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PubMed1999

Origin of pi-Facial Stereoselectivity in Nucleophilic Additions. Application of the Exterior Frontier Orbital Extension Model to Imines and Iminium Ions.

The experimental data of pi-facial stereoselection of the imines and the iminium ions of cyclohexanone, tropinone, and adamantan-2-ones have been explained by the exterior frontier orbital extension model (EFOE model) previously proposed. In all cases, facial difference in the pi-plane-divided accessible space (PDAS), which represents simple summation of the pi-plane-divided exterior three-dimensional space nearest to the reaction center outside the van der Waals surface, significantly depends on the structure of the imino moieties. In particular the formation of iminium salt significantly affects the magnitude of both the EFOE density and the PDAS values.

Journal Article↗
PubMed2000

Access to Wieland-Miescher ketone in an enantiomerically pure form by a kinetic resolution with yeast-mediated reduction.

Both enantiomers of Wieland-Miescher ketone [3,4,8, 8a-tetrahydro-8a-methyl-1,6(2H,7H)-naphthalenedione], in a highly enantiomerically enriched form, became readily available by a newly developed kinetic resolution with yeast-mediated reduction. From a screening of yeast strains, Torulaspora delbrueckii IFO 10921 was selected. The collected cells of this strain, obtained by an incubation in a glucose medium, smoothly reduced only the isolated carbonyl group of the (S)-enantiomer, while the (R)-enantiomer remained intact. Starting from both enantiomers ( approximately 70% ee) prepared by an established proline-mediated asymmetric Robinson annulation, the reduction with T. delbrueckii gave the (R)-enantiomer (98% ee) and the corresponding alcohol (4aS,5S)-4,4a, 5,6,7,8-hexahydro-5-hydroxy-4a-methyl-2(3H)-naphthalenone (94% ee, 94% de) in preparative scale in nearly quantitative yields. An approach for the asymmetric synthesis of the Wieland-Miescher ketone was also successful. 2-Methyl-2-(3-oxobutyl)-1,3-cyclohexanedione, the prochiral precursor, was reduced with this strain to give a cyclic acetal form of (2S, 3S)-3-hydroxy-2-methyl-2-(3-oxobutyl)cyclohexanone, in a stereomerically pure form.

Ketones↗
PubMed2000

Asymmetric synthesis of 4-deoxyverrucarol via two types of ring expansion reactions

Asymmetric synthesis of a trichothecane analogue, 4-deoxyverrucarol (2), was carried out through two types of ring expansion reactions. First, synthesis of the racemate of 2 was investigated. Thus, 1-[1-(tert-butyldimethylsiloxy)-ethyl]-1-methoxycarbonyl-2-hexen-4-on e (10), prepared by Diels-Alder reaction, was converted into the cyclopropylidene 15. The cyclobutanone (+/-)-18 was obtained from 15 via dihydroxylation, followed by successive treatments with SO(2)Cl(2) in the presence of imidazole and Florisil. After transformation of (+/-)-18 into the vinylcyclobutanol (+/-)-19, the second ring expansion reaction was performed with Pd(OAc)(2) to provide the cyclopentanone (+/-)-20. The product was converted into the racemate of 4-deoxyverrucarol (2) through the cyclohexenone (+/-)-22, but the diastereoselectivity during the introduction of the double bond was unsatisfactory. The selectivity was improved in the case of the asymmetric synthesis. The optically active cyclobutanone (+)-18 was prepared via AD reaction of 15 with 73% ee. After the transformation of (+)-18 into the cyclohexanone (-)-30 through the palladium-mediated ring expansion reaction, (-)-30 was subjected to the diastereoselective deprotonation reaction using the chiral amide. The key synthetic intermediate (-)-25 of 4-deoxyverrucarol (2) was synthesized in an optically pure form by taking advantage of a kind of kinetic resolution that occurred during the deprotonation step.

Journal Article↗
PubMed2000

Halonium ion-mediated reaction of unsaturated hydroperoxy acetals. Competition between the formation of cyclic peroxides and the migration of the methoxy (or hydroxy) group.

Monoozonolyses of dienes 2 in methanol gave in each case the corresponding unsaturated alpha-methoxy hydroperoxides 3. Capture of 2-alkyl-substituted cyclohexanone oxides by methanol was highly diastereoselective, thereby providing exclusively the hydroperoxides derived from attack by methanol from the less hindered face of the carbonyl oxide intermediates. Halonium ion-mediated reactions of the hydroperoxides 3 gave the novel methoxy- or hydroxy-migrated products, together with the expected halogen-substituted 1, 2-dioxanes and/or 1,2-dioxepanes, the composition of the product mixture being a function of the halogenating agent utilized and the structure of 3.

Acetals↗
PubMed2000

Equilibrium constants between boron trifluoride etherate and carbonyl compounds in chloroform solution.

[reaction: see text] Equilibrium constants for boron trifluoride complexation with carbonyl compounds relative to diethyl ether were determined in CDCl(3). With benzaldehyde the equilibrium constant is 0.208. There is a 1.28-fold preference for BF(3) bonding to benzaldehyde-D over benzaldehyde-H. The rho(+) value for complexation with substituted benzaldehydes is -2.0. Equilibrium constants with cyclohexanone and isobutyraldehyde were found to be not very different from those predicted from the heats of addition of BF(3) relative to that for diethyl ether. The heats of addition can be correlated with Taft's beta values and with beta' values.

Journal Article↗
PubMed2001

A new lithium alkoxide accelerated diastereoselective cyanation of ketones.

[reaction: see text] A remarkably general lithium heteroatom assisted TMSCN or TBSCN addition to aldehydes and ketones has been discovered. The process provides excellent selectivities and high rates. Conformationally constrained ketones such as camphor, fenchone, and nopinone give excellent diastereoselectivities with TMSCN. Reduction of 2 provided diastereopure amino alcohol 3 in good yield. alpha- and beta-Methyl cyclohexanones with TBSCN-LiOR afford high diastereoselectivities and yields.

Journal Article↗
PubMed2001

A new, ring closing metathesis-based synthesis of (-)-fumagillol.

[reaction: see text]. A new strategy to access the fumagillin/fumagillol skeleton is proposed. An Evans aldolization and a RCM involving an enone are used for the preparation of a key cyclohexanone intermediate, which was readily converted to fumagillol. The synthesis also features an efficient preparation of isogeraniol and isogeranic acid.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Inhibition of purified and membrane-bound flavin-containing monooxygenase 1 by (N,N-dimethylamino)stilbene carboxylates.

(E)-[2-(4-(Dimethylamino)phenyl)vinyl]benzenes bearing a nitrile or carboxyl group in the 2', 3', or 4' position were synthesized and tested for substrate activity with purified pig liver flavin-containing monooxygenase (FMO1). Although the nitrile derivatives were too insoluble to saturate the catalytic site at pH 7.4, they appeared to be substrates with K(m)'s somewhat above their maximum solubility (approximately equal to 0.1 mM) in the assay medium. Of the three carboxylic acid analogs, (E)-4-[2-(4(dimethylamino)phenyl)vinyl]benzoic acid had no detectable water solubility at pH 7.4, and measurements were restricted to (E)-3-[2-(4-(dimethylamino)phenyl)vinyl]benzoic acid (DS3CO) and (E)-2-[2-(4-(dimethylamino)phenyl)vinyl]benzoic acid (DS2CO). While DS3CO and DS2CO were substrates, they also inhibited FMO1 turnover. DS3CO was the more effective inhibitor, and at 2 mM it inhibited FMO1 and microsomal-catalyzed oxidation of methimazole (N-methyl-2-mercaptoimidazole) by 80-90%. Kinetic studies indicated that the aminostilbene carboxylates were noncompetitive with both the xenobiotic substrate, methimazole, and NADPH. However, inhibition constants calculated from double reciprocal plots of velocity vs NADPH were K(i)(comp) 130 and 150 microM for DS3CO and DS2CO, respectively, whereas the uncompetitive Ki's were 10-15 times higher, which suggests that inhibition of NADPH binding may be primarily responsible for inhibition of FMO1 by the aminostilbene carboxylates. This model is also consistent with inhibition of cyclohexanone monooxygenase, a bacterial analog of FMO. DS3CO and DS2CO were again noncompetitive with methimazole but primarily competitive with NADPH. The aminostilbene carboxylates had no detectable effects on activity of pig or rat liver NADPH-cytochrome P450 reductase, which suggests that they are not nonspecific flavoprotein antagonists.

Animals↗
PubMed2000

An Arabidopsis gene induced by wounding functionally homologous to flavoprotein oxidoreductases.

The regulation of genes in response to wounding is mediated in part by the octadecanoids 12-oxo-phytodienoic acid (OPDA), jasmonic acid (JA) and its methyl ester methyl jasmonate (MeJA). We identified, by differential display, an Arabidopsis gene (OPR3) induced after wounding. OPR3 is homologous to members of the flavin mononucleotide (FMN) binding proteins, including the old yellow enzyme (OYE) from yeast and 12-oxophytodienoate-10,11-reductase (OPR) from Arabidopsis. Transcripts of OPR3 rapidly accumulated in leaves after wounding and MeJA treatment, but they were detected in various tissues of unwounded plants at relatively low levels. Expression of the OPR3 gene was significantly reduced in wounded leaves of the coil mutant, indicating partial dependence on jasmonate perception for full induction of the gene. The recombinant protein of OPR3 cross-reacted with an antiserum raised against the OYE protein, and showed oxidation of beta-NADPH when OPDA or 15-deoxy-delta(12,14) prostaglandin J2 (PGJ2), an analogue of OPDA, was used as substrate. Beta-NADPH oxidation was not observed when MeJA, which lacks the double bond in the ketone ring, was used as substrate. The recombinant OPR3 protein also showed beta-NADPH oxidation activity in the presence of cyclohexenone, but not cyclohexanone, suggesting that the enzyme has specificity to cleavage of olefinic bonds in cyclic enones. The results show that the OPR3 gene product represents a new OPR of Arabidopsis induced after wounding.

Acetates↗
PubMed2001

Mechanism of the antigen formation of carvone and related alpha, beta-unsaturated ketones.

In the present study, the mechanism for the antigen formation of alpha, beta-unsaturated ketones was investigated. A series of analogues of carvone ((5R)-5-isopropenyl-2-methyl-2-cyclohexenone) with altered chemical reactivity and with retained overall structure or with retained reactivity and altered three-dimensional structure were synthesized. These analogues were tested for cross-reactivity in carvone-sensitized animals. Cross-reactivity was observed for analogue 3 ((5R)-5-isopropyl-2-methyl-2-cyclohexen-1-one). No cross-reactions were observed for analogues 1 ((2R,5R)-5-isopropenyl-2-methyl cyclohexanone) and 4 ((5R)-2,3-dimethyl-5-isopropenyl-2-cyclohexene-1-one). Both those compounds also failed to induce sensitization. These findings demonstrate that alpha, beta-unsaturated ketones form antigens after a nucleophilic attack at the beta-carbon with soft nucleophiles such as thiol in cysteine and not with the formation of a Schiff's base after a nucleophilic attack at the carbonyl carbon with nitrogen nucleophiles. Furthermore, no cross-reactivity was observed between R- and S-carvone indicating the importance of the 3-dimensional structure of haptens (and antigens) in T-cell recognition. The analogues were also tested for cross-reactivity on patients allergic to carvone. The results from the animal study were confirmed.

Allergens↗
PubMed1966

A new derivative of vitamin C and its application to the synthesis of labelled ascorbic acid.

1. The preparation of a mono-O-cyclohexylidene derivative of l-ascorbic acid is described. 2. The new compound is shielded by the cyclohexanone group at C-5 and C-6 of the ascorbic acid molecule, while the double bond between C-2 and C-3 is kept intact. 3. The double bond of the new derivative is more resistant to oxidation than its parent compound. 4. Ascorbic acid is easily regenerated by mild acid hydrolysis. 5. The new derivative facilitates the synthesis of (14)C-labelled vitamin C.

Ascorbic Acid↗
PubMed1972

The metabolites of cyclohexylamine in man and certain animals.

1. [1-(14)C]Cyclohexylamine hydrochloride was synthesized and given orally or intraperitoneally to rats, rabbits and guinea pigs (dose 50-500mg/kg) and orally to humans (dose 25 or 200mg/person). The (14)C is excreted mainly in the urine, most of the excretion occurring in the first day after dosing. Only small amounts (1-7%) are found in the faeces. 2. In the rat, guinea pig and man, the amine is largely excreted unchanged, only 4-5% of the dose being metabolized in 24h in the rat and guinea pig and 1-2% in man. In the rabbit about two-thirds of the dose is excreted unchanged and about 30% is metabolized. 3. In the rat, five minor metabolites were found, namely cyclohexanol (0.05%), trans-3- (2.2%), cis-4- (1.7%), trans-4- (0.5%) and cis-3-aminocyclohexanol (0.1% of the dose in 24h). 4. In the rabbit, eight metabolites were identified, namely cyclohexanol (9.3%), trans-cyclohexane-1,2-diol (4.7%), cyclohexanone (0.2%), cyclohexylhydroxylamine (0.2%) and trans-3- (11.3%), cis-3- (0.6%), trans-4- (0.4%) and cis-4-aminocyclohexanol (0.2%). 5. In the guinea pig, six minor metabolites were found, namely cyclohexanol (0.5%), trans-cyclohexane-1,2-diol (2.5%) and trans-3- (1.2%), cis-3- (0.2%), trans-4- (0.2%) and cis-4-aminocyclohexanol (0.2%). 6. In man only two metabolites were definitely identified, namely cyclohexanol (0.2%) and trans-cyclohexane-1,2-diol (1.4% of the dose), but man had been given a smaller dose (3mg/kg) than the other species (50mg/kg). 7. The hydroxylated metabolites of cyclohexylamine were excreted in the urine in both free and conjugated forms. 8. Although cyclohexylamine is metabolized to only a minor extent, in rats the metabolism was mainly through hydroxylation of the cyclohexane ring, in man by deamination and in guinea pigs and rabbits by ring hydroxylation and deamination.

Animals↗
PubMed2001

4-Hydroxyacetophenone monooxygenase from Pseudomonas fluorescens ACB. A novel flavoprotein catalyzing Baeyer-Villiger oxidation of aromatic compounds.

A novel flavoprotein that catalyses the NADPH-dependent oxidation of 4-hydroxyacetophenone to 4-hydroxyphenyl acetate, was purified to homogeneity from Pseudomonas fluorescens ACB. Characterization of the purified enzyme showed that 4-hydroxyacetophenone monooxygenase (HAPMO) is a homodimer of approximately 140 kDa with each subunit containing a noncovalently bound FAD molecule. HAPMO displays a tight coupling between NADPH oxidation and substrate oxygenation. Besides 4-hydroxyacetophenone a wide range of other acetophenones are readily converted via a Baeyer-Villiger rearrangement reaction into the corresponding phenyl acetates. The P. fluorescens HAPMO gene (hapE) was characterized. It encoded a 640 amino-acid protein with a deduced mass of 71 884 Da. Except for an N-terminal extension of approximately 135 residues, the sequence of HAPMO shares significant similarity with two known types of Baeyer-Villiger monooxygenases: cyclohexanone monooxygenase (27-33% sequence identity) and steroid monooxygenase (33% sequence identity). The HAPMO sequence contains several sequence motifs indicative for the presence of two Rossman fold domains involved in FAD and NADPH binding. The functional role of a recently identified flavoprotein sequence motif (ATG) was explored by site-directed mutagenesis. Replacement of the strictly conserved glycine (G490) resulted in a dramatic effect on catalysis. From a kinetic analysis of the G490A mutant it is concluded that the observed sequence motif serves a structural function which is of importance for NADPH binding.

Acetophenones↗
PubMed2002

Synthesis and antituberculosis activity of cycloalkylidenehydrazide and 4-aza-1-thiaspiro[4.5]decan-3-one derivatives of imidazo[2,1-b]thiazole.

New N2-cycloalkylidene-(6-phenyl/4-chlorophenylimidazo[2,1-b]thiazol-3-yl) acetic acid hydrazides (2a-h and 3a-b) were synthesized by reacting (6-phenyl/4-chlorophenylimidazo[2,1-b]thiazol-3-yl)acetic acid hydrazides with cyclohexanones or cyclopentanone. Furthermore, 2a-h were refluxed with thioglycolic or thiolactic acid to give 4-[[(6-phenyl/4-chlorophenylimidazo[2,1-b]thiazol-3-yl) acetyl]amino]-4-aza-1-thiaspiro[4.5]decan-3-ones (4a-h and 5a-h). The structures of the title compounds were established by spectral data (IR, 1H-NMR, 13C-NMR and EIMS (Electron Impact Mass Spectrometry)) and elemental analysis. The synthesized compounds were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). The compounds exhibited varying degrees of inhibition in the in vitro primary screening that was conducted at a concentration of 6.25 micrograms/ml against M. tuberculosis H37Rv (ATCC 27294) in Bactec 12B medium using the Bactec 460 radiometric system or a broth microdilution assay, the Microplate Alamar Blue Assay (MABA). Compounds 2f, 2h, 3b, 4a, 4c, 4d, 5a-e and 5h demonstrating at 1-east 90% inhibition in the primary screen were re-tested at lower concentrations against M. tuberculosis H37Rv (ATCC 27294) to determine the actual minimum inhibitory concentration (MIC) using MABA. The most active compounds were found to be 4d and 5c. The structure-activity relationships of the derivatives were investigated.

Alkanes↗
PubMed1983

Natural sniffing gives optimum odour perception for humans.

The characteristics of human sniffing episodes during odour perception have been described in an earlier paper, where it has been suggested that the techniques used by individuals may be close to those providing optimum perception. To investigate this suggestion, threshold and intensity tests with butanol, cyclohexanone, and pentyl acetate have been carried out on twenty-one subjects. Olfactory responses obtained by using natural sniffing techniques were compared with those where the number of sniffs, interval between sniffs, and size of sniffs were varied. The results indicate that it is very difficult to improve on the efficiency of sniffing techniques of individuals and that a single natural sniff provides as much information about the presence and intensity of an odour as do seven or more sniffs. A single natural sniff and the first sniff of a a natural sniffing episode were shown to have similar characteristics and most significantly both were unaffected by changes in the concentration and type of odour. Overall, the results indicate that humans achieve optimum odour perception during threshold and intensity measures with their natural multiple-sniff technique or with a single sniff. For the 'average' human this occurs with a sniff of inhalation rate 30 1 min-1, volume 200 cm3, and duration 0.4 s. The use of several sniffs in a sniffing episode appears to be a confirmatory action rather than a necessary one, except for the perception of odour mixtures where several sniffs are likely to be needed to aid discrimination of the components. Data from the present and earlier study provide the information necessary for the development of a standard olfactometer and standard procedures for measuring the olfactory responses of humans.

Adult↗
PubMed2001

Functional expression and characterization of a Drosophila odorant receptor in a heterologous cell system.

Odorant receptors (ORs) constitute the molecular basis for the detection of volatile odorous molecules and the perception of smell. Our understanding of chemical senses has been greatly expanded by the discovery of the OR gene families in vertebrates and in the nematode Caenorhabditis elegans. Recently, candidate Drosophila OR genes have been identified. The putative ORs do not possess any primary sequence identity with known vertebrate or C. elegans receptors, but belong to the family of G protein-coupled receptors according to their predicted seven transmembrane topology. To prove olfactory function of these proteins, we expressed a member of the putative Drosophila OR gene family, Or43a, in Xenopus laevis oocytes. Using two-electrode voltage-clamp recording we identified four odors (cyclohexanone, cyclohexanol, benzaldehyde, and benzyl alcohol) that activated the receptor at low micromolar concentration and structurally related substances that did not. This report shows the function and specificity of a member of the recently identified family of Drosophila ORs expressed in a heterologous system.

Animals↗
PubMed1992

Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination.

To investigate insulin-like growth factor I (IGF-I) and IGF-I receptor gene expression during experimental demyelination and myelin regeneration, young mice were fed cuprizone (( bis(cyclohexanone) oxaldihydrazone )). This copper-chelating agent produces demyelination in the corpus callosum and superior cerebellar peduncles, and when treatment is stopped, there is rapid remyelination. At intervals during cuprizone treatment and recovery, brain sections were hybridized with specific probes and immunostained with antibodies to determine the localization and relative amounts of IGF-I and IGF-I receptor mRNAs and peptides. In untreated littermates, IGF-I and IGF-I receptor mRNAs and peptides were not detected in white matter. In cuprizone-treated mice, high levels of both IGF-I mRNA and peptide were expressed by astrocytes in areas of myelin breakdown. Astrocyte IGF-I expression decreased rapidly during recovery and oligodendroglial expression of myelin-related genes increased. In severely demyelinated areas, immature oligodendroglia exhibited a transient increase in IGF-I receptor mRNA and peptide immunoreactivity during early recovery. This highly specific pattern of IGF-I induction in astrocytes during demyelination and the expression of the IGF-I receptor in regenerating oligodendrocytes during recovery suggest that IGF-I functions in the regulation of oligodendrocyte and myelin metabolism in vivo.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1999

The AcbC protein from Actinoplanes species is a C7-cyclitol synthase related to 3-dehydroquinate synthases and is involved in the biosynthesis of the alpha-glucosidase inhibitor acarbose.

The putative biosynthetic gene cluster for the alpha-glucosidase inhibitor acarbose was identified in the producer Actinoplanes sp. 50/110 by cloning a DNA segment containing the conserved gene for dTDP-D-glucose 4,6-dehydratase, acbB. The two flanking genes were acbA (dTDP-D-glucose synthase) and acbC, encoding a protein with significant similarity to 3-dehydroquinate synthases (AroB proteins). The acbC gene was overexpressed heterologously in Streptomyces lividans 66, and the product was shown to be a C7-cyclitol synthase using sedo-heptulose 7-phosphate, but not ido-heptulose 7-phosphate, as its substrate. The cyclization product, 2-epi-5-epi-valiolone ((2S,3S,4S,5R)-5-(hydroxymethyl)cyclohexanon-2,3,4,5-tetrol), is a precursor of the valienamine moiety of acarbose. A possible five-step reaction mechanism is proposed for the cyclization reaction catalyzed by AcbC based on the recent analysis of the three-dimensional structure of a eukaryotic 3-dehydroquinate synthase domain (Carpenter, E. P., Hawkins, A. R., Frost, J. W., and Brown, K. A. (1998) Nature 394, 299-302).

Acarbose↗