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The oligonucleotide therapeutics field has blossomed in recent years, with thirteen approved drugs today and the promise of accelerated growth in coming years. Much of the progress in this field is due to advances in the medicinal chemistry of oligonucleotides,combined with a judicious choice of molecular targets and disease areas. In this perspective, we describe the growth of this new class of drugs highlighting selected milestones in oligonucleotide medicinal chemistry.
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The development of a multigram synthesis of 3-exo-isopropylbicyclo[2.2.1]heptan-2-endo-amine hydrochloride (1) (also known as BRD4780 and AGN-192403) is described. The process involves protection of the amine as 4-nitrobenzyl carbamate, pNZ, which enables chiral SFC chromatography. The absolute configuration (AC) of the individual enantiomers has been determined by Mosher's amide method, VCD spectroscopy, and X-ray crystallography. We highlight the VCD approach as a rapid and effective means of AC determination that can be deployed directly on the target compounds.
Assuntos
Amidas , Dicroísmo Circular , Cristalografia por Raios X , EstereoisomerismoRESUMO
Roasting of Coffea arabica L. seeds gives rise to chemical reactions that produce more than 800 compounds, some being responsible for the desired organoleptic properties for which the beverage called "coffee" is known. In the industry, the "roasting profile," that is, the times and temperatures applied, is key to influence the composition of roasted coffee beans and the flavour of the beverage made from them. The impact of roasting on the chemical composition of coffee has been the subject of numerous studies, including by nuclear magnetic resonance (NMR) spectroscopy. However, the roasting equipment and profiles applied in these studies are often far from real industrial conditions. In this work, the effects of two critical technological parameters of the roasting process, namely, the "development time" (the period of time after the "first crack," a characteristic noise due to seed disruption) and the final roasting temperature on coffee extracts, were investigated. Seeds were roasted at pilot scale according to 13 industrial roasting profiles and extracted in D2 O. The extracts were analysed by 1 H NMR experiments. The NMR spectra were compared using (a) quantitative analysis of main signals by successive orders of magnitude and (b) chemometric tools (principal component analysis, partial least squares and sparse-orthogonal partial least squares analysis). This allowed to identify compounds, which may serve as markers of roasting and showed that changes in chemical composition can be detected even for slight change in final temperature (~1°C) or in total roasting time (~25 s).
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Non-ionic surfactants are commonly used in parenteral protein formulations and include polysorbate 20, polysorbate 80 and poloxamer188. Recently, quantification and characterization of surfactants has generated considerable interest due to their connection to visible particle formation, a critical quality attribute for parenteral formulations. Typically, surfactant quantification is performed by mixed mode chromatography with evaporative light scattering detection (ELSD) or charged aerosol detection (CAD). However, these methods often suffer from loss of specificity in highly concentrated protein formulations. Here we present a mixed mode chromatography method using single quad mass detection, overcoming current limitations for highly concentrated proteins. In addition to content determination of intact surfactants, this method allows to quantify and characterize the predominant degradation patterns of polysorbates within a single measurement. Formulations with up to 200 mg/mL active pharmaceutical product (API) containing surfactant levels between 0.16 and 0.64 mg/mL were tested during method qualification. The obtained results for linearity (r > 0.99), precision (max. 3.8 % RSD) and accuracy (96-116 % recovery) meet current requirements for pharmaceutical products as defined in ICH Q2.