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A sesquiterpene acid and flavonoids from Polygonum viscosum.

4-Isobutyl-6-methyl-5-oxo-3a,4,5,7a-tetrahydro-1H-inden-13-oic acid (named viscosumic acid) and quercetin 3-O-(6"-feruloyl)-beta-D-galactopyranoside, and the known 3',5-dihydroxy-3,4',5',7-tetramethoxyflavone have been isolated from Polygonum viscosum. The structures of these isolates were determined primarily on the basis of extensive 1D and 2D NMR spectral analyses, notably, 13C PENDANT, COSY45, TOCSY, GOESY, NOESY, HMQC and HMBC.

Flavonoids↗

Kinetic analysis of the inhibition of phenylalanine ammonia-lyase by 2-aminoindan-2-phosphonic acid and other phenylalanine analogues.

The conformationally restricted phenylalanine analogue 2-aminoindan-2-phosphonic acid (AIP) inhibits phenylalanine ammonia-lyase (PAL) competitively in a time-dependent manner. This phenomenon was investigated in more detail with the heterologously expressed, highly purified homotetrameric PAL-1 isozyme from parsley. The kinetic analysis revealed that the enzyme-inhibitor complex is formed in a single "slow" step with an association rate of k(2)=2.6+/-0.04 10(4) M(-1) s(-1). The inhibition is reversible with a dissociation rate of k(-2)=1.8+/-0.04 10(-4) s(-1) and an equilibrium constant of K(i)=7+/-2 nM. The previously described PAL inhibitor (S)-2-aminooxy-3-phenylpropanoic acid [(S)-AOPP] was also found to be a slow-binding inhibitor of PAL-1. The carboxyl analogue of AIP, 2-aminoindan-2-carboxylic acid, served as a substrate of PAL-1 and was converted to indene-2-carboxylic acid.

Binding Sites↗

Three isoflavanones with cannabinoid-like moieties from Desmodium canum.

Three further derivatives of 5,7,2',4'-tetrahydroxy-6-methyl isoflavanone have been isolated from the root extract of Desmodium canum and assigned the structures 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(1a,2,3,3a,8b,8c-hexahydro-6-hydroxy-1,1,3a-trimethyl-1H-4-oxabenzo[f]cyclobut[c,d]inden-7-yl)-4H-1-benzopyran-4-one (1) 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(6a,7,8,10a-tetrahydro-3-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-2-yl)-4H-1-benzopyran-4-one (2) 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(3-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-2-yl) 4H-1-benzopyran-4-one (3). The three compounds and the previously isolated chromene 4 all derive from the geranylated precursor 5 by a series of cannabinoid-like oxidative rearrangements.

Cannabinoids↗

PAHs composition of surface marine sediments: a comparison to potential local sources in Todos Santos Bay, B.C., Mexico.

The analysis of the 16 polyaromatic hydrocarbons (PAHs) listed as priority pollutants by EPA, was carried out on surface sediments at 32 stations at Todos Santos Bay, Baja California, Mexico. The purpose was to investigate concentration levels, distribution patterns and relate them to three suspected local sources. The PAHs composition of car exhaust, grass and shrubs combustion, and asphalt and tire dust, were all compared to the relative abundance of PAHs signature found on marine sediments of the bay. We used GC-MS analysis in selected ion monitoring (SIM) mode. The total concentration found was low (from 7.6 to 813 ng/g of dry sediment. The average concentration was 96 ng/g). PAHs concentration was somewhat correlated (r = 0.612; P < 0.05) with organic matter content. Surface distributions suggest depositional patterns conforming to the reported water circulation in the bay. The maximum concentration was found near Todos Santos Canyon. The largest concentrations found were those of fluoranthene (120.6 ng/g), Indene(1,2,3-c,d)pyrene (115.6 ng/g) and pyrene (109.9 ng/g). Percentagewise, the main components were PAHs with three and four rings. Several indexes were used to investigate origins including simple PAH ratios and ternary plots. These indexes and plots suggest the main origin as a combination of urban air and wood and brush fires with little influence of oil.

Geologic Sediments↗

Toxic by-products from the combustion of Kraft lignin.

Lignin samples, sub-product in the Kraft process of cellulose from eucalyptus wood, were burnt in a laboratory scale furnace at different residence temperatures and with distinct fuel-rich atmospheres. The yields of CO, CO(2), eight light hydrocarbons (methane, ethylene, ethane, propylene, acetylene, butane, etc.) and 60 semi-volatile+volatile compounds (benzene, toluene, ethylbenzene, styrene, indene, naphthalene, dibenzofuran, phenanthrene, chrysene, etc.) were determined, with nominal reactor temperatures between 800 and 1100 degrees C and residence times of the volatiles evolved and formed between 4 and 7 s. The collection of the gases and volatiles evolved was carried out with a Tedlar bag and by XAD-4 resin respectively, comparing the data obtained in both cases. The emission factor (mg/kg) of the CO was between 2500 and 90000, and under the poor-oxygen atmosphere, the emission factors of many by-toxic products were greater than 100 mg/kg. A pyrolysis run was also performed, obtaining emission factors between 30 and 3000 mg/kg, facilitating its identification. The behaviour of different compounds in the combustion runs was discussed considering three groups in accordance with their stability vs. oxygen, and two groups vs. temperature.

Air Pollutants↗

Atipamezole, an imidazoline-type alpha(2)-adrenoceptor inhibitor, binds to human platelets and inhibits their adrenaline-induced aggregation more effectively than yohimbine.

To investigate the usefulness of atipamezole [MPV-1248, 4-(2-ethyl-2, 3-dihydro-1H-inden-2-yl)-1H-imidazole], a novel alpha(2)-adrenoceptor-specific antagonist, as a tool in platelet studies, the ability of this antagonist: (1) to bind to platelet alpha(2)-adrenoceptors, and (2) to inhibit adrenaline-induced platelet aggregation was compared to that of yohimbine, another commonly used alpha(2)-adrenoceptor antagonist. It was found that atipamezole binds to platelet alpha(2)-adrenoceptors more effectively than yohimbine: [3H]atipamezole has more than three times higher alpha(2)-adrenoceptor binding affinity in intact gel-filtered human platelets (equilibrium dissociation constant (K(d)) 0.7+/-0.21 vs. 2.9+/-0.77 nM, p<0.05), but only one-third of the binding capacity of [3H]yohimbine (B(max) 27.0+/-3.8 vs. 100+/-19 pM/10(5) cells, p<0.01). Functionally, in comparison with yohimbine, an almost threefold lower concentration of atipamezole inhibited adrenaline (5 microM)-induced platelet aggregation. A concentration of atipamezole, which inhibited this aggregation by 50% (IC(50)), was 0.37+/-0.07 microM, whereas IC(50) for yohimbine was 0.98+/-0.12 microM, p<0.0001. Thus, atipamezole represents a functionally undisputed alpha(2)-adrenoceptor antagonist, more effective than yohimbine. Its distinct binding profile as a radioligand also suggests the presence of imidazol(in)e binding sites in platelets.

Adrenergic alpha-Agonists↗

Modulation of 5-HT(2A) receptor-mediated head-twitch behaviour in the rat by 5-HT(2C) receptor agonists.

The pharmacology of several commonly described 5-hydroxytryptamine (5-HT)(2C) receptor agonists was investigated in vivo and in vitro at rat 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. The 5-HT(2C) receptor agonist, (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine fumarate (Ro 60-0175), did not induce a significant head-twitch response when given alone, yet when administered to rats subsequent to an acute challenge with the selective 5-HT(2C) receptor antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbomyl] indoline (SB-242084), a robust head-twitch response was observed which was blocked by the selective 5-HT(2A) receptor antagonists R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl-ethyl)]-4-piperidine-methanol (MDL 100907) or ketanserin. The preferential 5-HT(2C) receptor agonists Ro 60-0175, 6-chloro-2-[1-piperazinyl]-pyrazine HCl (MK-212), 1-(3-chlorophenyl)piperazine hydrochloride (mCPP), 1-(3-trifluoromethylphenyl)piperazine hydrochloride (TFMPP), and (S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-pyrollidine HCl (ORG-37684), the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), the 5-HT(2B) receptor agonist 1-[5-thienylmethoxy-1-1H-3-indoyl] propan-2-amine hydrochloride (BW-723C86), and nor-D-fenfluramine were administered to rats subsequent to an acute challenge of SB-242084. Under such conditions, each agonist, with the exception of BW-723C86, induced a dose-dependent increase in the incidence of head twitches. The pharmacology of the same agonists was determined at cloned rat 5-HT(2) receptors using a fluorometric imaging plate reader (FLIPR). Both the in vivo and in vitro data suggest that for some ligands, previous reports have overestimated their in vivo selectivity for the 5-HT(2C) receptor.

Animals↗

Synthesis of ionones and carvone analogues: olfactory properties and preliminary toxicity assays.

Vilsmeier reagents react with alpha/beta-ionones and carvone to produce aldehydes 7-11 in a one-step procedure. The indene derivative 11, which came from the double iminoalkylation of carvone and ring closure with the elimination of dimethylamine, was practically odourless, while all the others had peculiar odours which were very different from the starting material. The cytotoxicity data of 9 and 10, which are the most promising potential perfume ingredients, are also reported.

Alkenes↗

Synthesis and in vivo evaluation of [11C]ICI 118551 as a putative subtype selective beta2-adrenergic radioligand.

Erytro-(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[ iso-propylamino]-2-butanol (ICI 118551) a potent clinically used beta2 adrenergic antagonist, was labelled with carbon-11 (t1/2 = 20.4 min) as a potential radioligand for the non-invasive assessment of beta2 adrenergic receptors in the lung with positron emission tomography (PET). The radiolabelled compound was prepared by reductive N-alkylation of its des-isopropyl precursor with [2-11C]acetone. (+/-)-[11C]ICI 118551 was obtained in greater than 98% radiochemical purity in 30 min with a radiochemical yield of 15 + 5% (non-decay corrected) and a specific radioactivity 2.5 +/- 0.5 Ci/micromol. The biological evaluation of racemic erythro (+/-)-[11C]ICI 118551 in rats and Macaca Nemestrina shows a high radioactivity uptake in lung and heart. However, in both animal models no detectable displacement of lung radioactivity concentration was observed after pre-treatment with propranolol or ICI 118551, which indicates that in this organ, radioligand uptake is mostly due to non-specific binding. The biological data suggest that erythro (+/-)-[11C]ICI 118551 is not adequate to be further developed as a tracer for beta2 adrenergic receptor imaging in vivo.

Adrenergic beta-2 Receptor Antagonists↗

Design and pharmacology of quinuclidine derivatives as M2-selective muscarinic receptor ligands.

In our search for M2-selective muscarinic receptor antagonists, we synthesized 1,3-disubstituted indenes. The effects of different basic moieties with regard to binding and selectivity towards the five distinct muscarinic receptor subtypes were investigated. The results show that the quinuclidine series afforded the most promising compounds in terms of both receptor affinity and M2-subtype selectivity.

Alzheimer Disease↗

Indanyl piperazines as melatonergic MT2 selective agents.

Optimization of a benzyl piperazine pharmacophore produced N-acyl-4-indanyl-piperazines that bind with high affinity to melatonergic MT(2) receptors. (R)-4-(2,3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine-carboxamide fumarate (13) is a water soluble, selective MT(2) agonist, which produces advances in circadian phase in rats at doses of 1-56 mg/kg that are no different from those of melatonin at 1 mg/kg. Unlike melatonin, 13 produced only weak contractile effects in rat tail artery.

3T3 Cells↗

3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB(1) cannabinoid receptor.

A series of 1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (9-11) and 2-methyl-1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (12-14) have been synthesized to investigate the hypothesis that cannabimimetic 3-(1-naphthoyl)indoles interact with the CB(1) receptor by hydrogen bonding to the carbonyl group. Indoles 9-11 have significant (K(i)=17-23nM) receptor affinity, somewhat less than that of the corresponding naphthoylindoles (5, 15, 16). 2-Methyl-1-indoles 12-14 have little affinity for the CB(1) receptor, in contrast to 2-methyl-3-(1-naphthoyl)indoles 17-19, which have affinities comparable to those of 5, 15, 16. A cannabimimetic indene hydrocarbon (26) was synthesized and found to have K(i)=26+/-4nM. Molecular modeling and receptor docking studies of naphthoylindole 16, its 2-methyl congener (19) and indolyl-1-naphthylmethanes 11 and 14, combined with the receptor affinities of these cannabimimetic indoles, strongly suggest that these cannabinoid receptor ligands bind primarily by aromatic stacking interactions in the transmembrane helix 3-4-5-6 region of the CB(1) receptor.

Cannabinoids↗

Structures of trihydroxynaphthalene reductase-fungicide complexes: implications for structure-based design and catalysis.

BACKGROUND: Trihydroxynaphthalene reductase catalyzes two intermediate steps in the fungal melanin biosynthetic pathway. The enzyme, a typical short-chain dehydrogenase, is the biochemical target of three commercial fungicides. The fungicides bind preferentially to the NADPH form of the enzyme. RESULTS: Three X-ray structures of the Magnaporthe grisea enzyme complexed with NADPH and two commercial and one experimental fungicide were determined at 1.7 A (pyroquilon), 2.0 A (2,3-dihydro-4-nitro-1H-inden-1-one, 1), and 2.1 A (phthalide) resolutions. The chemically distinct inhibitors occupy similar space within the enzyme's active site. The three inhibitors share hydrogen bonds with the side chain hydroxyls of Ser-164 and Tyr-178 via a carbonyl oxygen (pyroquilon and 1) or via a carbonyl oxygen and a ring oxygen (phthalide). Active site residues occupy similar positions among the three structures. A buried water molecule that is hydrogen bonded to the NZ nitrogen of Lys-182 in each of the three structures likely serves to stabilize the cationic form of the residue for participation in catalysis. CONCLUSIONS: The pro S hydrogen of NADPH (which is transferred as a hydride to the enzyme's naphthol substrates) is directed toward the carbonyl carbon of the inhibitors that mimic an intermediate along the reaction coordinate. Modeling tetrahydroxynaphthalene and trihydroxynaphthalene in the active site shows steric and electrostatic repulsion between the extra hydroxyl oxygen of the former substrate and the sulfur atom of Met-283 (the C-terminal residue), which accounts, in part, for the 4-fold greater substrate specificity for trihydroxynaphthalene over tetrahydroxynaphthalene.

Antifungal Agents↗

(+)-p-([18F]fluorobenzyl)spirotrozamicol [(+)-[18F]spiro-FBT]: synthesis and biological evaluation of a high-affinity ligand for the vesicular acetylcholine transporter (VAChT).

(+)-1'-[4-Hydroxy-1-(4-fluorobenzyl)piperidin-3-yl]spiro[1H- indene-1,4'- piperidine] {(+)-Spiro-FBT}, a high-affinity vesicular acetylcholine transporter ligand, was labeled with fluorine-18, and evaluated in the rat and monkey. In the rat brain, (+)-[18F]Spiro-FBT accumulated preferentially in the striatum, hippocampus, and cortex, brains regions containing high-to-moderate densities of cholinergic terminals. However, due to rapid metabolism, no preferential accumulation of the radiotracer was observed in corresponding regions of the monkey brain. Consequently, rapid metabolism renders (+)-[18F]Spiro-FBT unsuitable for studying cholinergic function with positron emission tomography.

Acetylcholine↗

A study of light-induced proton transfer from gas phase (radical) cations to reference bases. Bracketing of proton transfer from excited ions and associated reaction kinetics.

By use of Fourier transform ion cyclotron resonance, it is shown that protonated naphthalene when excited with laser light of 488 nm is more reactive in proton transfer to reference bases than in its ground state. The excitation leads to reaction with bases for which proton transfer in the ground state is endothermic up to a detected maximum of 60 kJ/mol. For indene radical cations excited at 514.5 nm, it is shown that the rate constant for proton transfer to 3-pentanone is either about 10 or about 100 times lower than the rate constant for relaxation by collisions with 3-pentanone. From the energy deposited in the ions, 0.5-0.6 eV is available for proton transfer to a base which seems reasonable when taking into account a complete randomization of the initially deposited energy.

Journal Article↗

Polycyclic aromatic hydrocarbons identified in soot extracts from domestic coal-burning stoves of Henan Province, China.

Using high-pressure liquid chromatography with ultraviolet-visible diode-array detection, we have analyzed polycyclic aromatic hydrocarbons (PAH) in the dichloromethane extracts of soot deposits from coal-burning stoves in several homes of Henan Province, China--including Linxian County, where esophageal cancer rates are some of the highest in the world. Thirty-two individual polycyclic aromatic compounds, ranging in size from three to eight fused aromatic rings, have been unequivocally identified among the soot extract components--including 20 benzenoid PAH, 6 fluoranthene benzologues, 1 cyclopentafused PAH, 1 indene benzologue, 3 oxygenated PAH, and 1 ring-sulfur-containing aromatic. Most of the identified compounds have been observed before among the products of laboratory coal pyrolysis experiments, but two of the components, the six-ring C24H14 napthol[1,2-b]fluoranthene and the eight-ring C30H16 tribenzo[e,ghi,k]perylene, have never before been documented as products of coal in any system. All of the Henan coal soot extracts are remarkably similar qualitatively in that they contain the same set of identified PAH, but absolute levels of individual species vary by up to 5 orders of magnitude, from sample to sample. The bulk of the identified component mass in all of these soot extracts lies in the five- and six-ring PAH--the largest single class being the family of five-ring C20H12 isomers, to which the samples' most abundant components, benzo[b]fluoranthene and benzo[e]pyrene, belong. The five- and six-ring PAH also account for the majority of the samples' known mutagens. The three strong mutagens identified in these soot samples are the C20H12 benzo[a]-pyrene and two C24H14 PAH, dibenzo[a,e]pyrene and naphtho-[2,1-a]pyrene. Seven moderate mutagens are found among the C20H12, C22H12, C22H14, and C24H14 PAH. A major class of mutagens, the cyclopenta-fused PAH, appears to be absent from these samples, but our detection of an oxidation product of the major mutagen cyclopenta[cd]- pyrene--itself mutagenic--suggests that these soot deposits may contain additional mutagenic cyclopentafused PAH oxidation products as well.

Air Pollutants↗

Bonding, Hyperfine Interactions, and Lattice Dynamics of Cationic and Neutral Ferrocenyl-Substituted Allylic and Cumulenic Compounds.

The synthesis and spectroscopic characterization (by mass, UV-visible, IR, NMR and (57)Fe Mössbauer spectroscopy) of three new compounds related to seven recently published ferrocenyl-substituted allylic and cumulenic compounds are reported and have made it possible to effect a systematic evaluation of the parameters extractable from temperature-dependent gamma ray resonance studies. For the neutral species, the hyperfine parameters (IS and QS) of the sigma-bonded ferrocenyl groups are insensitive to the structural details of the allylic or cumulenic carbon framework. The temperature dependence of the recoil-free fraction is dominated by the Cp ring-iron atom interaction, and is not diagnostic of the detailed molecular architecture. In the case of the carbocationic complexes, two distinct iron sites are resolvable from the Mössbauer data. The detailed temperature-dependent behavior of the hyperfine parameters and recoil-free fraction for 10 complexes with either equivalent termini, linked by similar, but different types of bridges (neutral 1-5), or with inequivalent moieties linked by related or identical connectors (cationic 6-10), has been elucidated over the temperature range 90 </= T </= 300 K. An X-ray crystallographic study of (R,S)-ferroceno[2,3-a]inden-1-one proved the racemic nature of this progenitor of compound 10: monoclinic, P2(1)/c, a = 9.29.3(2) pm, b = 1083.7(2) pm, c = 1345.7(3) pm, beta = 108.41(3), V = 1.2859(5) nm(3), Z = 4, R(F(o)) = 0.0574, R(w)() (F(o)(2)) = 0.1394.

Journal Article↗

Reaction of phenyl radicals with propyne.

The potential energy surface (PES) for the phenyl + propyne reaction, which might contribute to the growth of polycyclic aromatic hydrocarbons (PAHs) under a wide variety of reaction conditions, is described. The PES was characterized at the B3LYP-DFT/6-31G(d) and B3LYP-DFT/6-311+G(d,p) levels of theory. The energies of the entrance transition states, a direct hydrogen-transfer channel and two addition reactions leading to chemically activated C(9)H(9) intermediates, were also evaluated at the QCISD(T)/ 6-311G(d,p) and CCSD(T)/6-311G(d,p) levels of theory. An extensive set of unimolecular reactions was examined for these activated C(9)H(9)(dagger) intermediates, comprising 70 equilibrium structures and over 150 transition states, and product formation channels leading to substituted acetylenes and allenes such as PhCCH, PhCCCH(3), and PhCHCCH(2) were identified. The lowest energy pathway leads to indene, a prototype PAH molecule containing a five-membered ring. The title reaction thus is an example of possible direct formation of a PAH containing a five-membered ring, necessary to explain formation of nonplanar PAH structures, from an aromatic radical unit and an unsaturated hydrocarbon bearing an odd number of carbons. Extensive Supporting Information is available.

Journal Article↗