Nuclear magnetic resonance studies on polymer carbanions, 1. Living polystyrene and its model compounds

¹H and ¹³C NMR investigations were carried out on polystyryl carbanions and model compounds for the active chain end of living polystyrene, changing counter cation (Li, K, and Cs), solvent, and temperature. The structure of the model compounds with K and Cs as counter cation was planar with sp²-hybridized α-carbon, which indicates strongly hindered rotation of the phenyl ring. For the model compound with lithium as counter cation, the phenyl ring rotation was hindered at lower temperatures. The ¹³C? ¹H coupling constants of the compound indicated less sp² character of α-carbon. The differences in the chemical shifts of the two ortho or meta carbons depended on the type of counter cation, suggesting an interaction between counter cation and phenyl ring. Quantum chemical calculations on the structure of the model compounds were carried out and the results were compared with the excess charge distributions calculated from ¹³C NMR chemical shifts.     

Nuclear magnetic resonance studies on polymer carbanions, 2. Model compounds for α-methylstyrene and α-methylstyrene tetramer dianions

¹H and ¹³C NMR spectra of model compounds for the poly-α-methylstyryl anion, 2-lithio, 2-potassio, and 2-cesio-2-phenylbutane, were determined. The lithium compound had a higher charge density at the α-carbon and a lower charge on the phenyl ring than the other compounds and exhibited phenyl ring rotation at higher temperatures. The activation energy was calculated to be 61, 0 kJ/mol. The potassium and cesium compounds did not show phenyl ring rotation at 80°C. Quantum chemical calculations indicated that the larger cations interact with the phenyl ring especially with the ortho carbons. ¹³C NMR spectra of α-methylstyrene tetramer dianion with sodium and potassium as counter cation were also measured and compared with those of the model compounds.     

Nuclear magnetic resonance spectroscopic studies of interaction of bis-GMA analogues with phosphatidylcholine liposomes as a model for biomembranes

The interaction of bis-GMA analogues with dipalmitoylphosphatidylcholine liposomes was studied by 1H and 13C nuclear magnetic resonance spectroscopy. It was found that bis-GMA analogues did not diffuse from liposomes once they were incorporated into the lipid bilayers of dipalmitoylphosphatidylcholine. The mobility of iso-bis-GMA was strongly disturbed by dipalmitoylphosphatidylcholine. The large changes in nuclear magnetic resonance spectra of iso-bis-GMA indicated that the interaction of iso-bis-GMA with dipalmitylphosphatidylcholine was larger than that of bis-GMA. This seems to be due to the chemical structure of iso-bis-GMA with the primary hydroxyl group.     

Study of the propagation centre in the anionic polymerization of (meth)acrylic monomers, 5. Nuclear magnetic resonance study of the model dimer in tetrahydrofuran

Di-tert-butyl 2-lithio-2,4,4-trimethylglutarate ( 1 ) as a model of the living dimer of tert-butyl methacrylate was studied in deuterated tetrahydrofuran (THF-d₈) solution by ⁶Li, ⁷Li, ¹H and ¹³C NMR. In agreement with earlier observations from infrared spectroscopy and with quantum chemical ab initio and semiempirical self-consistent field calculations, 1 is shown to have a strong tendency to an intramolecular coordination of Li to the penultimate ester carbonyl group. The competing linear form of 1 (with uncoordinated penultimate ester group) is shown to exist due to its stabilization by self-aggregation to form a dimer of 1 . In contrast to the monomeric form of 1 , the dimer does not bind THF into a specific solvate. Given the entropy-driven solvation at low temperatures, the occurrence of the dimeric aggregate is enhanced by higher temperature and concentration of 1 . Both the cyclic and linear form of 1 are shown to exist in at least two different conformers and various solvation states. Their mutual exchange is several orders of magnitude slower than the anionic propagation reaction of tert-butyl methacrylate.     

Nuclear magnetic resonance spectroscopic studies of the interaction of methyl methacrylate and ethylene dimethacrylate with phosphatidylcholine liposomes as a model for biomembranes

The interaction of methyl methacrylate (MMA) and ethylene dimethacrylate (EDMA) with dipalmitoyl phosphatidylcholine (DPPC) liposomes was studied by 1H and 13C nuclear magnetic resonance spectroscopy (NMR). It was found that the changes in the 1H chemical shift of EDMA were larger than those of MMA when comparing membrane-bound state with free state and that the amount of EDMA incorporated into DPPC liposomes was approximately 74%, whilst MMA was approximately 41%. The major changes in chemical shifts of EDMA appeared to be due to its interaction with the acyl chains of DPPC liposomes.     

Nuclear magnetic resonance studies on bacterial copolyesters of 3-hydroxybutyric acid and 3-hydroxyvaleric acid

Copolyesters of 3-hydroxybutyric acid (HB) and 3-hydroxyvaleric acid (HV), P(HB-co-HV), were isolated from Alcaligenes eutrophus and characterized by solution NMR, solid-state ¹³C CP/MAS NMR, and differential scanning calorimetry. The ¹³C CP/MAS NMR analysis was compatible with that of a random copolyester of oxy-(1-methyl-3-oxotrimethylene) ( B ) and oxy-(1-ethyl-3-oxotrimethylene) ( V ) units which adopts a regular conformation of a 2₁ -helix in the solid state throughout a wide range of compositions varying from 0 to 90 mol-% V units. The chain dynamics of P(HB-co-HV) in chloroform was studied by analysis of the ¹³C and ¹H NMR spectra. The carbon-13 spin-lattice relaxation times (T₁) and nuclear Overhauser enhancements (NOE) indicated that the copolyester molecules in chloroform are not rigid but rather flexible. The conformational preferences of the copolyester molecules were determined by analysis of the ¹H NMR spectra.     

In vivo and ex vivo magnetic resonance spectroscopy as applied to pharmacokinetic studies with anticancer agents: a review.

The potential role of MRS in studying the pharmacokinetics of anticancer drugs is reviewed. In vivo and ex vivo MRS has been used extensively in studies with fluoropyrimidines. Results from preclinical models have demonstrated that biochemical modulation of 5-fluorouracil metabolism can be demonstrated by MRS. The more general potential of MRS is illustrated by studies with the antifolate CB3988 (C2-desamino-C2-methyl-N10-propargyl-2'-trifluoromethyl-5,8-dideazafolic acid). Studies in mice and rats have shown that hepatobiliary clearance and renal elimination can be measured non-invasively by MRS. Comparison of half-lives derived from MRS and high performance liquid chromatography data gave reasonable agreement. In addition, MRI was used to localize drug-derived material within the abdominal cavity. The application of ex vivo MRS is illustrated by studies on the urinary excretion of platinum complexes. 1H-MRS has been used to demonstrate the presence of the cyclobutanedicarboxylate leaving group, both free and platinum bound, in the urine of patients treated with carboplatin. With iproplatin 195Pt NMR has been used to demonstrate in vivo reduction of this Pt(IV) complex to Pt(II) complexes. Finally, the application of MRS to the study of the molecular pharmacology of alkylating agents (a nitrogen mustard and N-methyl-N-nitrosourea) is discussed.     

Polyimides, 1. Studies on the thermal curing of imide model compound with tricyclic structure by nuclear magnetic resonance and mass spectra

A model imide with a tricyclic structure was synthesized by reacting 3-phenyltricyclo[6.2.2.0^2,7]-2,11-dodecadiene-5,6 : 9,10-tetracarboxylic dianhydride with aniline. The thermogravimetry curve showed that it degraded at about 300°C, and its differential scanning calorimetry curve was found to be similar to that of its corresponding polyimides. The thermal curing of this model imide was studied in detail. A curing mechanism was proposed based on the analysis of the cured product using NMR and mass spectroscopy. The results show that the curing mechanism started with a reverse Diels-Alder reaction, forming an intermediate which either dehydrogenated or further decomposed into 1,1-diphenylethylene, and N-phenylsuccinimide. The 1,1-diphenylethylene and N-phenylsuccinimide would either polymerize or become hydrogenated to form 1,1-diphenylethane and N-phenylsuccinimide, respectively.     

Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome. Actions of modafinil

Functional magnetic resonance imaging (fMRI) can be used to detect regional brain responses to changes in sensory stimuli. We have used fMRI to determine the amount of visual and auditory cortical activation in 12 normal subjects and 12 subjects with the narcoleptic syndrome, using a multiplexed visual and auditory stimulation paradigm. In both normal and narcoleptic subjects, mean cortical activation levels during the presentation of periodic visual and auditory stimulation showed no appreciable differences with either age or sex. Normal subjects showed higher levels of visual activation at 10:00 hours than 15:00 hours, with a reverse pattern in narcoleptic subjects (P = 0.007). The group differences in spatial extent of cortical activation between control and narcoleptic subjects were small and statistically insignificant. The alerting action, and imaging response, to a single oral dose of the sleep-preventing drug modafinil 400 mg were then determined and compared with placebo in both the 12 normal (8 given modafinil, 4 placebo) and 12 narcoleptic subjects (8 modafinil, 4 placebo). Modafinil caused an increase in self-reported levels of alertness in 7 of 8 narcoleptic subjects, but there was no significant difference between mean pretreatment and post-treatment activation levels as determined by fMRI for either normal or narcoleptic syndrome subjects given modafinil. However, in the modafinil-treated group of 8 normal and 8 narcoleptic subjects, there was a clock time independent correlation between the initial level of activation as determined by the pretreatment scan and the post-treatment change in activation (visual, P = 0.002; and auditory, P = 0.001). No correlation was observed in placebo-treated subjects (P = 0.99 and 0.77, respectively). Although limited by the small number of subjects, and the lack of an objective measure of alertness, the findings of this study suggest that low cortical activation levels in both normal and narcoleptic subjects are increased following the administration of modafinil. Functional magnetic resonance imaging may be a valuable addition to established studies of attention.     

Structural study of compounds modelling elementary polymer units, 5. Molecular and crystal structures of C,C′-disubstituted o-carboranes

With the aim to determine the main structural characteristics of amorphous (branched and different-unit) polymers of the polyphenylene type, prepared by polycyclocondensation of carborane-containing mono- and diacetylaromatic compounds, an X-ray structural study of four model compounds was carried out, viz. of 1,2-bis[4-(4-acetylphenoxy)phenyl]-1,2-dicarba-closo-dodecaborane(12) ( 1 ) (triclinic crystals, a = 8,205 Å, b = 13,505 Å, c = 14,019 Å, α = 90,44°, β = 97,08°, γ = 97,24°, space group P1 , Z = 2, R = 0,045 for 2663 reflections), 1,2-bis(4-phenoxyphenyl)-1,2-dicarba-closo-dodecaborane(12) ( 2 ) (monoclinic crystals, a = 14,813 Å, b = 17,133 Å, c = 11,211 Å, β = 112,43°, space group P2₁/c, Z = 4, R = 0,066 for 3 286 reflections), 1,2-bis(4′-acetylbiphenyl-4-yl)-1,2-dicarba-closo-dodecaborane(12) ( 3 ) (orthorhombic crystals, at ?120°C a = 13,405 Å, b = 9,276 Å, c = 22,86 Å, space group Pnam, Z = 4 molecules on the m plane, R = 0,039 for 1 147 reflections), and 1,2-bis(4-acetylbenzyl)-1,2-dicarba-closo-dodecaborane(12) ( 4 ) (orthorhombic crystals, at ?120°C a = 22,03 Å, b = 26,23 Å, c = 8,026 Å, space group Fdd2, Z = 8 molecules lie on the two-fold axis, R = 0,051 for 577 reflections). The strained structure of the C,C′-o-diphenyl-substituted carboranyl fragment is established, the high conformational flexibility of 4-phenoxyphenyl linkages is confirmed and a tendency toward separate autoassociation of acetyl-containing polar groups and carborane nuclei is shown, with the autoassociation of polar groups completely suppressing that of carborane nuclei in case of conformational rigidity and shortness of the arylene linkages. These and other structural characteristics of the investigated model compounds and their crystals, in case they turn out to be characteristic also for the corresponding polymers and their precursors, should largely determine the structure and physico-chemical properties of their corresponding polymers.     

Polymeric protecting groups, 5. Polymerizable urea compounds with 2-methylpropyloxycarbonyl function as a modified tert-butoxycarbonyl-type amino-protecting group

1-[2-(4-chloroanilinocarbonyloxy)-2-methylpropyl]-3-methacryloylurea ( 4 ) was prepared by addition of 1-(2-hydroxy-2-methylpropyl)-3-methacryloylurea ( 3 ) to 4-chlorophenyl isocyanate as a model compound. The new monomer 4 acts as a modified tert-butoxycarbonyl (BOC)-type amino-protecting group which can be homopolymerized and copolymerized with methyl methacrylate (MMA) upon radical initiation. The kinetics of the deprotection of the aromatic amine under acidic conditions which leads to the formation of 2-methacryloylamino-5,5-dimethyl-Δ²-1,3-oxazoline ( 7 ) was followed by means of ¹H NMR spectroscopy.     

Polymethacrylates with benzylidenephthalimidine side chains, 1. Photochemical characteristics of model compounds and polymers

The photochemical behavior of polymers with benzylidenephthalimidine (BPI) side chains is described, together with the photochemistry of low-molecular BPIs in solution. The stereochemistry of BPIs is critically influenced by their N-substituent; Z-isomer of BPI itself without N-substituent is a thermally stable form, while E-isomer with a Z-stilbene skeleton is more thermally stable for N-substituted BPIs as a result of steric distortion due to repulsive interaction between the N-substituent and the benzylidene phenyl ring. UV irradiation of low-molecular N-substituted BPIs and polymethacrylates with E-BPI side chains in solution results exclusively in the E/Z photoisomerization without any side reaction including photodimerization, Photoirradiation of thin films of BPI polymers leads to photoisomerization at the early stage, followed by the gradual decrease of absorption bands ascribable to BPI moieties as a result of [2+2] photodimerization, leading to insolubilization. Quantum efficiencies for the photocrosslinking are much smaller, displaying that the photoisomerization is a predominant reaction even in solid films. Dichroism of the chromophores is induced by linearly polarized light irradiation of thin films of BPI polymers due to the photoisomerizability of BPI units. Further discussion is made on factors affecting the photochemical behavior of BPI polymers.     

Mapping of semantic, phonological, and orthographic verbal working memory in normal adults with functional magnetic resonance imaging.

Twelve neurologically normal participants (4 men and 8 women) performed semantic, phonological, and orthographic working memory tasks and a control task during functional magnetic resonance imaging. Divergent regions of the posterior left hemisphere used for decoding and storage of information emerged in each working memory versus control task comparison. These regions were consistent with previous literature on processing mechanisms for semantic, phonological, and orthographic information. Further, working memory versus control task differences extended into the left frontal lobe, including premotor cortex, and even into subcortical structures. Findings were consistent with R. C. Martin and C. Romani's (1994) contention that different forms of verbal working memory exist and further suggest that a reconceptualization of premotor cortex functions is needed.     

Dynamic NMR studies of equilibria involving active species in the polymerization of cyclic acetals. Reaction of the methoxymethyl cation with 5-, 6-, and 7-membered cyclic acetals

The cyclic acetals 1,3-dioxolane ( 4a ), 1,3-dioxane ( 4b ), and 1,3-dioxepane ( 4c ) give in their reactions with the methoxymethyl cation ( 1 ) a mixture of two isomeric tertiary oxonium ions: the simple products of cationation 5a-c and the cationated rings 6 , 7 , 9 , enlarged by two atoms. The equilibria for the studied monomers are shifted to the side of the oxonium ions as shown in the reaction schemes 2, 4, 5, and 6 (SbF^-₆ or SbCIF^-₅ being the corresponding anions). In the case of 4a the equilibrium is displaced almost completely to the enlarged ring 6 , whereas for the other two cyclic acetals 4b and 4c the first cationated products 5b and 5c dominate. Application of the dynamic ¹H NMR method allows the determination of the equilibrium constants of the reaction of 4a with 1 .     

Turnip yellow mosaic virus and its capsid have thermal stabilities with opposite pH dependence: studies by differential scanning calorimetry and 31P nuclear magnetic resonance spectroscopy

In the differential scanning calorimetry (DSC) scans of turnip yellow mosaic virus (TYMV) or its capsid a single endotherm was observed. The endotherm was attributed to disruption of the virion or capsid structure with accompanying protein denaturation. At pH 4.5 the thermal stabilities of the TYMV virion and capsid were similar. With increasing pH, the capsid stability increased while the virion stability decreased. At neutral pH the capsid disrupted at 83.5 degrees, and the virion disrupted at 69 degrees. Our results suggest that packaging of viral RNA in the TYMV capsid imparts instability. The pHmid for disruption of the TYMV capsid is 5.7, which is in the pKa range expected for histidine side chains. Hence repulsive interactions involving one or more of the three histidines of the TYMV coat protein may explain the decreased stability of the TYMV capsid at low pH. This conclusion is supported further by the observation that belladonna mottle virus (BDMV) capsid (BDMV and TYMV belong to the tymo virus group), which contains no histidine in its coat protein, did not exhibit pH-dependent stability. The size of the cooperative unit in the disruption of TYMV capsid was estimated to be approximately that of a dimer of the coat protein, at pH 7.0, but a larger oligomer at low pH. Several reports implicate pH-dependent protein-RNA interactions with a pHmid near 7 as important in stabilizing tymovirus virions. Both DSC and 31P nuclear magnetic resonance linewidth analyses of the TYMV virion showed a transition midpoint at pH 7.0.     

Studies on syntheses and permeabilities of special polymer membranes, 63 Active transport of adenine through cation exchange membranes with carboxyl groups

When a cation exchange membrane, prepared from poly(isobutylene-alt-maleic anhydride) and poly(vinyl alcohol), is fixed in a diaphragm type cell with one side of the solution being adjusted to be alkaline and the other one acidic, a metal ion is always actively transported from the alkaline side to the acidic side, but adenine is actively transported in symport or antiport with metal ions. The transport mechanism of these metal ions and of adenine is discussed in detail.     

Schistosoma japonicum-infected hamsters (Mesocricetus auratus) used as a model in experimental chemotherapy with praziquantel, artemether, and OZ compounds

The purpose of the study is to better understand the antischistosomal properties of artemether, praziquantel, and ozonide (OZ) compounds (synthetic trioxolanes, secondary ozonides) in hamster (Mesocricetus auratus) model. A total of 230 male hamsters infected each with 100 Schistosoma japonicum cercariae were used in the study. Groups of five to ten hamsters were treated orally with artemether, praziquantel, and OZ78 or OZ277 7-35 days post-infection at single doses of 50, 100, 150, or 200 mg/kg. Untreated but infected hamsters in each batch of test served as the control. All treated hamsters were sacrificed 4 weeks post-treatment for collection of residual worms using perfusion technique. Nonparametric method (Mann-Whitney test) was used to analyze the data. In groups of five hamsters treated with artemether 7, 14, 21, 28, and 35 days post-infection at single doses of 150 and 200 mg/kg, the difference of mean worm burden between each treated group and control group was statistically significant (P<0.01). Apart from individual group, no difference in mean worm burden between each two groups of them was seen (P>0.05). Further test with various single doses of 50-200 mg/kg confirmed the similar susceptibility of 7-day-old juvenile and 35-day-old adult schistosomes to artemether. After administration of praziquantel 100 mg/kg to groups of five hamsters 7, 21, and 35 days post-infection, higher worm burden reduction of 95.5% was seen in the group with 35-day-old adult schistosomes while in the groups with 7- and 21-day-old juvenile schistosomes, poor efficacy was seen with mean worm burden reductions of 36.6% and 35.6%. In the same batch of hamster treated with praziquantel 200 mg/kg, the moderate effect of the drug against 7- and 21-day-old worms was seen, but their mean worm burden was significantly higher than that of the group with adult schistosomes. In comparison of artemether and praziquantel against various stages of schistosomes, the results further demonstrated that artemether possessed similar effect against juvenile and adult schistosomes in hamsters, while praziquantel was more effective against adult schistosomes than the juvenile ones in the same host. Finally, after administration of OZ78 and OZ277 to the groups of four to six hamsters with 14- and 35-day-old schistosomes at a single dose of 200 mg/kg, promising effect against juvenile and adult schistosome was observed with the mean worm burden and female worm burden reductions of 69.6-94.2% and 64.2-100% as well as 73.3-80.7% and 68.3-81.1%, respectively. The results indicate that in hamster model, praziquantel exhibits higher effect against adult schistosomes than the juvenile ones, while artemether and OZ compound display similar effect against both juvenile and adult schistosomes.     

Kinetics and mechanism of the polymerization of cyclic acetals, 5. Spectroscopic studies of the polymer end-groups in poly(1,3-dioxolane)

Polymerization of 1,3-dioxolane ( 1 ) was initiated in CH₃NO₂ and CH₂Cl₂ solvents with benzoylium hexafluoroantimonate (C₆H₅CO⁺SbF), terminated with sodium ethanolate (C₂H₅ONa), and the endgroups were determined by using UV spectrophotometry and ¹H NMR methods. Polymers with high polymerization degrees DP _n were obtained (M?_n up to 3·10⁵); DP _n calculated for living polymerization conditions (DP _n=([ 1 ]₀?[ 1 ]_e)/[C₆H₅CO⁺SbF]₀; i.e. one molecule of initiator gives one macromolecule) agree well with DP _n measured by osmometry and DP _n found from ¹H NMR and UV methods assuming one respective end- group per macromolecule. ¹H NMR studies were performed on polymers from perdeuterated 1 (1,3-dioxolane-d₆). These polymers, after purification, were shown to bear benzoyloxy and ethoxy end-groups: \documentclass{article}\pagestyle{empty}\begin{document}${\rm C}_6 {\rm H}_5 \hbox{---} {\rm CO\rlap{--} (O} \hbox{---} {\rm CD}_2 {\rm CD}_2 {\rm OCD}_2 {\rm \rlap{--} )}_n {\rm OCH}_2 {\rm CH}_3$\end{document} Similar results were obtained for polymers initiated with triethyloxonium hexafluoroantimonate ((C₂H₅)₃O⁺SbF), and terminated with triphenylphosphine ((C₆H₅)₃P). These results indicate that initiation with stable oxocarbenium or oxonium ions leads to predominantly linear macromolecules, while initiation with perchloric acid (according to the data reported by Plesch) leads to polymers of low molecular weight and claimed to be mostly cyclic after killing with C₂H₅ONa.