Propyl Side Chain Research Articles

Hydrogen pressure dependence in the ring-opening reactions of propylcyclobutane over Pd/SiO2 catalyst

Temperature dependence and the effects of hydrogen pressure on the rate and regioselectivity were studied in the ring opening of propylcyclobutane over a low-dispersion Pd/SiO2 catalyst. At a certain composition (1.33 kPa of propylcyclobutane and 20 kPa of H2) the reaction rate versus temperature curve was found to pass through a maximum. At each temperature the ring opened selectively (or exclusively at 423 K) in the sterically more hindered direction over the clean surface as well as over the steady-state catalyst, yieldingn-heptane as the major product. The hydrogen pressure versus turnover frequency curves were of saturation type for both products over the initial surface at 523 K. Over the steady-state surface, however, the reaction mechanism changed: ring-opening rate versus hydrogen pressure curve passed through a maximum forn-heptane, while it remained of saturation type for 3-methylhexane. For rationalizing the high regioselectivity towardn-heptane formation, the anchoring effect of the propyl side-chain was suggested.

Surface Carbonaceous Deposits as Activity and Selectivity Influencing Species in Ring-Opening Reactions of Propylcyclobutane Catalyzed by Pt/SiO 2

Active site formation in the hydrogenative ring opening of propylcyclobutane over Pt/SiO 2 was investigated in a static reactor, mainly at 373 K. Changes in the ring-opening rates and selectivities on variously treated catalyst are described. Three types of treatment were applied: repeated runs with (i) only evacuation or (ii) inter-run reduction (H 2, 473 K, 0.5 h), or (iii) prepoisoning of the catalyst with propylcyclobutane at 373 K or 673 K. The observed (in some cases dramatic) increase in selectivity towards the formation of heptane (1,2 CC bond scission) is interpreted in terms of the formation of a metal-carbonaceous deposit interface where the deposit provides an anchoring site for the adsorption of the propyl side-chain and the ring opens on the clean Pt atoms. Changes in activity due to the various treatments are also discussed.

Iron porphyrin-catalyzed oxidation of 1,2-dimethoxyarenes: a discussion of the different reactions involved and the competition between the formation of methoxyquinones or muconic dimethyl esters

This paper describes the oxidation of an α,β-diarylpropane lignin dimer model and other dimethoxyarenes by several iron porphyrin-based biomimetic systems. From 1-(3,4-dimethoxyphenyl)-2-phenylpropanol (1), three types of products are identified: the 3,4-dimethoxybenzaldehyde derived from the C α -C β cleavage of the propyl side chain and either quinones or muconic dimethyl esters resulting from oxidations at the level of the dimethoxyaryl group. The selectivity of the reaction is discussed with respect to the nature and reactivity of the high-valent iron-oxo species formed upon reaction of the oxidants, H 2 O 2 or magnesium monoperoxyphthalate (MMP), with the iron porphyrins

Ligninolysis by a purified lignin peroxidase

The lignin peroxidases (LiPs) of white-rot basidiomycetes are generally thought to catalyze the oxidative cleavage of polymeric lignin in vivo. However, direct evidence for such a role has been lacking. In this investigation, 14C- and 13C-labeled synthetic lignins were oxidized with a purified isozyme of Phanerochaete chrysosporium LiP. Gel permeation chromatography of the radiolabeled polymers showed that LiP catalyzed their cleavage to give soluble lower-M(r) products. To a lesser extent, the enzyme also polymerized the lignins to give soluble higher-M(r) products. This result is attributable to the fact that purified LiP, unlike the intact fungus, provides no mechanism for the removal of lignin fragments that are susceptible to repolymerization. LiP catalysis also gave small quantities of insoluble, perhaps polymerized, lignin, but in lower yield than intact P. chrysosporium does. 13C NMR experiments with 13C-labeled polymer showed that LiP cleaved it between C alpha and C beta of the propyl side chain to give benzylic aldehydes at C alpha, in agreement with the cleavage mechanism hypothesized earlier. The data show that LiP catalysis accounts adequately for the initial steps of ligninolysis by P. chrysosporium in vivo.

The occurrence of furan fatty acids in Isochrysis sp. and Phaeodactylum tricornutum

Two algae species with a fundamentally different fatty acid composition were investigated for their furan fatty acid (F-acid) content. Isochrysis sp. contains different F-acids with a pentyl side chain in α'-position of the furan ring. In consideration of its fatty acid composition which is predominated by compounds with a C-18 chain, this result supports the assumption that pentyl-F-acids derive from linoleic acid. In contrast, only F-acids with propyl side chain were found in Phaeodactylum tricornutum. The low content of C-18 fatty acids in this diatomae contradicts the previous hypothesis that linolenic acid is the precursor of propyl-F-acids. But the presence of ( n − 4) unsaturated fatty acids with 16 carbon atoms in Phaeodactylum tricornutum suggests that propyl-F-acids are synthesized from 9,12-hexadecadienoic acid in a very similar biogenetic pathway than pentyl-F-acids.

Synthesis of metabolites of mosapramine. I. Synthesis of alcoholic metabolites

Four alcoholic metabolites of (+-)-3-chloro-5-[3-(2-oxo-1,2,3,5,6,7,8,8a-octahydroimidazo[1,2-a] pyridine-3-spiro-4'-peperidino)propyl]-10,11-dihydro-5'-dibenz[b,f ] azepine(mosapramine), a new antipsychotic drug, were synthesized in order to determine their chemical structures. A mixture of 10-ethoxy-3-chloro-10,11-dihydro-5H-dibenz[b,f]azepine and 11-ethoxy isomer was used as a starting material. Isomeric intermediates, i.e. 10-oxo-3-chloro-5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine and 11-oxo isomer, were separated by chromatography with silica gel. The metabolites were obtained by NaBH4 reduction of the corresponding 10-oxo or 11-oxo compounds followed by introduction of spiro-piperidine moieties into propyl side chain.

Impact of Structural Differences on the in Vitro Glucuronidation Kinetics of Potentially Dopaminergic Hydroxy‐2‐Aminotetralins and Naphthoxazines Using Rat and Human Liver Microsomes

The in vitro glucuronidation of seven monohydroxy-2-aminotetralins and two naphthoxazines has been determined using human and rat liver microsomes. All these compounds stimulate the D2 dopamine receptor. The influence of the position of the phenolic hydroxyl group was studied with rat microsomes in monohydroxy-2-(N,N-dipropylamino)-tretralins. The highest activity and intrinsic clearance was found for 7-OH-DPAT, but the latter values for 5-OH-DPAT and 6-OH-DPAT were much lower by a factor of 9 and 30, respectively. The 8-OH-isomer was not glucuronidated at all. Substitution of a propyl side chain by a thienylethyl-, or phenylethyl side chain, in 5-hydroxy-DPAT, or in (+)-4-propyl-9-hydroxyhexahydronaphthoxazine (PHNO, N-0500), showed a large increase of the UDPGT affinity and intrinsic clearance especially for N-0437. It also resulted for N-0437 in a much higher affinity towards the dopaminergic D2 receptor. Although the glucuronidation activity of human microsomes was found to be considerably lower than that of rat microsomes, the latter phenomenon was clearly visible with human microsomes as well. These findings may have serious implications for the ability of these drugs to adequately reach the brain.

2D-NMR Studies on Bis(Amidinohydrazones). I. A Proton-Carbon Heteronuclear Shift Correlation Study on the Enzyme Inhibitors Methylpropylglyoxal Bis(Amidinohydrazone) and Butylmethylglyoxal Bis(Amidinohydrazone)

Abstract The first 2D-NMR study on bis(amidinohydrazones) [‘(guanylhydrazones)’] is reported. Heteronuclear shift correlation (HETCOR) experiments were performed on the enzyme inhibitors methylpropylglyoxal bis(amidinohydrazone) (MPGBG) and butylmethylglyoxal bis(amidinohydrazone) (BMGBG). The results obtained made possible the unambiguous assignment of the previously unassigned resonances of the side-chain carbon atoms of MPGBG. The results indicate that the chemical shifts of the protons of the propyl side chain of MPGBG are positively correlated to the 13C chemical shifts of the corresponding carbon atoms. The chemical shifts of the carbon atoms of the propyl side chain decrease as a function of the position of the atom in the side chain, the terminal methyl group having the lowest shift value. These results are in full agreement with previous results on the analogous compound dipropylglyoxal bis(amidinohydra- zone), whose side-chain carbon resonances were assigned using totally different techniques. I...

Positive- and negative-ion mass spectrometry and rapid clean-up of 19 phenothiazines

Positive-ion electron impact (PIEI), positive-ion chemical ionization (PICI) and negative-ion chemical ionization (NICI) mass spectra of 19 phenothiazines are presented. In the PIEI mode, peaks due to M, M minus side chain (M − R 1), M − R 1 + H, and side chain itself (R 1) appeared for most compounds. The M − R 1 and R 1 ions were very useful for drug screening. In the PICI mode, most spectra showed base or intense peaks due to M + H, and small peaks due to M + C 2H 5; peaks due to M − R 1 + 2H and R 1 also appeared in many compounds. In the NICI mode, fragmentation modes were different in different compound groups; molecular or [M − H] − quasi-molecular anions appeared in many compounds with aliphatic side chains. Anions at m z 98 and 115 were characteristic for compounds with ( N-methylpiperazinyl)propyl side chains. Selected ion monitoring in the PIEI mode generally gave much higher sensitivity than in the PICI and NICI modes. Phenothiazines present in urine or plasma could be rapidly isolated by use of Sep-Pak C 18 cartridges. Thirteen of 19 phenothiazines could be detected by HP-17 wide-bore capillary gas chromatography with satisfactory separation from impurities in their underivatized forms.

On the pharmacokinetics and metabolism of propiverine in man.

The pharmacokinetics of 14C-propiverine was studied in 13 volunteers and in 2 patients after a single i.v. injection of 5 mg or after oral administration of 15 mg. To each dose 1.11 MBq 14C-propiverine was added. The radioactivity measured in plasma, urine (and bile fluid), and the metabolites were estimated by an extraction procedure together with TLC and radiochromatography. Propiverine was eliminated from the plasma with a half-life time (t0.5) of 4.1 h (i.v. and per os), while the plasma radioactivity decreased with a t0.5 of 21.2 (i.v.) or 10.4 h (per os). Within 4 days, 84.5 (i.v.) or 53.5% (per os) of the administered radioactivity was excreted in urine. The absorption of radioactivity of propiverine amounted to 84.5%, while the amount of available propiverine was only 48.9%. In two patients with cannulated ductus choledochus, 21.5 or 14.7% of the administered radioactivity was excreted within 2 days. The metabolic pattern of plasma, urine and bile fluid mainly consisted of amine oxides, substances oxidized in the propyl side chain, desalkylated metabolites, substances with a N-demethylated piperidino group or with ester cleavage, and glucuronide conjugates. Unchanged propiverine appeared in plasma, urine and bile at about 6 to 8% of the administered dose.

Compétition entre des chaînes propyle et isoamyle, vis à vis de l'hydroxylation hépatique, en série barbiturique

5-(3-Methylbutyl) 5-propyl barbituric acid could a priori undergo hepatic oxidation on either isoamyl or propyl side chains. Models of metabolites were synthesized and the barbiturate was administered to dogs and rats. Only a γ-hydroxy derivative was recovered in urine. This observation confirms the easy hydroxylation of the tertiary carbon in the 3-methyl-butyl group and establishes that the propyl side chain is less sensitive to oxidation than the ethyl side chain of amobarbital.

Correlation between reversed-phase high-performance liquid chromatography and plasma protein binding

As hydrophobic interactions are involved in both reversed-phase liquid chromatography and plasma protein binding, the relationship between retention time and binding was investigated experimentally in two series of compounds. For betaxolol and its O-alkyl analogues, the nature of the O-alkyl group strongly influences the retention time on a Spherisorb CN 5-μm column. With 0.03 M acetate buffer (pH 5.6)-acetonitrile (60:40) as the mobile phase, k′ values increase from 1.8 to 8.3 with a concomitant increase in plasma protein binding from 0.5% (R = H) to 88.2% (R = cyclopenthylmethyl). The relationship between the free fraction and log k′ is sigmoidal. In the second example, structural changes in the propyl side-chain of alpidem (a new anxiolytic) lead to minor variations in the protein binding: 98.9 to 84.9%. This slight decrease with the more polar metabolite is correlated with a sharp decrease in the k′ values from 14.7 to 0.94 on a Supelcosil LC 18 DB column. Based on retention times, it should be feasible to predict qualitatively, if not quantitatively in some instances, plasma protein binding in a series of structurally similar compounds.

Alkaloids from dendrobatid frogs: structures of two omega-hydroxy congeners of 3-butyl-5-propylindolizidine and occurrence of 2,5-disubstituted pyrrolidines and a 2,6-disubstituted piperidine.

Forty alkaloids were detected and characterized from skin extracts of high- and low-elevation populations of the poison frog Dendrobates histrionicus from northwestern Colombia. Combined gc/ms with NH3 or ND3 in a chemical ionization mode detected protonated parent ions and determined the number of exchangeable NH and OH hydrogens. Six previously unknown dendrobatid alkaloids were characterized. Two were 2,5-disubstituted pyrrolidines, which included pyrrolidine 197B, a trans-2-butyl-5-pentylpyrrolidine, while a third was a 2,6-dipentylpiperidine. Indolizidines 239AB and 239CD had the same relative configuration as the parent alkaloid 223AB [(5E,9E)3-butyl-5-propylindolizidine] and contained, respectively, a omega-hydroxy group in the propyl or butyl side chain. The profiles of alkaloids in the new northern populations of D. histrionicus are typical of the species in containing a set of about eight histrionicotoxins, in marked contrast to a related species, Dendrobates lehmanni, which does not contain histrionicotoxins.

Synthesis of deuterium labelled fluphenazine utilising borane reduction

AbstractTwo new procedures are described for the preparation of di‐ and tetra‐deuterated 10‐[[3‐[4‐(2‐hydroxyethyl)‐1‐piperazinyl]propyl]]‐2‐trifluoromethyl‐10H‐phenothiazine (fluphenazine). Deuterium was introduced in either the 1‐ or the 1‐ and 3‐positions of the propyl side chain by reduction with deuterated borane in tetrahydrofuran of the appropriately substituted N‐10 amide or amido ester. The isotopic purity of the synthesized deuterated products was greater than 99%.

The detailed conformational study of a leukotriene antagonist, FPL-55712, using high-field nuclear magnetic resonance spectroscopy.

High-field proton magnetic resonance measurements at 400 MHz and 600 MHz allowed the evaluation of the preferred conformations of a leukotriene antagonist, FPL-55712. The experiments involved an analysis of proton-proton coupling constants, longitudinal relaxation time data and nuclear Overhauser effect experiments. The NMR parameters confirm the conformational features expected from X-ray and microwave data for related substances, such as rotational freedom about C14-C15 and C15-C16, synperiplanar arrangements for C7-C8-O-C14 and C16-O-C17-C18 and segmental motion in the propyl side chains.

Mechanism of oxidative C alpha-C beta cleavage of a lignin model dimer by Phanerochaete chrysosporium ligninase. Stoichiometry and involvement of free radicals.

The hemoprotein ligninase of Phanerochaete chrysosporium Burds. catalyzes the oxidative cleavage of lignin model dimers between C alpha and C beta of their propyl side chains. The model dimers hitherto used give multiple products and complex stoichiometries upon enzymatic oxidation. Here we present experiments with a new model dimer, 1-(3,4-dimethoxyphenyl)-2-phenylethanediol (dimethoxyhydrobenzoin, DMHB) which is quantitatively cleaved by ligninase in air to give benzaldehyde and veratraldehyde according to the stoichiometry: 2DMHB + O2----2PhCHO + 2Ph(OMe)2CHO. Catalytic amounts of H2O2 are required for this aerobic reaction. Under anaerobic conditions, ligninase uses H2O2 as the oxidant for cleavage: DMHB + H2O2----PhCHO + Ph(OMe)2CHO. Electron spin resonance experiments done in the presence of spin traps, 2-methyl-2-nitrosopropane or 5,5-dimethyl-1-pyrroline-N-oxide, show that C alpha-C beta cleavage yields alpha-hydroxybenzyl radicals as intermediate products. Under anaerobic conditions, these radicals react further to give the final aldehyde products. In air, O2 adds to the carbon-centered radicals, probably giving alpha-hydroxybenzylperoxyl radicals which fragment to yield superoxide, benzaldehyde, and veratraldehyde. These results lead us to propose a mechanism for C alpha-C beta cleavage in which attack by ligninase and H2O2 on the methoxylated ring of DMHB yields a cation radical, which then cleaves to give either benzaldehyde and an alpha-hydroxy(dimethoxybenzyl) radical or veratraldehyde and an alpha-hydroxybenzyl radical (cf. Kersten, P. J., Tien, M., Kalyanaraman, B., and Kirk, T.K. (1985) J. Biol. Chem. 260, 2609-2612; Snook, M. E., and Hamilton, G. A. (1974) J. Am. Chem. Soc. 96, 860-869). Similar mechanisms probably apply to the enzymatic C alpha-C beta cleavage of natural lignin.

Mechanism of DNA methylation by N-nitroso(2-oxopropyl)propylamine.

Using an in vitro assay system for measuring 7-methylguanine formation in DNA, it was demonstrated that N-nitroso(2-oxopropyl)propylamine (NOPPA) is converted into a methylating agent by a microsomal, cytochrome P-450 dependent mixed function oxidase from rat liver. Formation of propionaldehyde, but not formaldehyde, in this assay system, indicated that a single alpha-oxidation reaction on the propyl side chain of NOPPA leads to the formation of a methylating agent. A mechanism for this reaction is proposed.

Lignin-degrading enzyme fromPhanerochaete chrysosporium

The extracellular fluid of ligninolytic cultures of the white-rot wooddestroying fungus,Phanerochaete chrysosporium Burds., contains an enzyme that degrades lignin model compounds as well as lignin itself (1). Like ligninolytic activity, the enzyme appears during idiophasic metabolism, which is triggered by nitrogen starvation. The enzyme has been purified to homogeneity by DEAE-Biogel A chromatography, as assessed by SDS polyacrylamide gel electrophoresis, isoelectric focusing, and gel filtration chromatography. These techniques also revealed a molecular weight of 42,000 daltons, and an isoelectric point of 3.4. The purified enzyme exhibits low substrate specificity. It is an oxygenase, but requires hydrogen peroxide for activity. The activity is optimum at 0.15 mM H2O2; at concentrations above 0.5 mM, H2O2is inhibitory. Model compound studies have shown that the enzyme catalyzes cleavage between Cα and Cs in compounds of the type aryl-CαHOH—CsHR-(R = -aryl or -O-aryl), and in the Cα-hydroxyl-bearing propyl side chains of lignin. This cleavage produces an aromatic aldehyde moiety from the Cα-portion, and a Cs-hydroxylated moiety from the Cα-portion. Cleavage between Cα and Cs in arylglycerol-Β-aryl ether structures leads indirectly to cleavage of the Β-aryl ether linkage, which is the most abundant intermonomer linkage in lignin. The Cs-hydroxyl oxygen comes from molecular oxygen, and not from H2O2, as determined by18O isotope studies. The pH optimum for these reactions is between 2.5 and 3.0; no activity is observed above pH 5. Formation of the expected aldehydes from spruce and birch lignins, and partial depolymerization of the lignins results from the action of the purified enzyme. In addition to Cα—Cs cleavage, the enzyme catalyzes aromatic alcohol oxidation, aryl methylene oxidation, hydroxylation at Cα and Cs in models containing a Cα—Cs double bond, intradiol cleavage in phenylglycol structures, and phenol oxidations.

An unexpected major groove binding of netropsin and distamycin A to tRNA(phe).

Crystalline complexes of yeast tRNA(phe) and the oligopeptide antibiotics netropsin and distamycin A were prepared by diffusing drugs into crystals of tRNA. X-ray structure analyses of these complexes reveal a single common binding site for both drugs which is located in the major or deep groove of the tRNA T-stem. The netropsin-tRNA complex is stabilized by specific hydrogen bonds between the amide groups of the drug and the tRNA bases G51 O(6), U52 O(4) and G53 N(7) on one strand, and is further stabilized by electrostatic interactions between the positively charges guanidino side chain of the drug and the tRNA phosphate P53 on the same strand and the positively charged amidino propyl side chain and the phosphates P61, P62 and P63 on the opposite strand of the double helix. These results are in contrast to the implicated minor groove binding of these drugs to non-guanine sequences in DNA. The binding to the GUG sequence in tRNA implies that major groove binding to certain DNA sequences is possible.

An ESR investigation of ester .pi.-cation radicals in a Freon matrix at low temperatures: evidence for unusual barriers to methyl group rotation and intramolecular bonding

..gamma..-Irradiation of dilute solutions of a number of esters in CFCl/sub 3/ at 77 K is shown by ESR spectroscopy to produce the ..pi..-cation radicals of these molecules. The ..pi..-cations formed are those of the methyl and ethyl formates, acetates, and propionates. Larger esters containing propyl and butyl side chains are suggested to be unstable toward deprotonation at 77 K. Synthesis of deuterium-labeled compounds was employed to assign proton hyperfine couplings to specific sites in the ..pi..-cation radicals. The ..pi..-cations of the ethyl esters show unusually large couplings to the terminal methyl groups. In addition, large barriers to methyl group rotation are found for both the methyl and ethyl ester cation radicals. The large barriers suggest intermolecular bonding between the alkyl group and the carbonyl oxygen in the ester functional group. Such a hypothesis is supported by the finding of a torsional motion in the terminal methyl group of ethyl formate ..pi..-cation which has a ca. 1.7 kcal/mol activation energy barrier. It is suggested that a new intramolecular ..pi..*-bond is responsible for the formation of cyclic rings in the methyl- and ethyl-substituted ester cation radicals.