Labile Metabolites

The importance of ascertaining the possible presence of unstable metabolites at an early stage in the drug development process cannot be underestimated. Failure to detect labile metabolites could lead to costly delays to development. Very often, erratic or difficult to explain analytical or kinetic data provide clues to metabolite degradation, the most commonly encountered reaction being the conversion of a metabolite to parent drug. Examples of unstable glucuronide conjugates, N-oxides, alcohols and phenols abound in the literature. They are not easy to find, however, and have to be ‘mined’ by extensive searching. This report, by no means exhaustive, brings together the major examples according to substance class. Remedial action to avoid metabolite degradation is discussed, as well as a number of specific examples which cannot be categorised under the main substance classes.     

How mobile NMR can help with the conservation of paintings

The conservation of paintings is fundamental to ensure that future generations will have access to the ideas of the grand masters who created these art pieces. Many factors, such as humidity, temperature, light, and pollutants, pose a risk to the conservation of paintings. To help with painting conservation, it is essential to be able to noninvasively study how these factors affect paintings and to develop methods to investigate their effects on painting degradation. Hence, the use of mobile nuclear magnetic resonance (NMR) as a method of investigation of paintings is gaining increased attention in the world of Heritage Science. In this mini-review, we discuss how this method was used to better understand the stratigraphy of paintings and the effect different factors have on the painting integrity, to analyze the different cleaning techniques suitable for painting conservation, and to show how mobile NMR can be used to identify forgeries. It is also important to keep in mind its limitations and build upon this information to optimize it to extend its applicability to the study of paintings and other precious objects of cultural heritage.     

Synthesis of heteroarylated ketones via bismuth(III) triflate-promoted regioselective 1,4- and 1,6-additions of electron-rich heteroarenes to cyclic enones and dienones

The development and optimization of bismuth(III) triflate-promoted regioselective 1,4- and 1,6-additions of electron-rich heteroarenes to cyclic, β,β-disubstituted enones and dienones is described. Additions of a range of heteroarenes, including furan, thiophene, pyrrole, and indole nucleophiles, to cyclic, β,β-disubstituted enones occur to form all-carbon quaternary centers in up to 88% yield. In addition, regioselective 1,6-additions of electron-rich heteroarenes to 3-vinyl-2-cyclohexenone occur to produce a variety of δ-heteroarylated, β,β-disubstituted enones in up to 93% yield. The high 1,6-selectivity for these reactions is attributed to the increased steric bulk at the β-position relative to the δ-position, and no competing 1,4-conjugate addition is observed.     

Asymmetry in the Multiprotein Systems of Molecular Biology

Signaling in living systems needs to achieve high specificity, to be reversible, and to achieve high signal to noise. Signaling mediated by multiprotein systems has evolved that avoids the requirement for high-affinity binary complexes that would be difficult to reverse and which, in the overcrowded cell, would lead to excessive noise in the system. Symmetrical structures are only occasionally formed. When they are, it is principally to colocate components, for example, the tyrosyl kinases of growth factors, where dimers form. Symmetry is, however, often broken, presumably to create more sensitivity and specificity in the signaling system by assembling other components, into higher-order multiprotein systems. The binding of a single heparin to two 1:1 FGF:FGFR complexes is an example, as is the binding of a single ligase to the Xrcc4 dimer, perhaps so creating a further DNA-binding site.     

Diene hydroacylation from the alcohol or aldehyde oxidation level via ruthenium-catalyzed C-C bond-forming transfer hydrogenation: synthesis of beta,gamma-unsaturated ketones

Under the conditions of ruthenium-catalyzed transfer hydrogenation, isoprene couples to benzylic and aliphatic alcohols 1a-g to deliver beta,gamma-unsaturated ketones 3a-g in good to excellent isolated yields. Under identical conditions, aldehydes 2a-g couple to isoprene to provide an identical set of beta,gamma-unsaturated ketones 3a-g in good to excellent isolated yields. As demonstrated by the coupling of butadiene, myrcene, and 1,2-dimethylbutadiene to representative alcohols 1b, 1c, and 1e, diverse acyclic dienes participate in transfer hydrogenative coupling to form beta,gamma-unsaturated ketones. In all cases, complete branch regioselectivity is observed, and, with the exception of adduct 3j, isomerization to the conjugated enone is not detected. Thus, formal intermolecular diene hydroacylation is achieved from the alcohol or aldehyde oxidation level. In earlier studies employing a related ruthenium catalyst, acyclic dienes were coupled to carbonyl partners from the alcohol or aldehyde oxidation level to furnish branched homoallylic alcohols. Thus, under transfer hydrogenative coupling conditions, all oxidation levels of substrate (alcohol or aldehyde) and product (homoallyl alcohol or beta,gamma-unsaturated ketone) are accessible.     

半夏淀粉的理化特性

研究了不同产地的4种半夏淀粉的理化特性,包括直链淀粉含量、膨胀度、溶解性、持水性、淀粉粒大小和形貌、结晶类型、热特性和糊化特性等。结果表明,这些半夏淀粉中直链淀粉含量为18.60%～23.91%;膨胀度21.53%～23.09%;溶解度11.5%～32.3%;持水性100.3%～119.0%。淀粉粒单粒球形,卵形或圆半球形,直径2～20μm,复粒由2～3个分粒组成,其结晶类型均为C型,结晶度15.0%～37.9%。用差示扫描量热仪测得的转变温度TO、TP和TC分别为71.58～77.75℃、83.03～83.84℃和89.41～90.99℃,热焓为4.316～5.809 J/g。用快速粘度分析仪测定了4种半夏淀粉的糊化特征值:峰值粘度、热糊粘度、冷糊粘度、稀懈值和回复值分别为149.5～226.2、97.7～127.2、141.8～194.3、50.4～99.0和44.2～67.2 RVU。糊化温度77.8～79.9℃,峰值时间8.3～8.7 min。     

Developing front‐end devices for improved sample preparation in MS‐based proteome analysis

Chemical analysis has long relied on instrumentation, from the simplest (eg, burets) to the more sophisticated (eg, mass spectrometers) to facilitate precision measurements. Regardless of their complexity, the development of a new instrumental device can be a valued approach to address problems in science. In this perspective, we outline the process of novel device design, from early phase conception to the manufacturing and testing of the tool or gadget. Focus is placed on the development of improved front‐end devices to facilitate protein sample manipulations ahead of mass spectrometry, which therefore augment the proteomics workflow. Highlighted are some of the many training secrets, choices, and challenges that are inherent to the often iterative process of device design. In hopes of inspiring others to pursue instrument design to address relevant research questions, we present a summary list of points to consider prior to innovating their own devices.     

Density functional theory for strongly-interacting electrons: perspectives for physics and chemistry

Improving the accuracy and thus broadening the applicability of electronic density functional theory (DFT) is crucial to many research areas, from material science, to theoretical chemistry, biophysics and biochemistry. In the last three years, the mathematical structure of the strong-interaction limit of density functional theory has been uncovered, and exact information on this limit has started to become available. The aim of this paper is to give a perspective on how this new piece of exact information can be used to treat situations that are problematic for standard Kohn-Sham DFT. One way to use the strong-interaction limit, more relevant for solid-state physical devices, is to define a new framework to do practical, non-conventional, DFT calculations in which a strong-interacting reference system is used instead of the traditional non-interacting one of Kohn and Sham. Another way to proceed, more related to chemical applications, is to include the exact treatment of the strong-interaction limit into approximate exchange-correlation energy density functionals in order to describe difficult situations such as the breaking of the chemical bond.     

Curvature Effects in the Analysis of Pendant Bubble Data: Comparison of Numerical Solutions, Asymptotic Arguments, and Data

The pendant bubble method is commonly used to measure the evolution of the surface tension of surfactant solutions. Initially, the bubble interface is free of adsorbed surfactant. As time progresses, surfactant diffuses to the interface, adsorbs, and reduces the surface tension. The surface tension is assumed to be in equilibrium with the instantaneous surface concentration. Therefore, surface tension data are analyzed in terms of interfacial thermodynamics and mass transfer models in order to infer the mechanisms which determine the surfactant transport. Diffusion from the bulk solution to the bubble can be approximated as diffusion to a spherical interface. Approximating this process as diffusion to a plane introduces significant errors into the data analysis. Mass transfer to a sphere differs from that to a plane; the equilibration of the spherical interface is more rapid simply because of geometry. The failure to account for this effect in the interpretation of pendant bubble data can lead to serious errors in the transport coefficients for the surfactants. In the diffusion-controlled limit, surfactant diffuses to the sublayer immediately adjacent to the interface and adsorbs in local equilibrium according to the adsorption isotherm. There is a closed-form solution for Fick's law describing adsorption to a sphere in an infinite solution which reduces to the Ward and Tordai solution when the bubble radius is large. This equation, along with the adsorption isotherm relating the surface concentration and the sublayer concentration, must be solved numerically in order to solve for the time evolution of the surface concentration. At early times, the adsorption isotherm can be expanded about the clean interface state. At long times, small departures from the equilibrium state can be assumed. In these limits, asymptotic expansions can be obtained. The short- and long-time expansions are found in this study for adsorption to a sphere and compared to those obtained previously for adsorption to a planar interface. In particular, the long-time asymptote for adsorption to a sphere is proportional to t(-3/2); this asymptote differs significantly from that for adsorption to a plane, which goes as t(-1/2). The full solution for adsorption to a sphere is compared to the Ward and Tordai solution for adsorption to a planar interface. From a comparison of the full solutions, it is established that curvature cannot be neglected unless the ratio of the adsorption depth to the bubble radius is negligible. This ratio can be calculated a priori from equilibrium isotherm parameters. Using constants which describe the surfactant C(12)E(8), for which curvature plays a strong role in the surfactant adsorption dynamics, the short- and long-time solutions for adsorption to the interface are compared to the full solutions and to dynamic surface tension data to infer the range of validity of the approximations. Copyright 2001 Academic Press.     

Water's polyamorphic transitions and amorphization of ice under pressure

Transformations of water's high density amorph (HDA) to low density amorph (LDA) and of LDA's to cubic ice (Ic) have been studied by in situ thermal conductivity kappa measurements at high pressures. The HDA to LDA transformation is unobservable at p of 0.07 GPa, indicating that, for a fixed heating rate, an increase in pressure increases the temperature of HDA to LDA transformation and decreases that of LDA to ice Ic, causing thereby the two transformations to merge, and HDA appears to convert directly to ice Ic. Thus either LDA forms but converts extremely rapidly to ice Ic, or LDA does not form. At a fixed p and T, in the range of pressure amorphization of hexagonal ice, kappa continues to decrease with time. Therefore, the amorphization of ice Ih is kinetically controlled. When HDA at 1 GPa was heated from 130 to 157 K and densified to very HDA, its kappa increased by 3%. Our findings and a scrutiny of earlier reports show that a reversible transition between HDA and LDA does not occur at approximately 135 K and approximately 0.2 GPa. Since there is no unique HDA, it is difficult to justify the conjecture for a second critical point for water.     

Surfing silica surfaces superciliously

The present mini-review summarizes the experience gathered by our group in developing different classes of novel quaternarized heterocyclic compounds able to modulate and reverse the electroendoosmotic flow (EOF) in a most peculiar manner. The first class comprises mono-salt compounds, with the determinant omega-iodoalkyl chains of different lengths (typically C4-C8), able to be adsorbed by silicas, at alkaline pH, and spontaneously alkylate ionised silanols, thus becoming covalently affixed to it. The second class is constituted by di-salt compounds, attached at the termini of an alkyl chain of variable lengths (here too, typically, C4-C8). This second class is unable to bind covalently silica surfaces, although, in thin-layer chromatography, it exhibits an extraordinary affinity for silica beads, contrary to the first one. On the basis of the strikingly different behaviour, structural rules are derived for the minimum requirements for general classes of amines to bind to silica walls and modify EOF. For compounds unable to bind covalently to the wall, the most important structural motif is two quaternary nitrogens spaced apart by a C4 chain: this seems to be the average distance (i.e., 0.8 nm) between two adjacent, ionized silanols for a snug fit. The other structural binding motif is the "hydrophobic decoration", i.e., the ratio of charged groups to alkyl residue in the various amines; amines with high levels of such alkane groups (i.e., with higher hydrophobicity), seem to bind more tenaciously to the wall, probably due to hydrophobic interaction not to the wall but among the amine derivatives themselves, when carpeting the silica.     

Acrylamide: considerations for risk management

The presence of acrylamide in many carbohydrate-rich foods is due to its formation during conventional heating and preparation methods. Although acrylamide is established to be a toxic substance, the implications to public health from the amounts found in food are not clear. A better scientific understanding is required to help determine whether, and to what extent, formal risk management action might be necessary. Since acrylamide in food was highlighted in 2002, numerous investigations and initiatives have been developed, including international collaborations across governments, industry, research organizations, and consumer representations. The newly generated information is being used to help the overall understanding of this issue. In particular, new information on health aspects will be important to update the scientific risk assessment. The basis for decisions on possible risk management measures would then be clearer. If future risk assessment concludes that the amounts of acrylamide in food can pose a health threat, then options for risk management will need to be considered, such as limits, guide levels, codes of practice, guidance information, and advice to the food and catering industries and to consumers. In the meantime, it is possible to benefit from progress already made on how acrylamide is formed in food and on ways to lower the amounts present. Raising awareness to the approaches that can reduce the presence of acrylamide in food should be encouraged. Where feasible, such approaches can be assessed for practical use in production, processing, and preparation of the relevant food products.     

STUDIES ON THE CAPACITY OF pR IN VITRO TO PHOTOCONVERT TO THE LONG-WVELENGTH Ffr-FORM. A SURVEY FO TEN PLANT SPECIES*

Studies on the capacity of Pr in uitro to photoconvert to the long wavelength in uioo-like Pfr form were performed with extracts from 10 species. Red irradiation, immediately after extraction of crude extracts from 9 species, photoconverted Pr to long-wavelength Pfr with an absorbance maximum around 735 nm. Red irradiation of soybean extracts, however, photoconverted Pr to short-wavelength Pfr, with an absorbance maximum at 725 nm. Red irradiation given later than 1.5-2 h after extraction, to extracts of oats, pea, cucumber, radish, sunflower and soybean, photoconverted Pr to a short-wavelength Pfr species with an absorbance maximum around 725 nm. In crude extracts of barley, corn, wheat and zucchini, red irradiation, even after a long dark-incubation period at 4°C of up to 48 h, photoconverted Pr to long-wavelength Pfr with an absorbance maximum around 735 nm. After incubation at 25°C for 3 h, however, Pr from barley also photoconverted to the short-wavelength form. It is suggested that in the group exemplified by oats, Pr rapidly undergoes an alteration following extraction, which results in the loss of the capacity of Pr to photoconvert to long-wavelength Pfr. In contrast, in extracts from the group exemplified by barley, Pr is much more stable and retains the capacity to photoconvert to long-wavelength Pfr for much longer periods.     

“The Fitness of Their Union”: Travel and Health in the Letters of Humphry and Jane Davy

The letters of Humphry Davy and his circle, to be published shortly, shed new light on his marriage to Jane Apreece. This paper examines the journeys undertaken by the couple, together and separately, with particular attention to the therapeutic benefits they sought from travel. I argue that their increasingly divergent itineraries reflected a growing understanding that Humphry and Jane had different humoral temperaments or constitutions, leading them to seek different climatic conditions to cure their ailments. While Jane’s temperament was classified as melancholic, requiring her to travel to warmer and sunnier climes during the English winter, Humphry’s was believed to be sanguine, meaning he had to avoid excessive heat along with stimulating food and drink. He relied on classical ideas about individuals’ different humoral constitutions, and the therapies appropriate to them, while measuring atmospheric variables to determine the best places to restore his health. The Davys’ letters reveal the beliefs about bodily differences and atmospheric conditions that shaped their therapeutic travels.     

Voronoi deformation density (VDD) charges: Assessment of the Mulliken, Bader, Hirshfeld, Weinhold, and VDD methods for charge analysis

We present the Voronoi Deformation Density (VDD) method for computing atomic charges. The VDD method does not explicitly use the basis functions but calculates the amount of electronic density that flows to or from a certain atom due to bond formation by spatial integration of the deformation density over the atomic Voronoi cell. We compare our method to the well-known Mulliken, Hirshfeld, Bader, and Weinhold [Natural Population Analysis (NPA)] charges for a variety of biological, organic, and inorganic molecules. The Mulliken charges are (again) shown to be useless due to heavy basis set dependency, and the Bader charges (and often also the NPA charges) are not realistic, yielding too extreme values that suggest much ionic character even in the case of covalent bonds. The Hirshfeld and VDD charges, which prove to be numerically very similar, are to be recommended because they yield chemically meaningful charges. We stress the need to use spatial integration over an atomic domain to get rid of basis set dependency, and the need to integrate the deformation density in order to obtain a realistic picture of the charge rearrangement upon bonding. An asset of the VDD charges is the transparency of the approach owing to the simple geometric partitioning of space. The deformation density based charges prove to conform to chemical experience.     

TG and DSC analyses of eucalyptus black liquor as alternative methods to estimate solids content

As a consequence of the continuous increase in the production rate of pulp and paper mills around the world, a great quantity of black liquor, a by-product of the wood digestion process, is produced. This by-product has a great potential as biomass, but needs to be concentrated to higher solids content to be burned as fuel in a recovery boiler. This is necessary to make the pulping process economically feasible, incinerating black liquor to produce high pressure steam, recycling inorganic chemicals to the process. The greater the solids content in black liquor, the better the combustion process in the boiler. Nevertheless, concentration of solids in black liquor above 75 mass/%, causes scaling formation on the heat transfer surfaces of evaporators and concentrators, due to the precipitation of sodium salts, reducing the overall efficiency of this equipment. The aim of this work is to evaluate the use of thermal analyses techniques, TG and DSC, as alternative methods to estimate solids content in eucalyptus black liquor samples since this information is essential to understand scaling formation process, allowing actions to reduce this industrial problem. Traditional techniques applied to determine solids content use gravimetric methods, which are simple, fine, but take a lot of time to be executed. Thermal analyses have proved to be very accurate and have the advantage to be faster than the traditional techniques. On the other hand, the cost-benefit relationship of the traditional technique is much greater and the final decision which one should be used depends on the conditions available.     

The Contribution of Carl (Speed) Marvel to Polymer Science

It is an exceptional honor and privilege for me to contribute to this special symposium “Polymer Synthesis-The 1980's”, and lam very much obliged to Eli Pearce for giving me the opportunity to present to you a short report on the life and on the extraordinary accomplishments of our new Honorary Doctor of Sciences. When, about a year ago a group of us thought that our Polymer Research Institute should recognize Professor Marvel's outstanding contribution to polymer science in an unusual manner, it was felt that a special symposium should be organized in his honor and that he should receive an Honorary Degree of Science at this occasion. The conferment of such a degree is, of course, a matter of the faculty, but our Provost, Professor Donaruma, succeeded to overcome all difficulties and we were able to issue the invitation for this symposium which, to our great satisfaction, is being attended by such a large group of friends and admirers of our honoree. A few who would have liked to be here were unable to come but sent letters with the expression of their sincere regrets to be absent and of their congratulations. I am giving these letters to Professor Marvel; they are signed by Ed Jefferson, Dick Heckert, Paul Flory, and Frank Press. But now to the topic of my address.     

Designing for sustainability with biocatalytic and chemoenzymatic cascade processes

Cascade reactions have been widely recognized to cut costs, decrease solvent usage, and reduce cycle times in chemical processes. Recently, biocatalytic cascades have altered how we design synthetic routes to complex molecules to achieve sustainable commercial processes for pharmaceutical, agricultural, and fine chemical industries. With advancements in protein engineering and an increase in the number of enzyme classes available to chemists, industrial and academic groups alike have endeavored to expand the scope of biocatalysis from single reactions to multi-enzyme cascades to rapidly build complex molecular structures. Recent reports have drawn inspiration from biosynthetic pathways and have applied engineered enzymes to in vitro enzymatic cascades. Furthermore, combining transition-metal catalysis and enzymes in one-pot chemoenzymatic cascades likewise serves to broaden the scope of biocatalysis, enabling traditional chemical reactions to be performed under mild aqueous conditions. In this article, we review recent biocatalytic and chemoenzymatic cascades from 2019 to 2021.     

Gel formation in free radical polymerization via chain transfer and terminal branching

Gel formation in free-radical polymerization via chain transfer to polymer, recombination termination, and terminal branching due to either chain transfer to monomer or disproportionation termination is investigated using the method of moments. It is found that no gel can possibly form in the systems consisting of initiation, propagation, and one of the above reactions. However, systems with the following combination of reactions are found to be capable of gelling. They are: chain transfer to polymer + recombination termination; chain transfer to polymer + terminal branching due to disproportionation termination; and terminal branching due to transfer to monomer + recombination termination. Systems with the following combination of reactions are incapable of gelling; transfer to polymer + terminal branching due to transfer to monomer; and terminal branching due to disproportionation termination + recombination termination. An examination of the gelation mechanisms reveals that the formation of multivinyl macromonomers during the course of polymerization is the reason that systems involving terminal branching gel. Sol/gel diagrams are generated to give critical kinetic parameters required for gelation. It is found that terminal branching does not always promote gelation due to the adverse effect on chain length through chain transfer to monomer and termination by disproportionation, reactions which generate terminal double bonds. © 1994 John Wiley & Sons, Inc.