High-performance liquid chromatographic determination of (R)-and (S)-proxyphylline in human plasma

A reversed-phase high-performance liquid chromatographic assay has been developed for determination of (R)-(--)-and (S)-(+)-proxyphylline in human plasma. The procedure is based on liquid-solid extraction of proxyphylline from plasma followed by derivatization of extracted proxyphylline with (--)-camphanoyl chloride. The ratio between the enantiomers is calculated from the peak areas of the corresponding diastereoisomeric proxyphylline camphanates after injection into the liquid chromatograph. The recovery of proxyphylline from plasma was 88% (coefficient of variation = 4%) and proxyphylline was detectable from a plasma concentration of 0.2 micrograms/ml. Three different plasma extraction procedures for proxyphylline using Extrelut, Bond Elut, and Chem Elut columns have been developed and compared, and the rate of derivatization of the proxyphylline enantiomers with camphanoyl chloride has been studied.     

Syntheses of (S)-(+)-trihexyphenidyl hydrochloride and (S)-(+)-procyclidine hydrochloride, two anticholinergics, using (S)-(-)-3-cyclohexyl-3-hydroxy-3-phenylpropanoic acid as chiral synthon

The absolute configuration of the more active (-)-enantiomer of the anticholinergic trihexyphenidyl hydrochloride has been established as (R) by syntheses of (S)-(+)-procyclidine hydrochloride, whose absolute configuration has been established previously, and (S)-(+)-trihexyphenidyl hydrochloride from the same chiral building block, viz. (S)-(-)-cyclohexyl-3-hydroxy-3-phenylpropanoic acid. Both enantiomers of this chiral synthon were prepared by optical resolution of the corresponding racemate, employing (R)- and (S)-1-phenylethylamine, respectively, as resolving agents.     

Compartmentalized polymerization initiated by oil-soluble initiators. Calculation of average number of radicals per particle

Expressions for calculating the stationary state distribution of radicals in compartmentalized systems with a constant number of reaction loci containing an oil-soluble initiator are given. Besides pairwise formation of radicals in the particles, desorption and reabsorption, water phase termination, solubility of the initiator in the aqueous phase, and the possibility of formation of a single radical species are taken into consideration. The calculation is based on a probabilistic analysis leading to a third-order recurrence relation solved using confluent, hypergeometric Kummer functions. Some calculated curves illustrating the de-pendence of the average number of radicals per particle on various relevant parameters are included. © 1995 John Wiley & Sons, Inc.     

Intramolecular bonding in a statistical associating fluid theory of ring aggregates

The first-order thermodynamic perturbation theory of Wertheim (TPT1) is extended to treat ring aggregates, formed by inter- and intramolecular association. The expression for the residual association contribution to the Helmholtz free energy for ring aggregates, incorporating the appropriate terms in Wertheim's fundamental graph sum of the TPT1 density expansion, is derived to calculate the distribution of the molecular bonding states. This requires the introduction of two new parameters to characterise each possible ring type: the ring size τ, which is equal to one in the case of intramolecular association, and a parameter W that captures the likelihood of two ring-forming sites bonding. The resulting framework can be incorporated in equations of state that account for the residual association contribution to the free energy, such as the statistical associating fluid theory (SAFT) family, or the cubic plus association (CPA) equation of state. This extends the applicability of these equations of state to mixtures with an arbitrary number of association sites capable of hydrogen bonding to form intramolecular and intermolecular rings. The formalism is implemented within SAFT-VR Mie to calculate the fluid-phase equilibria of model chain-like molecules containing two associating sites A and B, allowing for the formation of open-chain aggregates and intramolecular bonds. The effect of adding a second component that competes for the association sites that mediate intramolecular association in the chain is also examined. Accounting for intramolecular bonding is shown to have a significant impact on the phase equilibria of such systems.     

Tobacco Chemistry.29. (7S)-10-Oxo-4xi-methyl-7-isopropyl-5E-undecen-4-olide, a New Thunbergan-type Nor-isoprenoid isolated from Greek Nicotiana tabacum L.

The structure of a new C15-lactone, (7S)-10-oxo-4xi-methyl-7-isopropyl-5E-undecen-4-olide, isolated from Greek tobacco, has been determined mainly be 1H NMR, 13C NMR and high resolution MS, and its absolute configuration established by degradation to (2S)-5-oxo-2-isopropylhexanal. The carbon skeleton of the new compound indicated that it is derived from a thunbergane precursor and constitutes the first C15 nor-thunberganoid in tobacco.     

Discovery of fatty acid ester metabolites of spirolide toxins in mussels from Norway using liquid chromatography/tandem mass spectrometry

Cultured mussels sampled in the spring of 2002 and 2003 from Skjer, a location in the Sognefjord, Norway, tested positive in the mouse bioassay for lipophilic toxins. In a previous report, it was established that a number of spirolides, cyclic imine toxins produced by the phytoplankton Alexandrium ostenfeldii, were present in the mussels and were responsible for the observed toxicity. The main toxin proved to be a new compound named 20-methyl spirolide G. In subsequent studies, a delayed onset of spirolide-like symptoms in the mouse bioassay exceeding the usual time limit of 20 min was observed in some samples, with symptoms and death appearing as long as 45-50 min after injection. It is well known that shellfish can extensively metabolize other toxins, such as okadaic acid and the dinophysistoxins, to fatty acid acyl esters and it is also known that a delayed onset of toxic symptoms with such metabolites can occur. Analyses performed with liquid chromatography/tandem mass spectrometry (LC/MS/MS) have revealed a complex mixture of esters of 20-methyl spirolide G in the contaminated mussels. Precursor ion scanning has delineated the range of fatty acid esters involved, while product ion scanning has provided information on structure. Identity was also supported through reaction of 20-methyl spirolide G with palmitic anhydride, which produced a derivative with a retention time and spectrum identical with one putative metabolite, 17-O-palmitoyl-20-methyl spirolide G.     

Synthesis of analogs of D-Ala-D-Ala as potential inhibitors of bacterial cell wall biosynthesis

The syntheses of the L,L- and D,D-stereoisomers of N- phenoxyacetyl -X-alanine in which X = Ser, Ala( beta Cl ) or Arg, are described. The antibacterial activity of these peptides and some of their synthetic intermediates has been examined. Four of the intermediates in which X = Ala( beta Cl ) and Arg(NO2), which possess C-terminal benzyl ester groups, were active against viridans streptococci and Streptococcus agalactiae. The D,D-enantiomers were more active than the corresponding L,L-isomers. None of the compounds were active against beta-lactamase producing bacteria or acted as beta-lactamase inhibitors.     

Preparation and in vitro evaluation of a novel amphiphilic GdPCTA-[12] derivative; a micellar MRI contrast agent

A novel amphiphilic GdPCTA-[12] derivative has been prepared. The complex formed micelles in aqueous solution with a relatively low CMC, 0.15 mM (25 degrees C). The concentration dependent T1-relaxivity (r1) of the system has been described. The maximum T1-relaxivity, 29.2 s-1 mM-1 (20 MHz, 25 degrees C), was higher than for previously described micellar MRI contrast agents. This high T1-relaxivity is a consequence of the favourable water residence time (tau M) and the fact that the complex is heptadentate allowing two water molecules to coordinate to the gadolinium ion (q = 2).     

Synthesis of (+)-goniothalamin and its enantiomer by combination of lipase catalyzed resolution and alkene metathesis

(+)-Goniothalamin has been synthesized by lipase catalyzed resolution of (1E)-1-phenylhexa-1,5-dien-3-ol using vinyl acrylate as acyl donor followed by ring closing metathesis of the formed (1R)-1-[(E)-2-phenylvinyl]but-3-enyl acrylate. The unreacted alcohol from the resolution, (1E,3S)-1-phenylhexa-1,5-dien-3-ol, was esterified non-enzymatically, and used for synthesis of (−)-goniothalamin.