Synthetic bioantioxidants--inhibitors of acetylcholinesterase activity]

The inhibitory effects of synthetic antioxidants (3-oxypyridine, pyrimidine and hindered phenols) on the enzymic activity of membrane-bound acetylcholinesterase (AChE) was studied. In terms of estimated kinetic characteristics of AChE-reaction (KM, Vmax, KI), the pattern of enzyme inhibition by the hindered phenol compounds was found to be of non-competitive or mixed type depending on the inhibitor structure or on the substrate acetylcholine or acetylthiocholine used. The comparative study of the inhibitory action of water-soluble derivatives of hindered phenols and fatty-soluble ionol made it possible to reveal possible contributions to the inhibition of both direct and mediated (by the membrane microsurroundings) effects on the membrane-bound AChE by the studied synthetic bioantioxidants.     

Sterically hindered chlorinating agents that relate to terminal biological oxidations

N=Chloro-2,2,6,6-tetramethylpiperidine chlorinates primary hydrogen more rapidly than secondary hydrogen in 2,2-dimethylbutane and secondary hydrogen more rapidly than tertiary hydrogen in simple alkanes. With pentane, it chlorinates the less hindered 2-position five times faster than the more hindered 3-position. These selectivities approach the selectivity for ω (terminal) and ω-1 (penultimate) carbons that are widely exhibited by enzymic systems.     

Effects of mixing during acid addition on fractionally precipitated protein

Isoelectric fractionation of the two major proteins of soy is characterized. Fractions are acid precipitated and cen-trifugally collected at pH 6.0 (glycinin) and pH 4.8 (beta-conglycinin). Two extremes in the speed of acid addition (rapid, with no mixing, and slow, via acid dialysis, with complete mixing) are compared to determine their effects on the properties of the precipitate. Total protein yield, fraction composition, and aggregate microstructure do not depend significantly on the method of acid addition. Particle size distribution and hindered settling behavior do differ and are explained using a model of aggregate strength. The rapid acid addition produces larger primary particles, because of higher supersaturation, and yields larger aggregates, because of higher interparticle potential and stronger aggregates. Further aggregation in low-shear hindered settling is faster for the slowly precipitated aggregate because few of these bonding sites could survive the high-shear precipitator, whereas more can contribute to aggregation during hindered settling.     

Behaviour of the crossbridges in stretched or compressed muscle fibres

The maximum chord of the myosin heads is comparable to the closest surface-to-surface spacing between the myofilaments in a muscle at the slack length. Therefore, when the sarcomere length increases or when the fibre is compressed, the surface-to-surface myofilament spacing becomes lower than the head long axis. We conclude that, in stretched or compressed fibres, some crossbridges cannot attach, owing to steric hindrance. When the amount of compression is limited, this hindrance may be overcome by a tilting of the heads in the plane perpendicular to the filament axes; in this case, there is no consequence as concerns the crossbridge properties. In highly compressed fibres, the crossbridges become progressively hindered and all the crossbridges are hindered for an axis-to-axis spacing representing about 60% of the spacing observed under zero external osmotic pressure. In this case, both the isometric tension and the ATPase activity of the fibre are zero. In fibres stretched up to 3.77 microns (sarcomere length corresponding to the disappearance of the overlap between the thick and the thin filaments), the ratio of hindered crossbridges over the functional crossbridges may be estimated at about 55%. In stretched fibres, a noticeable proportion of crossbridges are sterically hindered and the crossbridges performance (e.g. constants of attachment and detachment) depends on filament spacing, i.e. on sarcomere length. Therefore, we think it is probably impossible to consider the crossbridges as independent force converters, since this idea requires that the crossbridge properties are independent of sarcomere length. In this connection, all the experiments performed on osmotically compressed fibres are of major importance for the understanding of the true mechanisms of muscle contraction.     

Sulfur-Specific Microbial Desulfurization of Sterically Hindered Analogs of Dibenzothiophene

Dibenzothiophenes (DBTs) bearing alkyl substitutions adjacent to the sulfur atom, such as 4,6-diethyldibenzothiophene (4,6-DEDBT), are referred to as sterically hindered with regard to access to the sulfur moiety. By using enrichment cultures with 4,6-DEDBT as the sole sulfur source, bacterial isolates which selectively remove sulfur from sterically hindered DBTs were obtained. The isolates were tentatively identified as Arthrobacter species. 4,6-DEDBT sulfone was shown to be an intermediate in the 4,6-DEDBT desulfurization pathway, and 2-hydroxy-3,3(prm1)-diethylbiphenyl (HDEBP) was identified as the sulfur-free end product.     

Differential polarized phase fluorometric investigations of diphenylhexatriene in lipid bilayers. Quantitation of hindered depolarizing rotations.

Differential polarized phase fluorometry has been used to investigate the depolarizing rotations of 1,6-diphenyl-1,3,5-hexatriene (DPH) in isotropic solvents and in lipid bilayers. For DPH dissolved in isotropic solvents, there is a precise agreement between the observed and predicted values for maximum differential tangents, indicating that in these media DPH is a free isotropic rotator. In lipid bilayers the tangent defects (i.e., the differences between the calculated and the observed maximum differential tangents) are too large to be explained by anisotropy in the depolarizing rotations but are accounted for by hindered isotropic torsional motions for the fluorophore [Weber, G (1978) Acta Phys. Pol A 54, 173]. This theory describes the depolarizing rotations of the fluorophore by its rotational rate R (in radians/second) and the limiting fluorescence anisotropy (r) at times long compared with the fluorescence lifetime. Through the combined use of both steady-state anisotropy measurements and differential phase measurements, we have demonstrated that one may obtain unique solutions for both R and r. For DPH embedded in vesicles prepared from dimyristoyl-, dipalmitoyl-, and distearoylphosphatidylcholines, the depolarizing motions are highly hindered at temperatures below the transition temperature (Tc) but are unhindered above Tc. The apparent rotational rates of the probe do not change significantly at Tc. These data suggest that the changes observed in the steady-state anisotropy near Tc derive primarily from changes in the degree to which the probe's rotations are hindered, and only to a small extent from changes in rotational rate. For DPH embedded in bilayers that contained 25 mol % cholesterol, no clear transition occurred and the rotations appeared to be hindered at all temperatures. The rotational motions of DPH embedded in dioleolyphosphatidylcholine were found to be far less hindered, but the rotational rates were similar to those obtained in the saturated phosphatidylcholines. Finally, the data show that in an anisotropic environment, such as that of a lipid bilayer, steady-state fluorescence anisotropy measurements alone cannot yield quantitatively meaningful rotational rates. Extrapolation of steady-state aniosotropy data to the quantitation of membrane viscosity is therefore difficult, if not invalid; however, qualitative comparisons can be useful.     

Asymmetric bioreduction of a bisaryl ketone to its corresponding (S)-bisaryl alcohol, by the yeast Rhodotorula pilimanae ATCC 32762

The screening of 310 microbial strains yielded eight as suitable biocatalysts for the asymmetric bioreduction of a highly hindered bisaryl ketone to its corresponding alcohols. The production of both enantiomers with elevated optical purity (ee>96%) was achieved by different microorganisms. When scaling up the asymmetric bioreduction process in laboratory bioreactors (23 l scale), the production of preparative amounts (1.5 g) of the (S) enantiomer with elevated optically purity (ee>96%) was achieved when employing the yeast Rhodotorula pilimanae ATCC 32762. Achieving this asymmetric bioreduction with enantiocomplementarity in employing such a hindered substrate is remarkable and highlights the potential of such biological approach.     

The anti-intellectual effects of intellectual property

Intellectual property considerations decrease research productivity in subtle and unanticipated ways. Chemical probe exchange between Pharma and academia is hindered by academic IP interests. These are perceived as a subtle nuisance by the academic researcher. Novel ligands for oral targets are historically few and numbers of economically attractive oral drug targets are limited. Economically speculative targets lie in the academic domain but the medicinal chemistry to explore these in a drug discovery sense lies in Pharma and cooperation between the two is hindered by very different academic and Pharma views on chemical quality. Tools and probes for academic target validation can accommodate looser chemical quality criteria as opposed to the very strict chemical quality criteria required in Pharma drug discovery.     

Reaction of N3-benzoyl-3',5'-O-(di-tert-butylsilanediyl)uridine with hindered electrophiles: intermolecular N3 to 2'-O protecting group transfer

The compound N3-benzoyl-3',5'-O-(di-tert-butylsilanediyl)uridine 2 was alkylated with various alkyl iodides in CH3CN in the presence of base. Normal 2'-O-alkylated products were obtained with methyl or benzyl iodide. If hindered alkyl iodides with beta-branching such as 2-ethylbutyl iodide were used as electrophiles under the same conditions, N3-alkyl-2'-O-benzoyl uridine derivatives were produced. This unexpected transformation is usually dormant with reactive alkylating agents, but expressed with sterically hindered, less reactive electrophiles. This unwanted reaction gives isomeric products whose spectra differ in only subtle ways from target compounds.     

Linking genomics and fish conservation decision making: a review

Reviews in Fish Biology and Fisheries - Despite the promising applications of genome-wide information to conservation, the field of conservation genomics remains hindered by a research-practice...     

Synthesis, structure-activity relationship, and p210(bcr-abl) protein tyrosine kinase activity of novel AG 957 analogs

A series of novel, sterically hindered lipophilic analogs of AG 957 was designed and synthesized as potential protein tyrosine kinase (PTK) inhibitors. The in vitro activity, in vivo anti-leukemia activity, and pharmacology of these PTK inhibitors were studied. Some aspects of the structure-activity relationship associated with the carboxylic acid, phenol ring, and linker modifications are discussed. We have demonstrated that the 1,4-hydroquinone moiety is essential for activity and that sterically hindered esters contribute to enhanced in vivo efficacy. Adaphostin (NSC 680410) has emerged as the improved compound with the maximum in vivo anti-leukemia hollow fiber activity, concordant with the original lead compound AG 957. Currently, adaphostin is undergoing preclinical toxicology studies.     

Spectroscopic properties of ferrous heme complexes of sterically hindered ligands.

Mesoheme IX complexes of sterically hindered ligands 2-methylimidazole, tert-butylamine and 2-methylpyridine in aqueous glycerol solutions are characterized by broad visible absorption spectra at ambient temperature exhibiting close similarities to high-spin ferrous hemeproteins. Spectrophotometric titrations of mesoheme IX with these ligands indicate well-defined equilibria for 2-methylimidazole and tert-butylamine corresponding to the formation of penta-coordinate strong-field ligand complexes. Variable temperature spectra of these complexes from ambient to 77 degrees K exhibit a change to hemochrome spectra characteristic of the low-spin unhindered ligand complexes. Corresponding changes in the visible spectra are not observed for the high-spin hemeproteins deoxymyoglobin, horse-radish peroxidase and cytochrome ?. The appropriate utilization of these hindered ligand heme complexes as model systems for high-spin ferrous hemeproteins has been discussed.     

Dialkylformamidines: depurination resistant N6-protecting group for deoxyadenosine.

Sterically hindered N6-dialkylformamidine protected deoxyadenosine is more stable to acidic depurination than N6-benzoyldeoxyadenosine and is potentially a valuable protecting group in the synthesis of deoxyoligonucleotides.     

Factors in Protobiomonomer Selection for the Origin of the Standard Genetic Code

Acta Biotheoretica - Natural selection of specific protobiomonomers during abiogenic development of the prototype genetic code is hindered by the diversity of structural, spatial, and rotational...     

Reverse K?nigs-Knorr reaction. Synthesis of beta-D-gluco-thio-cerebroside

The synthesis of 1-thio-beta-D-glucocerebroside by reaction of 1-iodo-3-O-benzoylceramide with 1-mercapto-beta-D-glucopyranose in the presence of sterically hindered amine (DBU) is described.     

Nutrient patches are transient and unpredictable in an unproductive mountain grassland

Plant Ecology - While plant roots respond consistently to nutrient availability under experimental conditions, our understanding of the role of such response in the field is hindered by poor...     

First Genomic Prediction of Single-Step Models in Large Yellow Croaker

Marine Biotechnology - Genome selection is mainly used in disease-resistant traits of aquatic species; however, its implementation is hindered by a high cost of genotype and phenotype data...     

The aromatic circular dichroism spectrum as a probe for conformational changes in the active site environment of hemocyanins.

The binding of various ligand molecules to the binuclear Cu(I) site of deoxy-hemocyanin has been investigated through the changes produced in the aromatic region of the circular dichroism spectrum of the protein, where a cluster of tryptophan residues located in the vicinity of copper site undergo conformational reorientations in the presence of exogenous ligands coordinated to the metal. In agreement with expectations, the binuclear site of arthropod hemocyanin is severely hindered to the access of exogenous ligands except for very small molecules like CO, O2 or CN- while for mollusc proteins ligands such as thiourea and 2-mercaptoethanol bind easily to the Cu(I) sites. However, the access of the ligand becomes progressively hindered and eventually prevented as the size of substituents on the ligand increases.     

Synthesis and Antiradical Activity of Hindered Phenol Derivatives of Flax Cellulose

Russian Journal of Bioorganic Chemistry - The modification of powdered ultradisperse cellulose by hindered phenol fragments was carried out. The modification was carried out by reacting cellulose...     

Effects of the pyrethroid deltamethrin on the acquisition and inoculation of viruses by Myzus persicae

The pyrethroid, deltamethrin, alone or as an emulsifiable formulation, hindered infection of healthy plants with the persistent beet mild yellowing virus (BMYV) and both acquisition of, and infection with, the non-persistent potato virus Y (PVY) and the semi-persistent sugar beet yellows virus (BYV) by Myzus persicae in glasshouse tests.
Another pyrethroid, RU-15525, also protected against infection with PVY. Even sub-lethal amounts of deltamethrin decreased virus transmission by rapidly incapacitating the aphids, the effect being least with aphids most resistant to organophosphorous insecticides and to certain pyrethroids including deltamethrin. Demeton-S-methyl hindered infection only with BMYV. This work shows that deltamethrin restricts transmission of persistent, semi-persistent and perhaps more importantly of non-persistent viruses in the glasshouse, and has potential for doing the same in the field.