxygen intermediates.

DCPIB, a potent volume-regulated anion channel antagonist, attenuates microglia-mediated inflammatory response and neuronal injury following focal cerebral ischemia.

PubMed

Han, Qingdong; Liu, Shengwen; Li, Zhengwei; Hu, Feng; Zhang, Qiang; Zhou, Min; Chen, Jingcao; Lei, Ting; Zhang, Huaqiu

2014-01-13

Accumulating evidence indicates that extensive microglia activation-mediated local inflammation contributes to neuronal injury in cerebral ischemia. We have previously shown that 4-(2-butyl-6, 7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), a potent volume-regulated anion channel (VRAC) inhibitor, suppresses pathological glutamate release and excitatory neurotoxicity in reversible middle cerebral artery occlusion (rMCAO) model in vivo. In the present study, we sought to determine whether DCPIB also attenuates microglia activation that could contribute to neuronal injury in the cerebral ischemia/reperfusion pathology. We show that oxygen-glucose deprivation (OGD) induced microglia proliferation, migration, and secretion of cytokines and all these pathological changes were effectively inhibited by DCPIB in vitro. In the microglia/neuron co-cultures, OGD induced neuronal damage was reduced markedly in the presence of DCPIB. In rat rMCAO animal model, DCPIB significantly attenuated microglia activation and neuronal death. Activation of mitogen-activated protein kinase (MAPK) signaling pathway is known to be a critical signaling pathway for microglia activation. We further explored a potential involvement of DCPIB in this pathway by western blot analysis. Under the conditions that MAPK pathway was activated either by lipopolysaccharides (LPS) or OGD, the levels of phosphorylated ERK1/2, JNK and p38 were reduced significantly in the presence of DCPIB. Altogether, our study demonstrated that DCPIB inhibits microglia activation potently under ischemic conditions both in vitro and in vivo. The DCPIB effect is likely attributable to both direct inhibition VRAC and indirect inhibition of MAPK pathway in microglia that are beneficial for the survival of neurons in cerebral ischemic conditions. © 2013 Elsevier B.V. All rights reserved.

Measurements of Selected Brominated Flame Retardants in Nursing Women: Implications for Human Exposure

PubMed Central

2014-01-01

We have examined several emerging brominated flame retardants (BFRs) including 2-ethyl-1-hexyl-2,3,4,5-tetrabromobenzoate (TBB), bis(2-ethylhexyl) tetrabromophthalate (TBPH), 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE), 4,5,6,7-tetrabromo-1,1,3-trimethyl-3-(2,3,4,5-tetrabromophenyl)-indane (OBIND), and decabromodiphenyl ethane (DBDPE) in paired human maternal serum (n = 102) and breast milk (n = 105) collected in 2008–2009 in the Sherbrooke region in Canada. Three legacy BFRs were also included in the study for comparison: decabromobiphenyl (BB-209), 2,2′,4,4′,5,5′-hexabromobiphenyl (BB-153), and 2,2′,4,4′,5,5′-hexabromodiphenyl ethers (BDE-153). TBB, BB-153, and BDE-153 had detection frequencies greater than 55% in both serum and milk samples. Their lipid weight (lw) adjusted median concentrations (ng g–1 lw) in serum and milk were 1.6 and 0.41 for TBB, 0.48 and 0.31 for BB-153, and 1.5 and 4.4 for BDE-153, respectively. The detection frequencies for the other BFRs measured in serum and milk were 16.7% and 32.4% for TBPH, 3.9% and 0.0% for BTBPE, 2.0% and 0.0% for BB-209, 9.8% and 1.0% for OBIND, and 5.9% and 8.6% for DBDPE. The ratio of TBB over the sum of TBB and TBPH (fTBB) in serum (0.23) was lower than that in milk (0.46), indicating TBB has a larger tendency than TBPH to be redistributed from blood to milk. Overall, these data confirm the presence of non-PBDE BFRs in humans, and the need to better understand their sources, routes of exposure, and potential human health effects. PMID:24992303

A novel screening method for 64 new psychoactive substances and 5 amphetamines in blood by LC-MS/MS and application to real cases.

PubMed

Vaiano, Fabio; Busardò, Francesco P; Palumbo, Diego; Kyriakou, Chrystalla; Fioravanti, Alessia; Catalani, Valeria; Mari, Francesco; Bertol, Elisabetta

2016-09-10

Identification and quantification of new psychoactive substances (NPS), both in biological and non-biological samples, represent a hard challenge for forensic toxicologists. NPS are increasingly emerging on illegal drug market. Many cases of co-consumption of NPS and other substances have also been reported. Hence, the development of analytical methods aiming at the detection of a broad-spectrum of compounds (NPS and "traditional" drugs) could be helpful. In this paper, a fully validated screening method in blood for the simultaneous detection of 69 substances, including 64 NPS (28 synthetic cannabinoids, 19 synthetic cathinones, 5 phenethylamines, 3 indanes, 2 piperazines, 2 tryptamines, 2 phencyclidine, methoxetamine, ketamine and its metabolite) and 5 amphetamines (amphetamine, methamphetamine, MDMA, MDA, 3,4-methylenedioxy-N-ethylamphetamine - MDEA-) by a dynamic multiple reaction monitoring analysis through liquid chromatography - tandem mass spectrometry (LC-MS/MS) is described. This method is very fast, easy to perform and cheap as it only requires the deproteinization of 200μL of blood sample with acetonitrile. The chromatographic separation is achieved with a C18 column. The analysis is very sensitive, with limits of quantification ranging from 0.1 to 0.5ng/mL. The method is linear from 1 to 100ng/mL and the coefficient of determination (R(2)) was always above 0.9900. Precision and accuracy were acceptable at any quality control level and recovery efficiency range was 72-110%. Matrix effects did not negatively affect the analytical sensitivity. This method was successfully applied to three real cases, allowing identification and quantification of: mephedrone and methamphetamine (post-mortem); ketamine, MDMA and MDA (post-mortem); AB-FUBINACA (ante-mortem). Copyright © 2016 Elsevier B.V. All rights reserved.

Inhibition of Bovine Viral Diarrhea Virus RNA Synthesis by Thiosemicarbazone Derived from 5,6-Dimethoxy-1-Indanone▿

PubMed Central

Castro, Eliana F.; Fabian, Lucas E.; Caputto, María E.; Gagey, Dolores; Finkielsztein, Liliana M.; Moltrasio, Graciela Y.; Moglioni, Albertina G.; Campos, Rodolfo H.; Cavallaro, Lucía V.

2011-01-01

In the present work, we described the activity of the thiosemicarbazone derived from 5,6-dimethoxy-1-indanone (TSC), which we previously characterized as a new compound that inhibits bovine viral diarrhea virus (BVDV) infection. We showed that TSC acts at a point of time that coincides with the onset of viral RNA synthesis and that it inhibits the activity of BVDV replication complexes (RCs). Moreover, we have selected five BVDV mutants that turned out to be highly resistant to TSC but still susceptible to ribavirin (RBV). Four of these resistant mutants carried an N264D mutation in the viral RNA-dependent RNA polymerase (RdRp). The remaining mutant showed an A392E mutation within the same protein. Some of these mutants replicated slower than the wild-type (wt) virus in the absence of TSC, whereas others showed a partial reversion to the wt phenotype over several passages in the absence of the compound. The docking of TSC in the crystal structure of the BVDV RdRp revealed a close contact between the indane ring of the compound and several residues within the fingers domain of the enzyme, some hydrophobic contacts, and hydrogen bonds with the thiosemicarbazone group. Finally, in the mutated RdRp from resistant BVDV, these interactions with TSC could not be achieved. Interestingly, TSC inhibited BVDV replication in cell culture synergistically with RBV. In conclusion, TSC emerges as a new nonnucleoside inhibitor of BVDV RdRp that is synergistic with RBV, a feature that turns it into a potential compound to be evaluated against hepatitis C virus (HCV). PMID:21430053

Inhibition of bovine viral diarrhea virus RNA synthesis by thiosemicarbazone derived from 5,6-dimethoxy-1-indanone.

PubMed

Castro, Eliana F; Fabian, Lucas E; Caputto, María E; Gagey, Dolores; Finkielsztein, Liliana M; Moltrasio, Graciela Y; Moglioni, Albertina G; Campos, Rodolfo H; Cavallaro, Lucía V

2011-06-01

In the present work, we described the activity of the thiosemicarbazone derived from 5,6-dimethoxy-1-indanone (TSC), which we previously characterized as a new compound that inhibits bovine viral diarrhea virus (BVDV) infection. We showed that TSC acts at a point of time that coincides with the onset of viral RNA synthesis and that it inhibits the activity of BVDV replication complexes (RCs). Moreover, we have selected five BVDV mutants that turned out to be highly resistant to TSC but still susceptible to ribavirin (RBV). Four of these resistant mutants carried an N264D mutation in the viral RNA-dependent RNA polymerase (RdRp). The remaining mutant showed an A392E mutation within the same protein. Some of these mutants replicated slower than the wild-type (wt) virus in the absence of TSC, whereas others showed a partial reversion to the wt phenotype over several passages in the absence of the compound. The docking of TSC in the crystal structure of the BVDV RdRp revealed a close contact between the indane ring of the compound and several residues within the fingers domain of the enzyme, some hydrophobic contacts, and hydrogen bonds with the thiosemicarbazone group. Finally, in the mutated RdRp from resistant BVDV, these interactions with TSC could not be achieved. Interestingly, TSC inhibited BVDV replication in cell culture synergistically with RBV. In conclusion, TSC emerges as a new nonnucleoside inhibitor of BVDV RdRp that is synergistic with RBV, a feature that turns it into a potential compound to be evaluated against hepatitis C virus (HCV).

Non-Halal biomarkers identification based on Fourier Transform Infrared Spectroscopy (FTIR) and Gas Chromatography-Time of Flight Mass Spectroscopy (GC-TOF MS) techniques

NASA Astrophysics Data System (ADS)

Witjaksono, Gunawan; Saputra, Irwan; Latief, Marsad; Jaswir, Irwandi; Akmeliawati, Rini; Abdelkreem Saeed Rabih, Almur

2017-11-01

Consumption of meat from halal (lawful) sources is essential for Muslims. The identification of non-halal meat is one of the main issues that face consumers in meat markets, especially in non-Islamic countries. Pig is one of the non-halal sources of meat, and hence pig meat and its derivatives are forbidden for Muslims to consume. Although several studies have been conducted to identify the biomarkers for nonhalal meats like pig meat, these studies are still in their infancy stages, and as a result there is no universal biomarker which could be used for clear cut identification. The purpose of this paper is to use Fourier Transform Infrared Spectroscopy (FTIR) and Gas Chromatography-Time of Flight Mass Spectroscopy (GC-TOF MS) techniques to study fat of pig, cow, lamb and chicken to find possible biomarkers for pig fat (lard) identification. FTIR results showed that lard and chicken fat have unique peaks at wavenumbers 1159.6 cm-1, 1743.4 cm-1, 2853.1 cm-1 and 2922.5 cm-1 compared to lamb and beef fats which did not show peaks at these wavenumbers. On the other hand, GC/MS-TOF results showed that the concentration of 1,2,3-trimethyl-Benzene, Indane, and Undecane in lard are 250, 14.5 and 1.28 times higher than their concentrations in chicken fat, respectively, and 91.4, 2.3 and 1.24 times higher than their concentrations in cow fat, respectively. These initial results clearly indicate that there is a possibility to find biomarkers for non-halal identification.

Effect of dissolved oxygen manipulation on diffusive emissions from NAPL-impacted low permeability soil layers.

PubMed

Clifton, Lisa M; Dahlen, Paul R; Johnson, Paul C

2014-05-06

Aquifer physical model experiments were performed to investigate if diffusive emissions from nonaqueous phase liquid (NAPL)-impacted low-permeability layers into groundwater moving through adjacent NAPL-free high-permeability layers can be reduced by creating an aerobic biotreatment zone at the interface between the two, and if over time that leads to reduced emissions after treatment ceases. Experiments were performed in two 1.2-m long × 1.2-m high × 5.4 cm wide stainless steel tanks; each with a high-permeability sand layer overlying a low-permeability crushed granite layer containing a NAPL mixture of indane and benzene. Each tank was water-saturated with horizontal flow primarily through the sand layer. The influent water was initially deoxygenated and the emissions and concentration distributions were allowed to reach near-steady conditions. The influent dissolved oxygen (DO) level was increased stepwise to 6.5-8.5 mg/L and 17-20 mg/L, and then decreased back to deoxygenated conditions. Each condition was maintained for at least 45 days. Relative to the near-steady benzene emission at the initial deoxygenated condition, the emission was reduced by about 70% when the DO was 6.5-8.5 mg/L, 90% when the DO was 17-20 mg/L, and ultimately 60% when returning to low DO conditions. While the reductions were substantial during treatment, longer-term reductions after 120 d of elevated DO treatment, relative to an untreated condition predicted by theory, were low: 29% and 6% in Tank 1 and Tank 2, respectively. Results show a 1-2 month lag between the end of DO delivery and rebound to the final near-steady emissions level. This observation has implications for post-treatment performance monitoring sampling at field sites.

Assessment of the discriminative stimulus effects of the D3 dopamine antagonist PNU-99194A in rats: comparison with psychomotor stimulants.

PubMed

Baker, L E; Miller, M E; Svensson, K A

1997-06-01

The present study examined the discriminative stimulus effects of the D3 dopamine receptor antagonist PNU-99194A [5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride] in male Sprague-Dawley rats. Eight rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline in a two-choice, water-reinforced drug discrimination procedure. In tests of stimulus generalization, PNU-99194A (1.25-40.0 mg/kg, s.c. and i.p.) did not substitute for cocaine. PNU-99194A (5.0-20 mg/kg) also did not significantly block the discrimination of cocaine (10 mg/kg), nor did it potentiate a low dose (1.25 mg/kg) of cocaine. A separate group of eight rats were trained to discriminate PNU-99194A from saline. These subjects met the discrimination criterion within an average of 68 (S.E.M. = 6.5) training sessions; the ED50 for PNU-99194A was 2.6 mg/kg. In stimulus generalization tests, cocaine (1.25-10 mg/kg) did not substitute for PNU-99194A, when administered by either i.p. or by s.c. injection. In addition, neither amphetamine (0.25-1.0 mg/kg) nor caffeine (8.0-64 mg/kg) produced stimulus generalization in these rats. These results indicate that D3 receptors do not play a critical role in the discriminative stimulus effects of cocaine. Furthermore, although PNU-99194A is capable of establishing and maintaining discriminative stimulus control in rats, the effects of this D3-preferring antagonist are dissimilar from those of psychomotor stimulants. Given the unique behavioral profile of D3 receptor antagonists, the potential utility of these agents as adjunctive treatments for psychostimulant abuse is discussed.

On the Involvement of Single-Bond Rotation in the Primary Photochemistry of Photoactive Yellow Protein

PubMed Central

Stahl, Andreas D.; Hospes, Marijke; Singhal, Kushagra; van Stokkum, Ivo; van Grondelle, Rienk; Groot, Marie Louise; Hellingwerf, Klaas J.

2011-01-01

Prior experimental observations, as well as theoretical considerations, have led to the proposal that C4-C7 single-bond rotation may play an important role in the primary photochemistry of photoactive yellow protein (PYP). We therefore synthesized an analog of this protein's 4-hydroxy-cinnamic acid chromophore, (5-hydroxy indan-(1E)-ylidene)acetic acid, in which rotation across the C4-C7 single bond has been locked with an ethane bridge, and we reconstituted the apo form of the wild-type protein and its R52A derivative with this chromophore analog. In PYP reconstituted with the rotation-locked chromophore, 1), absorption spectra of ground and intermediate states are slightly blue-shifted; 2), the quantum yield of photochemistry is ∼60% reduced; 3), the excited-state dynamics of the chromophore are accelerated; and 4), dynamics of the thermal recovery reaction of the protein are accelerated. A significant finding was that the yield of the transient ground-state intermediate in the early phase of the photocycle was considerably higher in the rotation-locked samples than in the corresponding samples reconstituted with p-coumaric acid. In contrast to theoretical predictions, the initial photocycle dynamics of PYP were observed to be not affected by the charge of the amino acid residue at position 52, which was varied by 1), varying the pH of the sample between 5 and 10; and 2), site-directed mutagenesis to construct R52A. These results imply that C4-C7 single-bond rotation in PYP is not an alternative to C7=C8 double-bond rotation, in case the nearby positive charge of R52 is absent, but rather facilitates, presumably with a compensatory movement, the physiological Z/E isomerization of the blue-light-absorbing chromophore. PMID:21889456

The 5HT(1A) receptor ligand, S15535, antagonises G-protein activation: a [35S]GTPgammaS and [3H]S15535 autoradiography study.

PubMed

Newman-Tancredi, A; Rivet, J; Chaput, C; Touzard, M; Verrièle, L; Millan, M J

1999-11-19

4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine (S15535) is a highly selective ligand at 5-HT(1A) receptors. The present study compared its autoradiographic labelling of rat brain sections with its functional actions, visualised by guanylyl-5'-[gamma-thio]-triphosphate ([35S]GTPgammaS) autoradiography, which affords a measure of G-protein activation. [3H]S15535 binding was highest in hippocampus, frontal cortex, entorhinal cortex, lateral septum, interpeduncular nucleus and dorsal raphe, consistent with specific labelling of 5-HT(1A) receptors. In functional studies, S15535 (10 microM) did not markedly stimulate G-protein activation in any brain region, but abolished the activation induced by the selective 5-HT(1A) agonist, (+)-8-hydroxy-dipropyl-aminotetralin ((+)-8-OH-DPAT, 1 microM), in structures enriched in [3H]S15535 labelling. S15535 did not block 5-HT-stimulated activation in caudate nucleus or substantia nigra, regions where (+)-8-OH-DPAT was ineffective and [3H]S15535 binding was absent. Interestingly, S15535 attenuated (+)-8-OH-DPAT and 5-HT-stimulated G-protein activation in dorsal raphe, a region in which S15535 is known to exhibit agonist properties in vivo [Lejeune, F., Millan, M.J., 1998. Induction of burst firing in ventral tegmental area dopaminergic neurons by activation of serotonin (5-HT)(1A) receptors: WAY100,635-reversible actions of the highly selective ligands, flesinoxan and S15535. Synapse 30, 172-180.]. The present data show that (i) [3H]S15535 labels pre- and post-synaptic populations of 5-HT(1A) sites in rat brain sections, (ii) S15535 exhibits antagonist properties at post-synaptic 5-HT(1A) receptors in corticolimbic regions, and (iii) S15535 also attenuates agonist-stimulated G-protein activation at raphe-localised 5-HT(1A) receptors.

Bipyrimidine ruthenium(II) arene complexes: structure, reactivity and cytotoxicity.

PubMed

Betanzos-Lara, Soledad; Novakova, Olga; Deeth, Robert J; Pizarro, Ana M; Clarkson, Guy J; Liskova, Barbora; Brabec, Viktor; Sadler, Peter J; Habtemariam, Abraha

2012-10-01

The synthesis and characterization of complexes [(η(6)-arene)Ru(N,N')X][PF(6)], where arene is para-cymene (p-cym), biphenyl (bip), ethyl benzoate (etb), hexamethylbenzene (hmb), indane (ind) or 1,2,3,4-tetrahydronaphthalene (thn), N,N' is 2,2'-bipyrimidine (bpm) and X is Cl, Br or I, are reported, including the X-ray crystal structures of [(η(6)-p-cym)Ru(bpm)I][PF(6)], [(η(6)-bip)Ru(bpm)Cl][PF(6)], [(η(6)-bip)Ru(bpm)I][PF(6)] and [(η(6)-etb)Ru(bpm)Cl][PF(6)]. Complexes in which N,N' is 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6-dione or 4,7-diphenyl-1,10-phenanthroline (bathophen) were studied for comparison. The Ru(II) arene complexes undergo ligand-exchange reactions in aqueous solution at 310 K; their half-lives for hydrolysis range from 14 to 715 min. Density functional theory calculations on [(η(6)-p-cym)Ru(bpm)Cl][PF(6)], [(η(6)-p-cym)Ru(bpm)Br][PF(6)], [(η(6)-p-cym)Ru(bpm)I][PF(6)], [(η(6)-bip)Ru(bpm)Cl][PF(6)], [(η(6)-bip)Ru(bpm)Br][PF(6)] and [(η(6)-bip)Ru(bpm)I][PF(6)] suggest that aquation occurs via an associative pathway and that the reaction is thermodynamically favourable when the leaving ligand is I > Br ≈ Cl. pK (a)* values for the aqua adducts of the complexes range from 6.9 to 7.32. A binding preference for 9-ethylguanine (9-EtG) compared with 9-ethyladenine (9-EtA) was observed for [(η(6)-p-cym)Ru(bpm)Cl][PF(6)], [(η(6)-hmb)Ru(bpm)Cl](+), [(η(6)-ind)Ru(bpm)Cl](+), [(η(6)-thn)Ru(bpm)Cl](+), [(η(6)-p-cym)Ru(phen)Cl](+) and [(η(6)-p-cym)Ru(bathophen)Cl](+) in aqueous solution at 310 K. The X-ray crystal structure of the guanine complex [(η(6)-p-cym)Ru(bpm)(9-EtG-N7)][PF(6)](2) shows multiple hydrogen bonding. Density functional theory calculations show that the 9-EtG adducts of all complexes are thermodynamically preferred compared with those of 9-EtA. However, the bmp complexes are inactive towards A2780 human ovarian cancer cells. Calf thymus DNA interactions for [(η(6)-p-cym)Ru(bpm)Cl][PF(6)] and [(η(6)-p-cym)Ru(phen)Cl][PF(6)] consist of weak coordinative, intercalative and monofunctional coordination. Binding to biomolecules such as glutathione may play a role in deactivating the bpm complexes.

Specific labelling of serotonin 5-HT(1B) receptors in rat frontal cortex with the novel, phenylpiperazine derivative, [3H]GR125,743. A pharmacological characterization.

PubMed

Millan, M J; Newman-Tancredi, A; Lochon, S; Touzard, M; Aubry, S; Audinot, V

2002-04-01

Although several tritiated agonists have been used for radiolabelling serotonin (5-hydroxytryptamine, 5-HT)(1B) receptors in rats, data with a selective, radiolabelled antagonist have not been presented. Inasmuch as [3H]GR125,743 specifically labels cloned, human and native guinea pig 5-HT(1B) receptors and has been employed for characterization of cerebral 5-HT(1B) receptor in the latter species [Eur. J. Pharmacol. 327 (1997) 247.], the present study evaluated its utility for characterization of native, cerebral 5-HT(1B) sites in the rat. In homogenates of frontal cortex, [3H]GR125,743 (0.8 nM) showed rapid association (t(1/2)=3.4 min), >90% specific binding and high affinity (K(d)=0.6 nM) for a homogeneous population of receptors with a density (B(max)) of 160 fmol/mg protein. In competition binding studies, affinities were determined for 15 chemically diverse 5-HT(1B) agonists, including 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694,247; pK(i), 10.4), 5-carboxamidotryptamine (5-CT; 9.7), 3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylamide (GR46,611; 9.6), 5-methoxy-3-(1,2,5,6-tetrahydro-4-pyridinyl)-1H-indole (RU24,969; 9.5), dihydroergotamine (DHE; 8.6), 5-H-pyrrolo[3,2-b]pyridin-5-one,1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl (CP93,129; 8.4), anpirtoline (7.9), sumatriptan (7.4), 1-[2-(3-fluorophenyl)ethyl]-4-[3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]piperazine (L775,606; 6.4) and (minus sign)-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-N-methyl-3,4-dihydro-1H-2-benzopyran-6-carboxamide (PNU109,291; <5.0). Similarly, affinities were established for 13 chemically diverse antagonists, including N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide (GR125,743; pK(i), 9.1), (-)cyanopindolol (9.0), (-)-tertatolol (8.2), N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiozol-3-yl)biphenyl-4-carboxamide (GR127,935; 8.2), N-[3-(1,4-benzodioxan-5-yl)piperidin-4-yl]N-(indan-2yl)amine (S18127; 7.9), metergoline (7.8), (-)-pindolol (7.6), 1'-methyl-5-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-biphenyl-4-ylcarbonyl]-2,3,6,7-tetrahydro-5H-spiro[furo[2,3-f]indole-3,4'-piperidine] (SB224,289; 7.5) and ketanserin (<5.0). These rank orders of affinity correspond to the binding profile of 5-HT(1B) rather than 5-HT(1D) receptors. The low affinities of L775,066 and PNU109,291 versus L694,247 should be noted, as well as the low affinity of ketanserin as compared to SB224,289. Finally, in line with species differences, the affinities of several ligands including CP93,129, RU24,969, (-)-pindolol and (-)-propanolol in rat 5-HT(1B) sites were markedly different to guinea pig 5-HT(1B) sites labelled with [3H]GR125,743. In conclusion, [3H]GR125,743 is an appropriate tool for the radiolabelling of native, rat 5-HT(1B) receptors and permitted determination of the affinities of an extensive series of ligands at these sites.