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At least 19 recordsLinked to original sources
PubMed1993

Neurosteroid analogues: structure-activity studies of benz[e]indene modulators of GABAA receptor function. 1. The effect of 6-methyl substitution on the electrophysiological activity of 7-substituted benz[e]indene-3-carbonitriles.

The effect of 6-methyl substitution of the ability of 7-(2-hydroxyethyl)benz[e]indene-3-carbonitriles to potentiate GABA-mediated chloride current and to directly gate a chloride current in the absence of GABA in cultured rat hippocampal neurons was investigated. Structurally analogous steroid 17-carbonitriles that either contained or did not contain a 19-methyl group were also investigated. Compounds were evaluated at 1 microM for their ability to potentiate GABA-mediated currents and at 10 microM for current activation in the absence of GABA. The benz[e]indene 3(R)-carbonitriles and analogous steroid 17 alpha-carbonitriles had no effects in either assay. The benz[e]indene-3(S)-carbonitriles and analogous steroid 17 alpha-carbonitriles were active in both assays. Relative to the 6-unsubstituted benz[e]indene 3(S)-carbonitrile, the following effects of 6-methyl substituents were observed: a 6(a)-methyl group increased both activities; a 6(e)-methyl group decreased both activities; and 6,6-dimethyl substituents had opposing effects so that both activities remained similar to those of the 6-unsubstituted compound. The activities of the steroid 17 beta-carbonitriles were not affected significantly by the presence or absence of a 19-methyl group. A conformational analysis using molecular modeling methods was also performed for the benz[e]indene 3S-carbonitriles and the steroid 17 beta-carbonitriles. The ability of the different 6-methyl substituents to differentially effect the conformations of the flexible benz[e]indenes and the inability of the steroid 19-methyl group to alter the conformations of the rigid steroid 17 beta-carbonitriles are suggested to explain the results.

Androstanols↗
PubMed1997

Tandem Enyne Allene-Radical Cyclization: Low-Temperature Approaches to Benz[e]indene and Indene Compounds.

In an effort to lower the temperatures required to prepare multicyclic compounds using the tandem enediyne-radical cyclization, we have developed the tandem enyne allene-radical cyclization which proceeds at temperatures as low as 37 degrees C. The reactions were carried out using three different methods for the preparation of the enyne allenes. The first method involved the [3,3] sigmatropic rearrangement of an enediyne followed by a tandem enyne allene-radical cyclization. This reaction could be effected either by thermolysis (150 degrees C) or by AgBF(4) rearrangement followed by heating at 75 degrees C. A second technique utilized a [2,3] sigmatropic shift of an enediyne at -78 degrees C followed by tandem cyclization at 37 or 75 degrees C depending on the substrate. The final method involved the base-catalyzed isomerization of propargyl sulfones which yielded enyne allenes that underwent cyclization at 37 degrees C. These three sequences provide a method for the synthesis of ring systems using conditions that may be compatible with the sensitive functionality needed during the synthesis of complex natural products.

Journal Article↗
PubMed1998

The bioactive conformation of aminoalkylindoles at the cannabinoid CB1 and CB2 receptors: insights gained from (E)- and (Z)-naphthylidene indenes.

The aminoalkylindoles (AAIs) are agonists at both the cannabinoid CB1 and CB2 receptors. To determine whether the s-trans or s-cis form of AAIs is their receptor-appropriate conformation, two pairs of rigid AAI analogues were studied. These rigid analogues are naphthylidene-substituted aminoalkylindenes that lack the carbonyl oxygen of the AAIs. Two pairs of (E)- and (Z)-naphthylidene indenes (C-2 H and C-2 Me) were considered. In each pair, the E geometric isomer is intended to mimic the s-trans form of the AAIs, while the Z geometric isomer is intended to mimic the s-cis form. Complete conformational analyses of two AAIs, pravadoline (2) and WIN-55, 212-2 (1), and of each indene were performed using the semiempirical method AM1. S-trans and s-cis conformations of 1 and 2 were identified. AM1 single-point energy calculations revealed that when 1 and each indene were overlayed at their corresponding indole/indene rings, the (E)- and (Z)-indenes were able to overlay naphthyl rings with the corresponding s-trans or s-cis conformer of 1 with an energy expense of 1.13/0.69 kcal/mol for the C-2 H (E/Z)-indenes and 0.82/0.74 kcal/mol for the C-2 Me (E/Z)-indenes. On the basis of the hypothesis that aromatic stacking is the predominant interaction of AAIs such as 1 at the CB receptors and on the demonstration that the C-2 H (E/Z)- and C-2 Me (E/Z)-indene isomers can mimic the positions of the aromatic systems in the s-trans and s-cis conformers of 1, the modeling results support the previously established use of indenes as rigid analogues of the AAIs. A synthesis of the naphthylidene indenes was developed using Horner-Wittig chemistry that afforded the Z isomer in the C-2 H series, which was not produced in significant amounts from an earlier reported indene/aldehyde condensation reaction. This approach was extended to the C-2 Me series as well. Photochemical interconversions in both the C-2 H and C-2 Me series were also successful in obtaining the less favored isomer. Thus, the photochemical process can be used to provide quantities of the minor isomers C-2 H/Z and C-2 Me/E. The CB1 and CB2 affinities as well as the activity of each compound in the twitch response of the guinea pig ileum (GPI) assay were assessed. The E isomer in each series was found to have the higher affinity for both the CB1 and CB2 receptors. In the rat brain membrane assay versus [3H]CP-55,940, the Ki's for the C-2 H/C-2 Me series were 2.72/2.89 nM (E isomer) and 148/1945 nM (Z isomer). In membrane assays versus [3H]SR141716A, a two-site model was indicated for the C-2 H/C-2 Me (E isomers) with Ki's of 10. 8/9.44 nM for the higher-affinity site and 611/602 nM for the lower-affinity site. For the Z isomers, a one-site model was indicated with Ki's of 928/2178 nM obtained for the C2 H/C-2 Me analogues, respectively. For the C-2 H/C-2 Me series, the CB2 Ki's obtained using a cloned cell line were 2.72/2.05 nM (E isomer) and 132/658 nM (Z isomer). In the GPI assay, the relative order of potency was C-2 H E > C-2 Me E > C-2 H Z > C-2 Me Z. The C-2 H E isomer was found to be equipotent with 1, while the C-2 Me Z isomer was inactive at concentrations up to 3.16 microM. Thus, results indicate that the E geometric isomer in each pair of analogues is the isomer with the higher CB1 and CB2 affinities and the higher pharmacological potency. Taken together, results reported here support the hypothesis that the s-trans conformation of AAIs such as 1 is the preferred conformation for interaction at both the CB1 and CB2 receptors and that aromatic stacking may be an important interaction for AAIs at these receptors.

Animals↗
PubMed2002

Application of multi-parameter flow cytometry using fluorescent probes to study substrate toxicity in the indene bioconversion.

The bioconversion of indene to cis-(1S,2R) indandiol, a potential key intermediate in the synthesis of Merck's HIV protease inhibitor, CRIXIVAN trade mark, can be achieved using a Rhodococcus strain. This study using Rhodococcus I24 reports on the application of multiparameter flow cytometry for the measurement of cell physiological properties based on cytoplasmic membrane (CM) integrity and membrane depolarization as indicators of toxic effects of the substrate, indene. Quantification of intact polarized CM, intact depolarized CM and permeabilized CM of a large population of bacterial cells has been conducted using specific intracellular and membrane-binding fluorescent stains. Measurements of oxygen uptake rate (OUR) and optical density (OD) as indicators of metabolic activity and biomass growth, respectively, were also made. Indene concentrations of up to 0.25 g/L (0.037 g indene/g dry cell weight) did not significantly (<5% compared to control) affect cell light-scattering properties, intact CM, membrane polarization, respiratory activity, or biomass growth. Between this value and 1.5 g/L (0.221 g indene/g dry cell weight), the changes in intact CM, respiratory activity and biomass growth were relatively insignificant (<5% compared to control), although dissipation of the membrane potential of a significant proportion of the cell population occurred at 0.50 g/L (0.074 g indene/g dry cell weight). At 2.5 g/L (0.368 g indene/g dry cell weight) there was a significant increase in the dead cell population, accompanied by changes in the extracellular cationic concentrations and substantial decrease in respiratory activity. The primary effect of indene toxicity was the disruption of the proton motive force across the cytoplasmic membrane which drives the formation of ATP. The disruption of the proton motive force may have been due to the measured changes in proton permeability across the membrane. In addition, indene may have directly inhibited the membrane-bound enzymes related to respiratory activity. The overall consequence of this was reduced respiratory activity and biomass growth. The cell physiological properties measured via flow cytometry are important for understanding the effects of toxicity at the cellular level which neither measurements of biomass growth or indandiol formation rates can provide since both are cell averaged measurements. The technique described here can also be used as a generic tool for measuring cell membrane properties in response to toxicity of other indene-resistant strains that may be possible to use as recombinant hosts to perform the biotransformation of indene. This study has demonstrated that flow cytometry is a powerful tool for the measurement of cell physiological properties to assess solvent toxicity on whole cell biocatalysts.

Adenosine Triphosphate↗
PubMedDate not supplied

Formation of methylthio metabolites of indene in the guinea pig and the rat.

The formation of methylthio metabolites of epoxides has been shown to be a significant route of metabolism in some species. Several aspects of this metabolic conversion for indene were examined. Two isomers of hydroxy(methylthio)indane were found in the urine of guinea pigs administered indene (14.3 and 100 mg/kg, ip). The major isomer, 2-hydroxy-1-methylthioindane (I) was present as 6-9% of the administered dose after 24 hr, while lower amounts (0-0.6%) of a minor isomer (II) were observed. A significant amount of isomer I was found as a urinary metabolite of indene oxide (14% of 12.5 mg/kg, ip). To further elucidate the route of formation of I, the glutathione (I-GLU) and mercapturic acid (I-MER) conjugates of indene oxide were synthesized and administered to the guinea pig. The methylthio metabolite I was present as a significant urinary metabolite of both conjugates of indene oxide, comprising 9.6% and 5.7% of the dose of I-GLU (5 mg, ip) and I-MER (4 mg, ip), respectively. These results show that the formation of a hydroxy(methylthio)indane is a significant route of metabolism for indene and indene oxide in the guinea pig, and that this metabolite arises via further metabolism of conjugates in the glutathione pathway. In the rat, isomer I is a minor metabolite. Mechanistic aspects of the formation of these thioether metabolites are discussed.

Acetylcysteine↗
PubMed2004

Indene bioconversion by a toluene inducible dioxygenase of Rhodococcus sp. I24.

Rhodococcus sp. I24 can oxygenate indene via at least three independent enzyme activities: (i) a naphthalene inducible monooxygenase (ii) a naphthalene inducible dioxygenase, and (iii) a toluene inducible dioxygenase (TID). Pulsed field gel analysis revealed that the I24 strain harbors two megaplasmids of approximately 340 and approximately 50 kb. Rhodococcus sp. KY1, a derivative of the I24 strain, lacks the approximately 340 kb element as well as the TID activity. Southern blotting and sequence analysis of an indigogenic, I24-derived cosmid suggested that an operon encoding a TID resides on the approximately 340 kb element. Expression of the tid operon was induced by toluene but not by naphthalene. In contrast, naphthalene did induce expression of the nid operon, encoding the naphthalene dioxygenase in I24. Cell free protein extracts of Escherichia coli cells expressing tidABCD were used in HPLC-based enzyme assays to characterize the indene bioconversion of TID in vitro. In addition to 1-indenol, indene was transformed to cis-indandiol with an enantiomeric excess of 45.2% of cis-(1S,2R)-indandiol over cis-(1R,2S)-indandiol, as revealed by chiral HPLC analysis. The Km of TID for indene was 380 microM. The enzyme also dioxygenated naphthalene to cis-dihydronaphthalenediol with an activity of 78% compared to the formation of cis-indandiol from indene. The Km of TID for naphthalene was 28 microM. TID converted only trace amounts of toluene to 1,2-dihydro-3-methylcatechol after prolonged incubation time. The results indicate the role of the tid operon in the bioconversion of indene to 1-indenol and cis-(1S,2R)-indandiol by Rhodococcus sp. I24.

Chromatography, High Pressure Liquid↗
PubMed2000

Simultaneous determination of ethylbenzene, indan, indene and acenaphthene in air by capillary gas chromatography.

An attempt was made to establish a method for the simultaneous determination of ethylbenzene, indan, indene and acenaphthene by capillary gas chromatography with flame ionization detection. The air was sampled on charcoal tubes and extracted with carbon disulfide-methanol (60:1, v/v). The four analytes were separated by gas chromatography using a capillary column of cross-linked 5% phenylmethylsilicone. Under the applied conditions the method showed detection limits of 1.8 microg/m3 for ethylbenzene, 2.1 microg/m3 for indan, 2.8 microg/m3 for indene and 3.4 microg/m3 for acenaphthene. Relative standard deviations were as follows: ethylbenzene, 6.2%; indan, 9.9%; indene, 13.6%; and acenaphthene, 14.4%. The recoveries for these compounds were 98.6, 97.9, 55.7 and 52.1%, and the accuracies were 2.5, 3.0, 44.3 and 47.8%, a working range of 1.5-30 ng/microl for ethylbenzene and 0.75-15 ng/microl for indan, indene and acenaphthene. The method was found to be suitable for the determination of environmental and occupational analysed ethylbenzene, indan, indene and acenaphthene exposure.

Acenaphthenes↗
PubMed2001

Metabolic engineering of indene bioconversion in Rhodococcus sp.

We have applied the methodology of metabolic engineering in the investigation of the enzymatic bioreaction network in Rhodococcus sp. that catalyzes the bioconversion of indene to (2R)-indandiol suitable for the synthesis of cis-1-amino-2-indanol, a precursor of the HIV protease inhibitor, Crixivan. A chemostat with a novel indene air delivery system was developed to facilitate the study of steady state physiology of Rhodococcus sp. 124. Prolonged cultivation of this organism in a continuous flow system led to the evolution of a mutant strain, designated KY1, with improved bioconversion properties, in particular a twofold increase in yield of (2R)-indandiol relative to 124. Induction studies with both strains indicated that KY1 lacked a toluene-inducible dioxygenase activity present in 124 and responsible for the formation of undesired byproducts. Flux analysis of indene bioconversion in KY1 performed using steady state metabolite balancing and labeling with [14C]-tracers revealed that at least 94% of the indene is oxidized by a monooxygenase to indan oxide that is subsequently hydrolyzed to trans-(1R,2R)-indandiol and cis-(1S,2R)-indandiol. This analysis identified several targets in KY1 for increasing (2R)-indandiol product yield. Most promising among them is the selective hydrolysis of indan oxide to trans-(1R,2R)-indandiol through expression of an epoxide hydrolase or modification of culture conditions.

Catalysis↗
PubMed2002

Engineering an indene bioconversion process for the production of cis-aminoindanol: a model system for the production of chiral synthons.

Cis-aminoindanol, a key chiral precursor to the HIV protease inhibitor CRIXIVAN, can be derived from indene oxidation products of (2R) stereochemistry. A number of different microorganisms, notably strains of the genera Pseudomonas and Rhodococcus, have been isolated that catalyze the oxygenation of indene to indandiol with greater stereospecificity than is achievable through traditional chemical synthesis. The yield and ultimate optical purity of indandiol produced in such biocatalytic processes is influenced by the intrinsic stereospecificity of the oxygenase(s), enantioselective dehydrogenation, and the loss of substrate to alternate, undesirable metabolites. Metabolic engineering of any indene bioconversion system for the commercial-scale production of cis-aminoindanol must account for these influences, as well as pathway fluxes and enzyme regulation, to optimize the formation of oxygenated precursors with useful stereochemistry. As such, the process by which bacterial systems carry out the bioconversion of indene to indandiol serves as a model for biological production of industrially relevant chiral synthons.

Biotechnology↗
PubMed1999

Isolation and characterization of indene bioconversion genes from Rhodococcus strain I24.

Rhodococcus strain 124 is able to convert indene into indandiol via the actions of at least two dioxygenase systems and a putative monooxygenase system. We have identified a cosmid clone from 124 genomic DNA that is able to confer the ability to convert indene to indandiol upon Rhodococcus erythropolis SQ1, a strain that normally can not convert or metabolize indene. HPLC analysis reveals that the transformed SQ1 strain produces cis-(1R,2S)-indandiol, suggesting that the cosmid clone encodes a naphthalenetype dioxygenase. DNA sequence analysis of a portion of this clone confirmed the presence of genes for the dioxygenase as well as genes encoding a dehydrogenase and putative aldolase. These genes will be useful for manipulating indene bioconversion in Rhodococcus strain 124.

Amino Acid Sequence↗
PubMed2003

Microbial production of isoquinoline from indene.

A purified microbial isolate, identified as a strain of Rhodococcus sp., metabolized indene primarily to iso quinoline and lesser amounts of indandiol and indanone. Isoquinoline production was dependent on the presence of microbial culture, indene, and ammonium ions as the source of nitrogen in the molecule. The ability to produce isoquinoline was induced by growth on benzene or naphthalene and by the presence of indene itself. The culture produced compounds tentatively identified as 3-methylisoquinoline and 3-ethylisoquinoline from 2-methylindene and from 2-ethylindene, respectively. Deuterated indene was converted to deuterated isoquinoline, deuterated indanone, and deuterated indandiol. Experiments with [15N]ammonium nitrate and ammonium [15N]nitrate confirmed ammonium as the source of nitrogen in the isoquinoline products.

Biodegradation, Environmental↗
PubMed2004

Cobalt-catalyzed regioselective carbocyclization reaction of o-iodophenyl ketones and aldehydes with alkynes, acrylates, and acrylonitrile: a facile route to indenols and indenes.

An efficient cobalt-catalyzed carbocylization for the synthesis of indenols and indenes and a new method for reductive decyanation are described. 2-Iodophenyl ketones and aldehydes 1a-g undergo carbocyclization with various disubstituted alkynes 2a-k in the presence of Co(dppe)I(2) and zinc powder in acetonitrile at 80 degrees C for 3 h to afford the corresponding indenol derivatives 3a-s and4a-m in good to excellent yields. For some unsymmetrical alkynes, the carbocyclization was remarkably regioselective, affording a single regioisomer. The cobalt-catalyzed carbocyclization reaction was successfully extended to the synthesis of indene derivatives. Thus, the reaction of 2-iodophenyl ketones and aldehydes (1) with acrylates H(2)C=CHCO(2)R (7a-d) and acrylonitrile H(2)C=CHCN (7e) proceeds smoothly in the presence of Co(dppe)Cl(2)/dppe and zinc powder in acetonitrile at 80 degrees C for 24 h to afford the corresponding indenes 8a-k and 9a-c in moderate to good yields. Interestingly, when 7e was employed for the carbocylization, reductive decyanation also occurred to give an indene derivative without the cyano functionality. A possible mechanism for this cobalt-catalyzed carbocyclization reaction is also proposed.

Journal Article↗
PubMed1997

Mechanistic Study of the Jacobsen Asymmetric Epoxidation of Indene.

The asymmetric epoxidation of indene using aqueous NaOCl, catalyzed by Jacobsen's chiral manganese salen complex, provides indene oxide in 90% yield and 85-88% enantioselectivity. The axial ligand, 4-(3-phenylpropyl)pyridine N-oxide (P(3)NO), increases the rate of epoxidation without affecting enantioselectivity and also stabilizes the catalyst. These two effects afford a reduction in catalyst loading to <1%. The turnover-limiting step in the catalytic cycle has been determined to be the oxidation of the manganese catalyst, based on reaction orders of 0 in indene and 1 in catalyst and also based on the dependence of the rate on the hypochlorite concentration. In the presence of the ligand P(3)NO, this rate-limiting oxidation occurs in the organic phase with HOCl as oxidant, as shown by the dependence of the rate on the NaOH concentration. P(3)NO assists the transport of HOCl to the organic layer as demonstrated by titration studies and by measuring the rates of oxidation of a redox indicator, diphenylbenzidine. On the other hand, stirring speed studies indicate that, in the absence of the ligand, oxidation occurs at the interface. Thus, the axial ligand plays at least two roles in the epoxidation of indene: it stabilizes the catalyst, presumably by ligation, and it increases the epoxidation reaction rate by drawing the active oxidant, HOCl, into the organic layer.

Journal Article↗
PubMed2003

Measurement of strain-dependent toxicity in the indene bioconversion using multiparameter flow cytometry.

The bionconversion of indene to cis-(1S,2R)-indandiol, a potential key intermediate in the synthesis of Merck's HIV protease inhibitor, CRIXIVAN trade mark, can be achieved using Rhodococcus, Pseudomonas putida, and Escherichia coli strains. This study reports on the application of multiparameter flow cytometry for the measurement of cytoplasmic membrane integrity and membrane depolarization as indicators of toxic effects of the substrate, product, and by-products using each of these strains. Measurements of oxygen uptake rate (OUR) and optical density (OD) as indicators of metabolic activity and biomass growth, respectively, were also made. Measurements of the cytoplasmic membrane potential, cell viability, and respiratory activity provided a sensitive set of parameters to assess toxicity in the indene bioconversion and provided the basis for process improvements and strain selection. The toxic concentrations of the substrate, product, and by-products for each strain have been determined. The results show that it is possible to accumulate cis-(1S,2R)-indandiol and cis-1-amino-2-indanol up to 20 g/L without significant negative effects on cell physiology using any of the strains tested. The Gram-negative P. putida (421-5 and GM 730) and E. coli strains were more resistant to indene and the isolated chemicals of the biotransformation than the Gram-positive Rhodoccoccus I24 strain, possibly due to the presence of the outer membrane and efflux pump mechanisms. P. putida GM 730 and the E. coli TDO 123 strains responded similarly to toxic effects, and the E. coli TDO 123 strain was more resistant than the P. putida 421-5 strain. In addition to the recommendations for strain selection, the identified targets for bioprocess improvement include a combination of genetic as well as process engineering approaches.

Bioreactors↗
PubMed2003

Calenzanane sesquiterpenes from the red seaweed Laurencia microcladia from the Bay of Calenzana, Elba Island: acid-catalyzed stereospecific conversion of calenzanol into indene- and guaiazulene-type sesquiterpenes.

It is shown here that calenzanane sesquiterpenes (1 and 6) can be isolated from organic extracts from the red seaweed Laurencia microcladia Kützing from the Bay of Calenzana, Elba Island, provided contact with acidic media is minimized. Such contact induces rearrangements of 1 in dry solvents to indene-type 5 and the blue-colored guaiazulenium-type ion 17, via spectrometrically (NMR) characterized indene-type transient intermediates 10, 14, and 12. Addition of NEt(3) to the reaction mixture at appropriate stages allowed the isolation of 12 (and 8 on workup on SiO(2)), and guaiazulene (18). Prolonged contact with silica gel led to complete degradation of 1, giving calenzanane-type epimeric enones 20 a/20 b as well as indene-type epimeric carbinols 22 a/22 b and fulvene 7. The latter was also formed during silica-gel flash chromatography of the algal extracts. A unifying mechanistic view of these branching and cascade transformations may have both heuristic value, suggesting possible artefact origin of azulenoids, and synthetic applications.

Azulenes↗
PubMed1999

Microbial conversion of indene to indandiol: a key intermediate in the synthesis of CRIXIVAN.

Indene is oxidized to mixtures of cis- and trans-indandiols and related metabolites by Pseudomonas putida and Rhodococcus sp. isolates. Indene metabolism is consistent with monooxygenase and dioxygenase activity. P. putida resolves enantiomeric mixtures of cis-1,2-indandiol by further selective oxidation of the 1R, 2S-enantiomer yielding high enantiomeric purity of cis-(1S, 2R)-indandiol, a potential intermediate in the synthesis of indinavir sulfate (CRIXIVAN), a protease inhibitor used in the treatment of AIDS. Molecular cloning of P. putida toluene dioxygenase in Escherichia coli confirmed the requirement for the dihydrodiol dehydrogenase in resolving racemic mixtures of cis-indandiol. Rhodococcus sp. isolates convert indene to cis-(1S, 2R)-indandiol at high initial enantiomeric excess and one isolate also produces trans-(1R, 2R)-indandiol, suggesting the presence of monooxygenase activity. Scale up and optimization of the bioconversions to these key synthons for chiral synthesis of potential intermediates for commercial manufacture of indinavir sulfate are described.

Drug Design↗