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PubMed1984

Identification and quantitative determination of fentanyl metabolites in patients by gas chromatography--mass spectrometry.

Although fentanyl has been used widely as a short-acting narcotic analgesic, its metabolism in humans has not been clarified. In this study, three fentanyl metabolites were identified in the urine of eight surgical patients receiving 0.3-0.5 mg of fentanyl intravenously. The metabolites 4-N-(N-propionylanilino)piperidine, 4-N-(N-hydroxypropionylanilino)piperidine and 1-(2-phenethyl)-4-N-(N-hydroxypropionylanilino)piperidine, and unchanged fentanyl were identified by GC-mass spectrometry in urine collected 6 h after administration. Fentanyl and its main metabolite, 4-N-(N-propionylanilino)piperidine, were determined quantitatively in the urine of five additional patients receiving 0.5 mg fentanyl intravenously. Urinary excretion of fentanyl and 4-N-(N-propionylanilino)-piperidine during the first 12 h after injection accounted for 0.3-4.0% and 26 to 55% of the dose, respectively.

Adult↗
PubMed1979

Metabolites of loperamide in rats.

Following intraperitoneal administration to rats of [14C]loperamide, [carbonyl-14] 4-(p-chlorophenyl)-4-hydroxy-N,N-dimethyl-alpha, alpha-diphenyl-1-piperidine butyramide, metabolites in feces and urine were separated, and identified by means of mass spectrometry. In feces, six metabolites were identified in addition to the unchanged drug. The main metabolic pathways involved are dealkylation in the dimethyl amide moiety to give desmethyl- and didesmethylloperamide, both of which were in turn monohydroxylated either in the alpha-phenyl ring or possibly in the alpha-carbon in the piperidine ring. It is noteworthy that metabolites hydroxylated in the piperidine ring were isolated as pyridinium derivatives, possibly due to spontaneous aromatization of its 2,4-dihydroxy-4-(p-chlorophenyl)piperidine ring. In urine, only two metabolites were found and identified to be desmethyl- and didesmethylloperamide, since [14C]loperamide was excreted into urine only in a small amount.

Animals↗
PubMed1994

In vivo pharmacokinetics of nitroxides in mice.

The in vivo reduction kinetics of twenty different nitroxide compounds in mice has been investigated by using an electron paramagnetic resonance (EPR) spectrometer, equipped with an S-band loop-gap resonator, operating at 3.5 GHz. The diameter of the resonator (4 mm) fits well the tip of the mouse tail, thus allowing the direct detection of in vivo free radicals in the blood circulation. After intravenous injection, the nitroxide signal in the circulation of the mouse tail was followed with time; no anesthetic agent was used. For the pyrrolidine nitroxides (five-member rings) with different functional groups, the t1/2 values followed the order: = O > COO- > OH > CONH2 approximately CH2NH2 > NH2. A different trend was obtained for the piperidine nitroxides (six-member rings): COO- > CH2NH2 > OH approximately NH2 > CONH2 > = O. The most striking observation was that while the t1/2 value of the cabonyl pyrrolidine is the longest among all the nitroxides tested for this property, that of the carbonyl piperidine is the shortest. Comparison of the in vivo decay kinetics of six pairs of pyrrolidine nitroxides and piperidine nitroxides with same functional groups showed that the t1/2 values of the former are 2 to 28 times longer than the latter. It is concluded here that the pyrrolidine nitroxides are more resistant to cellular metabolism in vivo when compared to the piperidine nitroxides.

Animals↗
PubMed2002

The effects of derivatives of the nitroxide tempol on UVA-mediated in vitro lipid and protein oxidation.

Derivatives of tetramethylpiperidines are extensively employed in polymers to prevent photooxidation, and their stabilizing effect is attributed to the activity of the nitroxide radical derived from the parent amine. In this study, we examined the photoprotective effect of a commercial polymer photostabilizer, HALS-1, its corresponding nitroxide, bis(2,2,6,6-tetramethyl-piperidine-1-oxyl-4-yl)sebacate (TINO), and two derivatives of the piperidine nitroxide TEMPOL, 2,2,6,6-tetramethyl-piperidin-4-acetyloxy-1-oxyl (TEMP2) and 2,2,6,6-tetramethyl-piperidin-4-octanoyloxy-1-oxyl (TEMP8) synthesized by us, in liposomes exposed to ultraviolet A (UVA) radiation. For comparison, the UVA-absorber, 4-tert-butyl-4'-methoxydibenzoylmethane (Parsol 1789) used in many suncream formulations, was also included. The nitroxide TINO resulted extremely efficient at inhibiting aldehydic breakdown products deriving from 30 min exposure of liposomes to UVA and the protection was dose-dependent (10-100 microM). The corresponding amine HALS-1 was the least efficient while protection increased in the order: TEMP2 < Parsol 1789 < TEMP 8. HALS-1, TINO, and the two TEMPOL derivatives were also tested in a simple protein system consisting of bovine serum albumin (BSA) exposed to UVA. In this case, these compounds did not inhibit nor enhance UVA-mediated protein carbonyl formation in BSA. The differences in protection between the compounds are discussed in relation to their chemical reactivity, UVA-absorbing capacities, and their molecular structure. Overall, the results obtained envisage the potential use of nitroxide compounds as topical antioxidants.

Animals↗
PubMed2005

Piperidinyl amides with insecticidal activity from the maritime plant Otanthus maritimus.

Two new piperidine amides, N-[(2E,4E,8Z)-tetradecatrienoyl]piperidine (1) and N-[(2E,4E,8Z,11Z)-tetradecatetrenoyl]piperidine (2), along with the known metabolites N-[(2E,4E)-tetradecadienoyl]piperidine (3), N-isobutyl-(2E,4E,)-tetradecadienamide (4), N-isobutyl-(2E,4E,8Z)-tetradecatrienamide (5), N-isobutyl-(2E,4E,8Z,11Z)-tetradecatetraenamide (6), sesamine (7), pinoresinol (8), and espeletone (9), were isolated from the dichloromethane/methanol extracts of the plant Otanthus maritimus Hoffman & Link collected from coastal areas in Greece. Pinoresinol (8) and espeletone (9) are reported for the first time as metabolites of O. maritimus. The structures of the new natural products were elucidated by interpretation of their NMR and high-resolution mass spectral measurements. The insecticidal properties of the crude extracts, essential oil, and isolated metabolites 1-9 were evaluated on Crematogaster scutellaris (Olivier) ants and Reticulitermes balkanensis (Clement) termites, showing significant levels of activity.

Alkenes↗
PubMed1994

Spirovesamicols: conformationally restricted analogs of 2-(4-phenylpiperidino)cyclohexanol (vesamicol, AH5183) as potential modulators of presynaptic cholinergic function.

In an effort to develop selective inhibitors of vesicular acetylcholine storage, we have synthesized a series of semirigid vesamicol receptor ligands based on the structure of 2-(4-phenylpiperidino)-cyclohexanol (vesamicol, AH5183, 1). In these compounds, the planes of the phenyl and piperidyl moieties of the parent ligand 1 are held at right angles by vinyl, ethylene, and propylene bridges to form N-substituted derivatives of spiro[indene-1,4'-piperidine], 2,3-dihydrospiro[indene-1,4'-piperidine], and 3,4-dihydrospiro[naphthalene-1(2H),4'-piperidine], respectively. Preliminary evaluation of these compounds in electric organ synaptic vesicles revealed several potent vesamicol receptor ligands, such as 1'-(2-hydroxy-1,2,3,4-tetrahydronaphth-3-yl)spiro[1H-indene-1,4'-p iperidine (11b) and 1'-(2-hydroxy-1,2,3,4-tetrahydronaphth-3-yl)spiro[2-bromo-1H-in den e- 1,4'-piperidine] (14), which display subnanomolar affinity for this receptor. In general, the vinyl and ethylene bridges yielded the most potent analogs while the propylene-bridged analogs were among the least potent compounds. The increased rigidity of these spiro-fused compounds, relative to the corresponding simple 4-phenylpiperidine derivatives of vesamicol, is expected to confer greater selectivity for the vesamicol receptor.

Acetylcholine↗
PubMed1992

Synthesis, configuration, and activity of isomeric 2-phenyl-2-(N-piperidinyl)bicyclo[3.1.0]hexanes at phencyclidine and sigma binding sites.

The novel semirigid derivatives (+)-cis-1-[2-phenyl-2-bicyclo[3.1.0]hexyl]piperidine [(+)-8], its enantiomer (-)-8, and (+-)-trans-1-[2-phenyl-2-bicyclo[3.1.0]hexyl]piperidine [(+/-)-9] were synthesized as probes to investigate the mode of interaction of phencyclidine (PCP) with its binding site on the N-methyl-D-aspartate receptor complex. Each target compound was obtained in five steps starting from cyclopent-2-enone. (+)- and (-)-8 were obtained in greater than 98% optical purity through three recrystallizations from ethanol of the (S)-(+)- and (R)-(-)-mandelate salts of intermediate (+-)-cis-2-phenyl-2-bicyclo[3.1.0]hexylamine ([(+/-)-16]. Crystallization of the (R)-(-)-mandelate salt afforded (1R,2R,5S)-(-)-16, whereas the (S)-(+)-mandelate salt afforded (1S,2S,5R)-(+)-16; the absolute configuration was determined by single-crystal X-ray analysis of (-)-16.(R)-(-)-mandelate. Single-crystal X-ray analysis of (+/-)-9-picrate confirmed its trans configuration and provided conformational data. (+)- and (-)-8 and (+/-)-9 were examined for their ability to interact with PCP and sigma binding sites in vitro using [3H]TCP and [3H]pentazocine as radioligands. The binding was compared with that of PCP and contrasted with the rigid symmetrical phencyclidine derivatives cis- and trans-1-[3-phenyl-3-bicyclo[3.1.0]hexyl]piperidines (6 and 7). The results of the study indicated that the conformations of PCP represented by 6-9 are not optimal for potent interaction at either of these sites. Affinities ranged from 582 nM [(+/-)-9] to 29,000 nM [(+)-8] at PCP binding sites and from 1130 nM [(-)-8] to 16,300 nM (7) at sigma sites. In this assay, PCP exhibited affinities of 64.5 nM at PCP and 1090 nM at sigma sites. Qualitative correlation between the sigma and PCP binding data suggests some similarities between these binding sites. An axial phenyl and equatorial piperidine ring with the nitrogen lone pair of electrons antiperiplanar to the phenyl ring has been postulated as the receptor-active conformation of PCP-like ligands at the PCP binding site. Comparison of the binding data of 7-9 with that of the previously described methylcyclohexyl-PCP derivatives allowed its rationalization in terms of this model. It is likely that the lowered affinity in this bicyclo[3.1.0]hexane series is a consequence of nonoptimal geometry (pseudoequatorial phenyl or pseudoboat) for binding as opposed to the presence of steric bulk which proved deleterious in the methylcyclohexyl-PCP derivatives.

Animals↗
PubMed1997

4-Heterocyclylpiperidines as selective high-affinity ligands at the human dopamine D4 receptor.

5-(4-Chlorophenyl)-3-(1-(4-chlorobenzyl)piperidin-4-yl)pyrazole (3) was identified from screening of the Merck sample collection as a human dopamine D4 (hD4) receptor ligand with moderate affinity (61 nM) and 4-fold selectivity over human D2 (hD2) receptors. Four separate parts of the molecule have been examined systematically to explore structure-activity relationships with respect to hD4 affinity and selectivity over other dopamine receptors. It was found that the 4-chlorophenyl group attached to the pyrazole is optimal, as is the 4-substituted piperidine. The lipophilic group on the basic nitrogen is more amenable to change, with the optimal group found to be a phenethyl. The aromatic heterocyle can be altered to a number of different groups, with isoxazoles and pyrimidines showing improved affinities. This heterocycle can also be advantageously alkylated, improving the selectivity of the compounds over D2 receptors. It is hypothesized that the conformation around the bond joining the aromatic heterocycle to the piperidine is important for D4 affinity, based on crystal structures of isoxazoles (29 and 30) and on a conformationally constrained compound (28). Putting all the favorable changes together led to the discovery that 5-(4-chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)iso xazole (36) is a nanomolar antagonist at human dopamine D4 receptors with > 500-fold selectivity over hD2 and > 200-fold selectivity over hD3. Compound 36 is an antagonist of hD4 receptors with good oral bioavailability of 38%, a half life of 2 h, and brain levels 10-fold higher than plasma levels.

Cell Line↗
PubMed1998

N-[omega-(Tetralin-1-yl)alkyl] derivatives of 3,3-dimethylpiperidine are highly potent and selective sigma1 or sigma2 ligands.

Several 3, 3-dimethyl-N-[omega-(tetrahydronaphthalen-1-yl)alkyl]piperidine derivatives and some related compounds were prepared. Their affinities and sigma-subtype selectivities were investigated by radioligand binding assays, labeling sigma1 receptors with [3H]-SKF 10047 and sigma2 receptors with [3H]-DTG. Many tested compounds bound sigma1 and/or sigma2 receptors with nanomolar or subnanomolar IC50 values. Compound (+)-22, (+)-3,3-dimethyl-1-[3-(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-propyl]piperidine, was the most potent (IC50 = 0.089 nM) and selective sigma1 ligand (1340-fold), showing a 10-fold enantioselectivity. Compounds 29 (3, 3-dimethyl-1-[4-(6-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-butyl]piperidine) and 31 (3, 3-dimethyl-1-[5-(1,2,3, 4-tetrahydronaphthalen-1-yl)-n-pentyl]piperidine) were highly potent (IC50 = 0.016 nM and IC50 = 0.008 nM, respectively) and highly selective sigma2 ligands (more than 100000-fold).

Animals↗
PubMed1999

Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors.

The aim of this work was to improve the oral bioavailability of a recently discovered, novel structural class of 5-HT1A receptor agonists: aryl-{[4-(6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1 -yl-metha none. Incorporation of a fluorine atom in the beta-position to the amino function in the side chain led to analogues that exhibited, in general, enhanced and long-lasting 5-HT1A agonist activity in rats after oral administration. Location of the fluorine atom at the C-4 position of the piperidine ring was the most favorable, and among the various substituents tested, the ability of the fluorine was unique in improving the oral activity of this family of ligands. Thus, the derivatives 39, 46, and 61 bound with higher affinity and selectivity to 5-HT1A receptors (versus dopaminergic D2 and adrenergic alpha1 receptors) and displayed more potent 5-HT1A agonist activity in vitro and in vivo than their C-4 desfluoro analogues. To examine the relationship between the conformation of the pharmacophore and the level of agonistic activity of this type of ligand, we synthesized a series of 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-(H or CH3)-6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-+ ++methanone derivatives and found that the combination of a 5-methyl and a 6-methylamino substituent on the pyridine ring synergistically affected their 5-HT1A agonist properties. Thus, the 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-6-methylamino-pyridin- 2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone 40 behaved as a more potent 5-HT1A receptor agonist in vitro and in vivo than its 5-unsubstituted analogue 38. The antidepressant potential of the lead compounds 40, 45, and 54 was examined by means of the forced swimming test (FST) in rats. The results indicated that, after a single oral administration, these compounds inhibited immobility in the FST more potently and more extensively than the clinically used antidepressant imipramine. Thus, 40, 45, and 54 are potent, orally active 5-HT1A receptor agonists with marked antidepressant potential.

Administration, Oral↗
PubMed1999

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety.

We have previously described compound 1a as a high-affinity subtype selective alpha(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a mu-opioid agonist, 4-methoxycarbonyl-4-phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to mu-opioid activity. Modification of the linker gave several compounds with good alpha(1a) binding affinity (K(i) = < 1 nM) and selectivity (>300-fold over alpha(1b) and alpha(1d)). In vitro analysis in the microsomal assay revealed these modifications did not significantly affect N-dealkylation and the formation of the piperidine 3. The second approach, however, yielded several piperidine replacements for 3, which did not show significant mu-opioid activity. Several of these compounds maintained good affinity at the alpha(1a) adrenoceptor and selectivity over alpha(1b) and alpha(1d). For example, the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the mu-opioid receptor (IC(50) > 30 microM vs 3 microM for 3). Compounds (+)-73 and (+)-83 were subjected to detailed in vitro and in vivo characterization. Both these compounds, in addition to their excellent selectivity (>880-fold) over alpha(1b) and alpha(1d), also showed good selectivity over several other recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional potency in isolated human prostate tissues, with K(b)s comparable to their in vitro alpha(1a) binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs, similar to 1a.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2000

Peroxynitrite-induced secondary oxidative lesions at guanine nucleobases: chemical stability and recognition by the Fpg DNA repair enzyme.

Synthetic oligodeoxynucleotides containing secondary oxidative lesions at guanine nucleobases have been prepared by the site-specific oxidation by ONOO(-) of oligomers containing 8-oxoguanine (8-oxo-G). The oligomers have been tested for their stability to the standard hot piperidine treatment that is commonly used to uncover oxidized DNA lesions. While DNA containing oxaluric acid and oxazolone was cleaved at the site of modification under hot piperidine conditions, the corresponding cyanuric acid and 8-oxo-G lesions were resistant to piperidine. The recognition of the oxidative lesions by formamidopyrimidine glycosylase (Fpg enzyme) was examined in double-stranded versions of the synthetic oligodeoxynucleotides. Fpg efficiently excised 8-oxo-G and oxaluric acid and to some extent oxazolone, but not cyanuric acid. These data suggest that some DNA lesions formed via ONOO(-) exposures (cyanuric acid) are not repaired by Fpg and are not uncovered by assays based on piperidine cleavage at the site of lesion. Our results indicate that cryptic secondary and tertiary oxidation products arising from 8-oxo-G may contribute to the overall mutational spectra arising from oxidative stress.

Chromatography, High Pressure Liquid↗
PubMed1980

Increased excretion of a brain depressor amine in infantile coeliac disease and in healthy infants on a high protein milk diet.

Urinary excretion of piperidine, a heterocyclic pressor amine of gut bacterial origin and nicotine-like activity in the brain, has been estimated by a gas chromatography method in healthy men and women, in normal breast-fed and formula-fed infants and in infants with untreated coeliac disease. The excretion of piperidine cannot usually be detected during the first week of life. The amount present in urine increases upon weaning with higher excretion in formula-fed than in breast-fed infants at four to six months of age. When premature infants fed on human milk are weaned, the urinary content of piperidine rises from undetectable amounts to normal for age. The high content present in untreated coeliac disease may be responsible for the initial mental depression commonly seen in this disease and suggests that piperidine is one of the "auto-intoxicating" substances arising from the bacterial decomposition of protein postulated by Metchnikoff in 1903 but hitherto unidentified.

Adult↗
PubMed1987

Interaction of some 2-hydroxybenzylpiperidines with dopamine receptors.

Some N-alkyl derivatives of 2-(3-hydroxybenzyl)piperidine and of 2-(3,4-dihydroxybezyl)piperidine were synthesized and evaluated pharmacologically in vitro by competition with [3H]spiperone for binding to a homogenized rat striatal tissue, and for ability to stimulate adenylate cyclase. The N-methyl-2-(3,4-dihydroxybenzyl)piperidine shows a fairly good affinity for the D-2 dopamine receptor. The N-alkyl 2-(3,4-dihydroxybenzyl)piperidines produce a faible stimulation of adenylate cyclase activity.

Adenylyl Cyclase Inhibitors↗
PubMed1995

Pharmacological characterization of LY303870: a novel, potent and selective nonpeptide substance P (neurokinin-1) receptor antagonist.

LY303870 [(R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane] is a new, potent and selective nonpeptide neurokinin-1 (NK-1) receptor antagonist. LY303870 bound selectively and with high affinity to human peripheral (Ki = 0.15 nM) and central (Ki = 0.10 nM) NK-1 receptors. LY303870 inhibited [125I]substance P (SP) binding to guinea pig brain homogenates with similar affinity; however, it had approximately 50-fold lesser affinity for rat NK-1 sites. The less active enantiomer, LY306155 [(S)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]-propane], was 1,000- to 15,000-fold less potent in all the species examined. LY303870 antagonized in vitro NK-1 receptor effects as demonstrated by blockade of SP-stimulated phosphoinositide turnover in UC-11 MG human astrocytoma cells (Ki = 1.5 nM) and interleukin-6 secretion from U-373 MG human astrocytoma cells (Ki = 5 nM). In addition, LY303870 inhibited SP-induced rabbit vena cava contractions (pA2 = 9.4) with high (50,000-fold) selectivity vs. NK-2 or NK-3 receptor-mediated responses. In vivo, LY303870 inhibited [Sar9,Met(O2)11]-SP induced guinea pig bronchoconstriction (ED50 = 75 micrograms/kg i.v.) and pulmonary microvascular leakage in the bronchi (ED50 = 12.8 micrograms/kg i.v.) and trachea (ED50 = 18.5 micrograms/kg i.v.). Therefore, LY303870 is a potent and selective NK-1 receptor antagonist in vitro and in vivo. The use of LY303870 will facilitate a better understanding of NK-1 receptors in physiological processes.

Airway Resistance↗
PubMed1996

Synthesis and anti-cancer activity of 2,6-disubstituted N-methylpiperidine derivatives and their N-oxides.

Bioreducible anti-tumour agents are prodrugs which are intended to be inactive in normal cells, but are able to undergo metabolic reduction in cancer cells to produce toxic species that can damage biomolecules. A series of N-oxides of heterocyclic aliphatic amines were designed and prepared as mentioned below as bioreducible drugs based on the reported anti-cancer activity of 2,6-bis(halomethyl)piperidines. In order to study structure-activity relationships in these conformationally restricted nitrogen mustards, samples of cis- and trans-2,6-dihydroxymethyl-N-methylpiperidine were prepared and converted into a number of carbamate or halogen derivatives. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation. The corresponding N-oxides were also prepared for comparison in cytotoxicity tests. In total, 21 new compounds were synthesized plus cis-N-methyl-2,6-bis(chloromethyl)-piperidine (prepared previously but lacking spectroscopic data) and tested against two human colon carcinoma cell lines, HT 29 (high DT-diaphorase) and BE (no DT-diaphorase), under oxic and hypoxic conditions. The majority of the free bases were equally toxic against both cell lines. The most toxic compounds were cis- and trans-N-methyl-2,6-bis(bromomethyl)piperidine with oxic IC50 values between 6 and 11 microM against both cell lines. The N-oxides were relatively non-toxic under both oxic and hypoxic conditions apart from the N-oxide of trans-N-methyl-2,6-bis(bromomethyl)-piperidine. Their low toxicity suggested that the N-oxides are not reduced under hypoxic conditions. We conclude that: (i) 2,6-disubstituted N-methylpiperidine derivatives are chemically versatile cytotoxic entities that are suitable for prodrugging to enhance their therapeutic selectivity; and (ii) N-oxide prodrugs of these compounds are deactivated chemically and display reduced cytotoxicity compared to the parent amines but are apparently not reduced under hypoxic conditions. At least in the colorectal cell lines tested the latter issue would need to be addressed by modifying the redox properties in future work to progress this approach.

Antineoplastic Agents, Alkylating↗
PubMed1998

Analysis of 9-fluorenylmethoxycarbonyl (FMOC) loading of solid-phase synthesis resins by gas chromatography

Base-catalyzed cleavage of the 9-fluorenylmethoxycarbonyl (FMOC) group and subsequent analysis by UV spectrophotometry is commonly employed to measure the "loading" of functional groups on solid support. Recent work suggests that 1,8-diazabicyclo[5.4. 0]undec-7-ene (DBU) may be superior to piperidine (the most commonly used base for the cleavage) for quantitative analysis by UV. We have compared deprotection of FMOC-bearing compounds by both DBU and piperidine, and have observed by GC-MS the formation of a dibenzofulvene-piperidine adduct (piperidine deprotection), and the formation of unassociated dibenzofulvene (DBU deprotection). We have further been able to use GC analysis of dibenzofulvene produced in the DBU deprotection mixture in a quantitative analysis of resin loading, which gave results comparable to UV methods. Sample preparation for this method has been automated using the Nautilus 2400 organic synthesizer to reduce the amount of operator time and increase throughput of sample analysis. Copyright 1998 John Wiley & Sons, Inc.

Journal Article↗
PubMed1989

Site-specific laser modification (cleavage) of oligodeoxynucleotides.

Sequence-specific photomodification of oligodeoxynucleotide pAGAGTATTGACTTA ("a target") has been carried out with the aid of complementary fluorescent probes. Such a probe consisted of oligodeoxynucleotide pAATACTCT and a chromophore group attached to its 5' end. Three different derivatives of ethidium bromide were used as a chromophore. The photomodification was induced by nitrogen laser radiation (337 nm, 15 MW/cm2). The irradiation induces the following photodamages: target cleavage at the specific binding site with a cutting off of the 8-mer from its 5' end (yield up to 12%), formation of specific covalent adduct target-probe with a yield of 20-70%, and piperidine-sensitive target modifications with a 7-27% yield (for different chromophores). The total yield of specific photodamages of all kinds is 50-80%. The target cleavage and generation of piperidine-sensitive modifications are optically nonlinear processes. Piperidine treatment of the irradiated samples led to specific cleavage of the target with the yield up to 40%. All kinds of observed modifications are not influenced by high concentrations of free radical scavengers: 1.3M tBuOH and 10 mM cystamine. The pattern of cleavage indicates that the most probable position of the chromophore is between T8 and G9 of the target, i.e., the chromophore stacks on top of the last A.T base pair of the duplex. The aggregate of evidence is in agreement with the mechanism of nonlinear photomodification (the cleavage and generation of piperidine-sensitive modifications) based on the transfer of two-photon excitation energy from the chromophore to the target.

Base Sequence↗