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41.
CAP256 is one of the highly potent, broadly neutralizing monoclonal antibodies (bNAb) designed for HIV-1 therapy. During the process development of one of the constructs, an unexpected product-related impurity was observed via microfluidics gel electrophoresis. A panel of complementary LC-MS analyses was applied for the comprehensive characterization of CAP256 which included the analysis of the intact and reduced protein, the middle-up approach, and a set of complementary peptide mapping techniques and verification of the disulfide bonds. The designed workflow allowed to identify a clip within a protruding acidic loop in the CDR-H3 region of the heavy chain, which can lead to the decrease of bNAb potency. This characterization explained the origin of the additional species reflected by the reducing gel profile. An intra-loop disulfide bond linking the two fragments was identified, which explained why the non-reducing capillary electrophoresis (CE) profile was not affected. The extensive characterization of CAP256 post-translational modifications was performed to investigate a possible cause of CE profile complexity and to illustrate other structural details related to this molecule’s biological function. Two sites of the engineered Tyr sulfation were verified in the antigen-binding loop, and pyroglutamate formation was used as a tool for monitoring the extent of antibody clipping. Overall, the comprehensive LC-MS study was crucial to (1) identify the impurity as sequence clipping, (2) pinpoint the clipping location and justify its susceptibility relative to the molecular structure, (3) lead to an upstream process optimization to mitigate product quality risk, and (4) ultimately re-engineer the sequence to be clip-resistant.
Graphical Abstract ?
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42.
43.
The instability of hydroxy peroxyesters, the elusive Criegee intermediates of the Baeyer–Villiger rearrangement, can be alleviated by selective deactivation of the stereoelectronic effects that promote the 1,2‐alkyl shift. Stable cyclic Criegee intermediates constrained within a five‐membered ring can be prepared by mild reduction of the respective hydroperoxy peroxyesters (β‐hydroperoxy‐β‐peroxylactones) which were formed in high yields in reaction of β‐ketoesters with BF3?Et2O/H2O2.  相似文献   
44.
The content of residual monomers is one of the most important characteristics of polymer dispersions. As a result of the similar physicochemical parameters of ethyl acrylate and methyl methacrylate, it is very difficult to determine the residual monomers in acrylate dispersions obtained by emulsion polymerization of both monomers. Gas chromatography with capillary columns, however, permits separation of these monomers and their quantitative determination in acrylate dispersions.  相似文献   
45.
In the last decade, our research group set up and optimised analytical techniques for the characterisation of the major components of atmospheric aerosol (i.e. secondary inorganic ions and carbonaceous material) and source markers (e.g. levoglucosan, carbonates). In this study, we present a complete overview on the most problematic aspects that can be encountered during the quantification of the two main components of aerosol, i.e. the ionic and carbonaceous fractions. More in detail, different liquid chromatographic approaches were set up for main ions and anhydrosugars determination. Quality assurance procedures (i.e. tests on data reliability) were applied during the set-up phase and they are presented in this work. As regards the carbonaceous component characterisation, two evolved gas analysis techniques were set up and applied: the thermogravimetric technique coupled to the Fourier transformed infrared spectroscopy (TGA/FTIR) and the thermal–optical transmittance method (TOT). A suitable protocol for organic and elemental carbon separation was set up for the TGA/FTIR system and a comparison with the results obtained by the TOT method was carried out. Studies on the impact of filter load, field blanks, and sample composition on OC/EC quantification by the TOT method were performed. Moreover, approaches for carbonate carbon quantification on different kinds of filters were developed. It was demonstrated that this approach allows to reach the ionic balance in samples impacted by carbonate compounds. The optimised methods have been applied for the analysis of thousands of PM filters allowing the obtainment of reliable results.  相似文献   
46.
Most alkyl phenyl sulfones are readily alpha-chlorinated with CCl(4) and alpha-brominated with CBrCl3 in KOH-t-BuOH via radical-anion radical pair (RARP) reactions. While isopropyl mesityl sulfone (4) is easily alpha-chlorinated with CCl(4), it was completely recovered when treated with the more reactive CBrCl3. Subsequent investigations showed the latter result to be due to the poor acidity of 4 together with the rapid depletion of CBrCl3 and KOH by their reaction with each other, and led to a variety of other important results. 4-Hydroxyphenyl isopropyl sulfone (6) is unreactive with either CCl4 or CBrCl3 in KOH-t-BuOH, its phenoxide anion strongly reducing the electronegativity of the sulfonyl group, thereby inhibiting alpha-anion formation. This effect is reversed by the electron-withdrawing influence of two alpha-phenyls, so that benzhydryl 4-hydroxyphenyl sulfone (8) is readily alpha-halogenated in KOH-t-BuOH with CCl4 or CBrCl3. On further contact with KOH-t-BuOH the alpha-halogenated sulfones from 8 are decomposed into benzophenone and phenol. While the alpha-halogenated derivatives of 4-methoxyphenyl benzhydryl sulfone (9) are stable to base, they are decomposed even under mildly acidic conditions into 4-methoxyphenyl 4-methoxybenzenethiolsulfonate (9c), phenol, and benzophenone. Mono-alpha-halogenation of benzyl phenyl sulfone (10) enhances the rate of the subsequent halogenation, so that alpha,alpha-dihalogenation is attained while much substrate is still present and the mono-alpha-halogenated product is not detected. The ease of reductive debromination of alpha-bromo sulfones with Cl3C- was correlated with the stability of the formed alpha-anions, explaining the success with alpha-bromobenzylic sulfones but failure with alpha-bromoalkyl sulfones. In the presence of air and the absence of competing halogenation, formation of the alpha-anions of alkyl aryl sulfones is quickly accompanied by oxidative cleavage by atmospheric O2, leading to the formation of arenesulfonyl alcohols, arenesulfonyl halides, and haloarenes.  相似文献   
47.
The method of capillary isotachophoresis with conductivity detection was applied for the determination of the physico-chemical characteristics (conditional stability constants log beta') of holmium and yttrium complexes with DTPA (diethylenetriaminepentaacetic acid) and DOTA (1,4,7,10-tetraazadodecane-N,N',N',N'-tetraacetic acid). The log beta' determination is based on the linear relation between the stability constants of lanthanide-DTPA (lanthanide-DOTA) complexes and the reduction of the zone of the complex owing to the bleeding phenomena (liberating free metal ion). The stability constants calculated using this relationship are comparable with the literary data obtained by other methods for both holmium (log beta'(Ho-DTPA)=21.9, log beta'(Ho-DOTA)=24.5) and yttrium complexes (log beta'(Y-DTPA)=21.2, log beta'(Y-DOTA)=24.4). Capillary isotachophoresis was applied for the determination of the optimum composition of the reaction mixture (metal:ligand ratio) as well.  相似文献   
48.
Two triarylamine centers bridged through an aliphatic bridge feature unexpected charge transfer properties, bearing an important electronic coupling between them in the absence of a π linker; EPR, electrochemistry, electronic spectroscopy and first principles molecular calculations are combined to study the electronic structure of this compound.  相似文献   
49.
The native form of Cu/Zn-superoxide dismutase, isolated from fungal strain Humicola lutea 103 is a homodimer that coordinates one Cu(2+) and one Zn(2+) per monomer. Cu(2+) and Zn(2+) ions play crucial roles in enzyme activity and structural stability, respectively. It was established that HLSOD shows high pH and temperature stability. Thermostability of the glycosylated enzyme Cu/Zn-SOD, isolated from fungal strain H. lutea 103, was determined by CD spectroscopy. Determination of reversibility toward thermal denaturation for HLSOD allowed several thermodynamic parameters to be calculated. In this communication we report the conditions under which reversible denaturation of HLSOD exists. The narrow range over which the system is reversible has been determined using the strongest test of two important thermodynamic independent variables (T and pH). Combining both these variables, the "phase diagram" was determined, as a result of which the real thermodynamic parameters (ΔC(p), ΔH(exp)°, and ΔG(exp)°) was established. Because very narrow pH-interval of transitions we assume they are as result of overlapping of two simple transitions. It was found that ΔH(o) is independent from pH with a value of 1.3 kcal/mol and 2.8 kcal/mol for the first and the second transition, respectively. ΔG(o) was pH-dependent in all studied pH-interval. This means that the transitions are entropically driven, these. Based on this, these processes can be described as hydrophobic rearrangement of the quaternary structure. It was also found that glycosylation does not influence the stability of the enzyme because the carbohydrate chain is exposed on the surface of the molecule.  相似文献   
50.
The reaction of trimethyl(vinyl)silane 1 and dimethyl(divinyl)silane 2 with various sulfonamides in the oxidative system (tert-BuOCl + NaI) has been studied and shown to be an efficient approach for the synthesis of silylated N-heterocycles. Triflamide demonstrated the reactivity principally different from that of arenesulfonamides. With silane 1, it afforded the products of iodochlorination and bis(triflamidation) (major), whereas arenesulfonamides gave N-arenesulfonylaziridines in up to 91% yield. Silane 2 with arenesulfonamides yielded the products of mono and bis(iodochlorination), mono and bis(aziridination), and 3,5-diiodo-4,4-dimethyl-1-(arylsulfonyl)-1,4-azasilinanes. By contrast, triflamide, apart from the products of halogenation and iodotriflamidation, unexpectedly gave 3-(trifluoromethylsulfonyl)-5-(triflamido)oxazolidine as the main product. The structure of most heterocyclic products is proved by X-ray analysis. The effect of the silyl group in the substrate and of the substituent in the reagent on the course of oxidative sulfamidation is discussed by comparing with all-carbon analogues.  相似文献   
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