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PubMed1994

Sonochemical activation of hematoporphyrin: an ESR study.

The production of 2,2,6,6-tetramethyl-4-piperidone-N-oxyl by reaction of 2,2,6,6-tetramethyl-4-piperidone (TMPone) with ultrasonically generated active species in oxygenated solutions of hematoporphyrin (Hp) was studied by electron spin resonance spectroscopy. The nitroxide production rate in air-saturated TMPone solutions in phosphate-buffered saline of pH 9.0 was significantly higher in the presence of Hp than in its absence. The enhancement of nitroxide production by Hp was significantly inhibited in the presence of sodium azide or histidine in the solution. The production rate with Hp was doubled by substitution of deuterium oxide, while the rate without Hp increased only modestly. These results suggest that a substantial amount of active oxygen can be generated by ultrasound in aqueous solutions of Hp. Since the production rate was not reduced by mannitol and no nitroxide was produced in nitrogen-saturated solutions, it appears that hydroxyl radicals do not account for a major portion of the active oxygen species which reacted with TMPone to yield a nitroxide.

Electron Spin Resonance Spectroscopy↗
PubMed1996

Scavenging activity of "beta catechin" on reactive oxygen species generated by photosensitization of riboflavin.

"beta CATECHIN", a preparation containing green tea extract, ascorbic acid, sunflower seed extract, dunaliella carotene and natural vitamin E, has been designed as a model "universal antioxidant" that offers protection via its scavenging action on a wide range of free radicals, both water-soluble and fat-soluble. Reactive oxygen species like singlet oxygen, hydroxyl and superoxide radicals, are often generated in biological systems during photosensitized oxidation reactions. We report on the simultaneous effect of "beta CATECHIN" on active oxygen species generated during the photosensitized oxidation of riboflavin using 2,2,6,6-tetramethyl-4-piperidone (TMPD) as a "spin-trapping" agent. The intensities of the resulting stable nitroxide radical adduct, 2,2,6,6-tetramethyl-4-piperidone-1-oxyl (TEMPONE), were detected by electron spin resonance (ESR) spectroscopy. Results show simultaneous, nonspecific and complete scavenging action of reactive oxygen species generated in our in vitro model system by "beta CATECHIN". It is therefore suggested that "beta CATECHIN" could offer protection against free radical insult and in preventing cancer and other diseases that are mediated by reactive oxygen species.

Animals↗
PubMed1979

Thermolysis chemical ionization of a complex polar lipid.

Vaporization of a ornithine-containing polar lipid from Thiobacillus thiooxidans has been accomplished by thermolysis in a chemical ionization source. The thermolysis has been shown to be more extensive than previously thought. It occurs in at least two steps, the first being dehydration of the ornithine to produce a substituted piperidone. This fragment undergoes a facile elimination to produce two neutral lipid components: a long chain fatty acid and piperidone-containing fatty amide. The results demonstrate the utility of chemical ionization for developing an understanding of a thermolysis process.

Bacteria↗
PubMed1987

Synthesis of some 3-hydroxy-5-aminopentanoic acid derivatives.

The 5-amino analogues of mevalonic acid and mevalonolactone, 5-amino-3-hydroxy-3-methylpentanoic acid (VII a) and 4-hydroxy-4-methyl-2-piperidone (III a), and some related compounds were synthesized as possible inhibitors of cholesterol biosynthesis. None of them was found effective on the synthesis of cholesterol in rat liver slices and on HMG-CoA reductase activity in vitro, but 4-hydroxy-4-(4-chlorophenyl)-2-piperidone (III b) raised high density lipoproteins (HDL) in normolipaemic rats.

Amino Acids↗
PubMed2006

Synthesis and NMDA-receptor affinity of 4-oxo-dexoxadrol derivatives.

A synthesis of novel dexoxadrol analogues is described, which allows modifications of the piperidine substructure. The key step of the synthesis is a hetero Diels-Alder reaction of the imine 12 with Danishefsky's diene 6. After separation of the diastereomeric piperidones 14a and 14b, the relative configuration of the unlike configured piperidone 15b was determined by X-ray crystal structure analysis. In receptor binding studies the like configured secondary amine 15a (racemate) showed considerable affinity toward the phencyclidine binding site of the NMDA receptor (Ki=470 nM).

Binding Sites↗
PubMed2001

Singlet oxygen generation from phosphatidylcholine hydroperoxide in the presence of copper.

This study pursued whether singlet oxygen ((1)O2) is generated from phosphatidylcholine hydroperoxide (PCOOH), the oxidized modification product of a major constituent of biomembranes and serum lipoproteins. The (1)O2 formation was detected, by utilizing the oxidation of 2,2,6,6-tetramethyl-4-piperidone (TMPD) by (1)O2 to yield 2,2,6,6-tetramethyl-4-piperidone-1-oxyl (TEMPONE), which generates electron spin resonance (ESR) signals. The TEMPONE signal was detected in human plasma with addition of PCOOH by ESR determination after introducing copper(II). The TEMPONE formation was proportional to the amounts of PCOOH added according to moles of active oxygen. The TEMPONE signal intensity was weakened significantly in the presence of beta-carotene and histidine in a concentration-dependent manner, but was not at all decreased by mannitol, Mn-superoxide dismutase and catalase. In addition, HPLC-chemiluminescence analysis demonstrated that incubation with the PCOOH/Cu(II) combination oxidized cholesterol, a relatively oxidation-resistant component, to the cholesterol hydroperoxide. These results reveal that (1)O2 is generated from PCOOH in contact with copper(II). In conclusion, this in-vitro study provides directly the (1)O2 formation in living organisms following the advancement of peroxidation of constitutive lipids.

Catalase↗
PubMed1997

Influence of secondary structure on the decay kinetics of fluorescent donor-acceptor labelled peptides.

Time-resolved fluorescence decays from a series of methoxynaphthalene labelled peptides in ethyl acetate were monitored over the temperature range -40 to 60 degrees C. The quenching effect of a piperidone acceptor group placed at various positions along the peptide chain relative to the fluorescent methoxynaphthalene donor was studied. In this moderately polar solvent the mechanism of quenching is most likely electron transfer, although a Dexter exchange mechanism cannot be ruled out. Both donor and acceptor moieties were covalently attached to the side-chains of glutamic acid residues. These were either placed adjacently, in the case of a dipeptide, or separated by three and six amino acids within a 12 and 15 amino-acid oligopeptide, respectively. The presence of the piperidone group resulted in a reduction in the fluorescence lifetime and a change from a simple monoexponential decay to more complex behaviour. This was found to vary reversibly with temperature and not to be caused by impurities. Modelling of the fluorescence decays was carried out using either the sum of two exponentials or a distribution of decays. For the dipeptide the best fit was a distribution while in the case of the 12-mer two clearly distinguishable populations could be observed. The results for the 15-mer were equivocal. Importantly, regardless of the fitting method used the quenching rate was found to be fastest for the 12-mer. The slower quenching rates observed for the dipeptide compared to the oligopeptides provide strong evidence that secondary structure promotes better electronic coupling between the donor and acceptor. The biexponential fluorescence behaviour for the 12 amino-acid oligopeptide is ascribed to two slowly (> 10 ns) interconverting conformational states. Comparison with circular dichroism and infrared obtained in acetonitrile indicates these two conformers are likely to be an alpha-helix and a 3(10)-helix with electronic coupling strongest in the latter case.

Fluorescence↗
PubMed2000

Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: synthesis and biological effects.

Flavopiridol analogues, thio- and oxoflavopiridols which contain a sulfur (16) or oxygen (18) atom linker between a chromone ring and the hydrophobic side chain, are selective cyclin-dependent kinase 1 (CDK1) inhibitors with an IC(50) of 110 and 130 nM. These analogues were prepared from key intermediate 7 by substituting the ethyl sulfoxide. Enantio pure intermediate piperidone 10 was obtained from the racemic piperidone 8 via a very efficient "dynamic kinetic resolution" in 76% yield. Hydrophobic side chains such as chlorophenyl or tert-butyl produced potent CDK1 inhibitory activity, while hydrophilic side chains such as pyrimidine or aniline caused a severe reduction in CDK inhibitory activity. These analogues are competitive inhibitors with respect to ATP, and therefore activity was dependent upon the CDK subunit without being affected by the cyclin subunit or protein substrate. Thio- and oxoflavopiridols 16 and 18 are not only selective within the CDK family but also discriminated between unrelated serine/threonine and tyrosine protein kinases. CDK1 selective thio- and oxoflavopiridol analogues inhibit the colony-forming ability of multiple human tumor cell lines and possess a unique antiproliferative profile in comparison to flavopiridol.

Antineoplastic Agents↗
PubMed1999

Synthesis and pharmacology of the baclofen homologues 5-amino-4-(4-chlorophenyl)pentanoic acid and the R- and S-enantiomers of 5-amino-3-(4-chlorophenyl)pentanoic acid.

(RS)-5-Amino-4-(4-chlorophenyl)pentanoic acid (10) and the R-form (11) and S-form (12) of (RS)-5-amino-3-(4-chlorophenyl)pentanoic acid, which are homologues of the 4-aminobutanoic acidB (GABAB) receptor agonist (RS)-4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), were synthesized. Compound 10 was synthesized by homologation at the carboxyl end of baclofen using a seven-step reaction sequence. N-Boc-protected (4R, 5R)-4-(4-chlorophenyl)-5-hydroxy-2-piperidone (18) was deoxygenated via a modified Barton-McCombie reaction to give N-Boc-protected (R)-4-(4-chlorophenyl)-2-piperidone (20), which was ring opened and deprotected to give 11.HCl. The corresponding S-enantiomer, 12.HCl, was synthesized analogously from the 4S,5S-enantiomer of 18, compound 21. The enantiomeric purities of 11.HCl (ee = 99.8%) and 12. HCl (ee = 99.3%) were determined by chiral HPLC. Compound 10 did not show detectable affinity for GABAA or GABAB receptor sites and was inactive as an agonist or an antagonist at GABAB receptors in the guinea pig ileum. Like the enantiomers of baclofen, neither 11 nor 12 showed detectable affinity for GABAA receptor sites, and in agreement with the findings for (S)-baclofen, 12 did not interact significantly with GABAB receptor sites. Compound 11 (IC50 = 7.4 +/- 0.6 microM), a homologue of (R)-baclofen (2), was shown to be some 50 times weaker than 2 (IC50 = 0.14 +/- 0.01 microM) as an inhibitor of GABAB binding. Accordingly, 11 (EC50 = 150 +/- 23 microM) was shown to be weaker than 2 (EC50 = 11 +/- 1 microM) as an inhibitor of electrically induced contractions of the guinea pig ileum. However, whereas this effect of 2 was sensitive to the GABAB antagonist, CGP35348 (4), the inhibition by 11 was not significantly affected. Furthermore, 12 (EC50 = 310 +/- 16 microM) was shown to be one-half as potent as 11 in this test system, and this effect of 12 also was insensitive to 4. The dissimilarities of the pharmacological effects of 2 and compounds 11 and 12 were emphasized by the observation that whereas 2 only inhibits the ileum contraction by 59 +/- 5%, 11 as well as 12 were shown to inhibit this response by approximately 94%. Neither 11 nor 12 appeared to affect significantly cholinergic mechanisms in the ileum, and their mechanism(s) of action remain enigmatic.

Animals↗
PubMed1997

Design and Synthesis of Transition State Analogs for Induction of Hydride Transfer Catalytic Antibodies.

Alcohol dehydrogenases and related aldehyde reductase enzymes catalyze the oxidation of alcohols to aldehydes and the simultaneous reduction of a nicotinamide derivative (NAD(+) or NADP(+)) to the corresponding 1,4-dihydronicotinamide. Herein we report the design and synthesis of a stable transition state analog for this hydride transfer process. Compound 1 is a rigid [3.2.2] bicyclic structure containing 3-piperidone oxime as a mimic for 1,4-dihydronicotinamide. The piperidone is held in the boat conformation corresponding to the transition state by a three-atom lactam bridge between N(1) and C(4). The oxime function mimics the carboxamide group in nicotinamide. The lactam nitrogen serves as an attachment point for the alkyl group of the alcohol substrate, and the amide oxygen atom mimics its hydroxyl group. Compound 1 was prepared in 10 steps from N-benzylpiperidone, functionalized with substrate and cofactor recognition elements into transition state analogs 2 and 3 and conjugated to carrier proteins for immunization. These novel analogs open the way for the exploration of the dehydrogenase reaction using catalytic antibodies.

Journal Article↗
PubMed1998

Synthesis of the Pentacyclic Skeleton of the Aspidosperma Alkaloids Using Rhodium Carbenoids as Reactive Intermediates.

A series of diazo amido keto esters prepared from N-alkenyl-substituted 3-carbalkoxy-2-piperidone derivatives was treated with rhodium(II) acetate. Attack of the amido carbonyl oxygen at the resultant rhodium carbenoid center produced a transient push-pull carbonyl ylide dipole which underwent an intramolecular dipolar cycloaddition reaction. A related annulation sequence was used to prepare the pentacyclic skeleton of the aspidosperma family of alkaloids. Synthesis of the required diazo imide was carried out from 3-carboxy-3-ethyl-2-piperidone and N-methyl-3-indoleacetic acid. Treatment of the diazo imide with rhodium(II) acetate afforded a transient 1,3-dipole which subsequently underwent cycloaddition across the indole pi-bond. The resulting cycloadduct is the consequence of endo cycloaddition with respect to the dipole which is fully in accord with the lowest energy transition state. The cycloadduct was converted in three steps into desacetoxy-4-oxo-6,7-dihydrovindorosine. The stereochemistry of the final product was established by a X-ray crystallographic study.

Journal Article↗
PubMed1967

The oxidation of lysine and oxalysine by Mytilus edulis: Identification of the products formed in the presence and the absence of catalase.

1. O-(2-Aminoethyl)serine (oxalysine) was shown to be a substrate of the l-amino acid oxidase of the digestive gland of the common mussel, Mytilus edulis. 2. Three atoms of oxygen were consumed per mole of oxalysine oxidized in the presence of catalase; l-lysine under the same conditions consumed only one atom. 3. The products of oxidation of oxalysine in the presence and the absence of catalase were: ethanolamine, N-oxalylethanolamine and 3-morpholone (the oxygen analogue of 2-piperidone). After acid hydrolysis 70% of the oxalysine oxidized was recovered as ethanolamine. 4. In the absence of catalase 2-aminoethoxyacetic acid was also detected. 5. The products identified account quantitatively for the oxalysine oxidized and for the oxygen uptake. 6. N-Oxalylethanolamine and 2-aminoethoxyacetic acid have been synthesized. 7. Treatment of extracts of the digestive gland at pH3.0 completely inactivated the catalase, leaving the l-amino acid oxidase unaffected. 8. The major product of the oxidation of lysine in the absence of catalase was 2-piperidone.

Journal Article↗
PubMed1993

Enhancement of ultrasonically induced cell damage by a gallium-porphyrin complex, ATX-70.

Enhancement of ultrasonically induced cell damage by a gallium-porphyrin complex [ATX-70, 2,4-bis(1-decyloxyethyl)-Ga(III)-1,3,5,8- tetramethylporphryin-6,7-dipropionyl diaspartic acid] was investigated. The rate of damage to isolated sarcoma 180 cells in air-saturated suspension induced by 2 MHz ultrasound irradiation was enhanced more than four times by 80 microM ATX-70 in contrast to only twice by the same concentration of hematoporphyrin (Hp). The enhancement was almost completely inhibited in the presence of 10 mM histidine in the suspension, but not at all by 100 mM mannitol, which suggests that the enhanced cell damage was mostly mediated by singlet oxygen. Ultrasonically induced active oxygen generation in an air-saturated aqueous solution of ATX-70 was studied by detecting the electron spin resonance signals of 2,2,6,6,-tetramethyl-4-piperidone-N-oxyl produced by the reaction of 2,2,6,6-tetramethyl-4-piperidone with the generated active oxygen species. The rate of ultrasonically induced nitroxide generation was enhanced five times by 80 microM ATX-70 in contrast to only twice by Hp. The enhancement was inhibited significantly in the presence of 10 mM histidine in the suspension, but not at all by 100 mM mannitol. The singlet oxygen generation in air-saturated aqueous solution was further confirmed by the bleaching of N,N-dimethyl-4-nitrosoaniline in the presence of imidazole. The ultrasonically induced bleaching rate was enhanced six times by ATX-70, in contrast to only twice by Hp.

Animals↗
PubMed1988

Synthesis and nuclear magnetic resonance spectroscopic, mass spectroscopic, and plasma amine oxidase inhibitory properties of analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Seventeen analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine were synthesized using three reaction pathways: condensation of phenols with 1-methyl-4-piperidone, reaction of Grignard reagents with 1-methyl-4-piperidone followed by dehydration of the product, and aminomethylation of olefins. The identity of the products of synthesis was established by nuclear magnetic resonance spectroscopy, mass spectroscopy, and elemental analysis. Thirteen analogues were shown to inhibit the oxidation of benzylamine by bovine plasma amine oxidase. Increasing the length of the aliphatic chain of N-substituted analogues resulted in increased inhibition. In 4-phenyl-substituted analogues, both the position and electronic character of the substituent group affected the degree of inhibition.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Synthesis and antimalarial activity of febrifugine derivatives.

The regioisomers (2a,b) of the piperidine ring of febrifugine (1a) and isofebrifugine (1b) were synthesized from 4-allyl-3-piperidone (5). Reduction of 5 afforded a mixture of the trans and cis alcohols (6a,b) without diastereoselectivity; this result differentiated it from the reduction of 2-allyl-3-piperidone (14). The antimalarial activity of 2a,b and related compounds was tested.

Antimalarials↗
PubMedDate not supplied

Simultaneous production of superoxide radical and singlet oxygen by sulphonated chloroaluminum phthalocyanine incorporated in human low-density lipoproteins: implications for photodynamic therapy.

Sulfonated chloroaluminum phthalocyanines have been studied for their use in the photodynamic therapy (PDT) of tumors. Plasma low-density lipoproteins (LDL) are important carriers of phthalocyanines in the blood, but on exposure to visible light, phthalocyanine-loaded LDL undergo an oxidation process that propagates to erythrocytes. We attempted to identify the reactive species involved in LDL and erythrocyte oxidation by means of electron paramagnetic resonance (EPR) spectroscopy in the presence of 2,2,6,6-tetramethyl-4-piperidone (TEMP) and the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO). Irradiation of phthalocyanine-loaded LDL in the presence of DMPO resulted in the formation of a four-line EPR spectrum with relative intensity of 1:2:2:1 (a(N) = a(H) = 14.8 G), characteristic of DMPO-hydroxyl radical spin adduct. This signal was sensitive to superoxide dismutase and slightly sensitive to catalase, but a mixture of the two enzymatic activities was the most efficient in promoting a decrease in the intensity of the EPR signal. In the presence of erythrocytes, an increase in the quartet intensity for a hematocrit of 1% and 4% was observed, decreasing for higher erythrocyte concentrations. The irradiation of phthalocyanine-loaded LDL in the presence of TEMP resulted in the formation of a nitroxide radical, 2,2,6,6-tetramethyl-4-piperidone-N-oxyl radical, intensity of which was sensitive to histidine, a singlet oxygen ((1)O(2)) quencher. Under both incubation conditions, with DMPO and TEMP, the formation of the respective EPR signals required the sensitizer (phthalocyanine), light and oxygen. Overall, the results are compatible with the simultaneous formation of superoxide anion and (1)O(2), implying that Type-I and Type-II mechanisms of photochemistry are simultaneously operative in phthalocyanine-loaded LDL. However, for a constant LDL/phthalocyanine ratio, the formation of oxygen free radicals shows a biphasic behavior with the concentration of LDL increasing and reaching a plateau, whereas the formation of (1)O(2) increases linearly with LDL concentration. Erythrocytes at high (physiological) concentrations induced a decrease in the intensity of both EPR signals. The physiological relevance of these findings in the framework of PDT is briefly discussed.

Cyclic N-Oxides↗
PubMed1998

Metallothionein, neurotrophins and selegiline in providing neuroprotection in Parkinson's disease.

The finding that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits parkinsonism in human beings suggests that endogenous or xenobiotic neurotoxic compounds may be involved in the etiology of Parkinson's disease (PD). We have shown that cerebrospinal fluid (CSF) of newly diagnosed and drug untreated patients with PD contains a low molecular weight substance(s) which inhibits the growth and function of dopaminergic neurons in culture. In addition, selegiline in a dosage below the level that inhibits monoamine oxidase B (MAO-B), protects dopaminergic neurons in culture against toxic factor(s) present in the CSF of patients with PD, and the said effect is mediated via elaboration of brain-derived neurotrophic factor (BDNF). In view of the fact that 6-hydroxydopamine (6-OHDA) or MPTP causes parkinsonism by generating free radicals, and inducers of metallothionein (MT) isoforms avert the said neurotoxicity, we intended to learn whether MT isoforms were capable of scavenging free radicals. By employing electron spin resonance spectroscopy (ESR), we examined for the first time the free radical scavenging effects of MT-I and MT-II isoforms on four types of free radicals. Solutions of 0.15 mM of MT-I and 0.3 mM of MT-II scavenged the 1,1-diphenyl-2-picrylhydrazyl radicals completely. Furthermore, they were able to scavenge hydroxyl radicals generated in a Fenton reaction. Moreover, MT-I scavenged almost 90% of the superoxide generated by the hypoxanthine and xanthine oxidase system, while MT-II could only scavenge 40%. By using 2,2,6,6-tetramethyl-4-piperidone as a "spin-trap" for the reactive oxygen species (containing singlet oxygen, superoxide and hydroxyl radicals) generated by photosensitized oxidation of riboflavin, and measuring the relative signal intensities of the resulting stable nitroxide adduct, 2,2,6,6-tetramethyl-4-piperidone-1-oxyl, we observed that MT-II could scavenge 92%, while MT-I could completely scavenge all the reactive species generated. The results of this investigation are interpreted to suggest that selegiline by preventing the generation of free radicals, MT isoforms by scavenging free radicals, and neurotrophins by rescuing dopaminergic neurons are capable of attenuating oxidative stress and of providing neuro-protection in PD.

Journal Article↗
PubMed1989

[Screening of drugs and chemicals by wide-bore capillary gas chromatography with flame ionization and nitrogen phosphorus detectors].

A method is presented for forensic toxicological screening of drugs and chemicals in blood and urine by wide-bore capillary gas chromatography with flame ionization detectors (FID) and nitrogen phosphorus detectors (NPD). The presence of drugs and chemicals in blood and urine specimens was confirmed by comparing these gas chromatograms with those of typical drug-free specimens. Peak components of drug-free specimens were piperidone, p-cresol, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, n-butylphthalate, bis (2-ethylhexyl) phthalate, squalene, cholesterol and two alcohols (unidentified) on FID chromatograms and were piperidone, indole, nicotine, cotinine, hydroxycotinine, caffeine and several unknown urine constituents on NPD chromatograms. In practical cases, the presence of drugs and chemicals in postmortem specimens was easily ascertained by the present method.

Adult↗