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The Chemical Synthesis of Lipid A
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Shoichi Kusumoto, Koichi Fukase, Masato Oikawa
The anomeric a-configuration is retained in both of them. A malonic acid-type structure [-CH(C02H)2] where two carboxyl groups are located on the same carbon atom is not stable and readily loses one of them as carbon dioxide; the -CH(CH2C02H)2 structure in 23 is the minimum one containing two equivalent carboxyl groups. The distance between acidic moieties and the glucosamine residues are not the same in 23 and 24. Furthermore, fatty acyl groups in these compounds are also different from the natural ones. Therefore, no direct effects of the substitution of the phosphate into carboxylic acid can be discussed. Nevertheless, it was again confirmed that the glycosyl phosphate can be replaced with other acidic group without loss of activity. It should be noted here that oxidation of the aldehyde function in 21 into a carboxyl group gives easy and direct access to carboxymethyl analogs like 24.
Peripheral Mechanisms of Mammalian Sweet Taste
Published in Robert H. Cagan, Neural Mechanisms in Taste, 2020
William Jakinovich, Dorothy Sugarman
Ideally, the structure-activity requirements of sugar taste responses can be studied using methyl glycosides, 1,5 anhydrotols (1-deoxy-sugars), and cyclitols. Unlike the reducing sugars, these compounds do not mutarotate to form a mixture of isomers, but adopt well-defined conformations and configurations.64 Because cyclitol and anhydrotol derivatives are not readily available, the methyl d-glycosides have been used most frequently in monosaccharide structure-activity studies involving gustation. Those methyl glycopyranosides that differ in the orientation of their C-l substituents are known as anomers: the axially oriented substituent is known as a and the equatorially oriented substituent is known as β. Those methyl d-glycopyranosides that differ in orientation at C-2, C-3, C-4, or C-5 are known as epimers.
Developmental Aspects of the Alveolar Epithelium and the Pulmonary Surfactant System
Published in Jacques R. Bourbon, Pulmonary Surfactant: Biochemical, Functional, Regulatory, and Clinical Concepts, 2019
Jacques R. Bourbon, Caroline Fraslon
In a recent study,99 β-D-xyloside, an inhibitor of proteoglycan synthesis, was added to the culture medium of lung primordia explanted from the 16-d-old fetal mouse lung. Compared with control medium or medium containing the inactive α-anomer of the drug, the treated expiants contained fewer specialized cells, especially alveolar type II cells, and accumulated less surfactant. For instance, DSPC accumulation was reduced fourfold on 5 d in vitro. The authors interpreted these results as suggesting that deposition of an extracellular matrix rich in proteoglycans is required to support maturation of the respiratory epithelium.
Advances in biocatalytic and chemoenzymatic synthesis of nucleoside analogues
Published in Expert Opinion on Drug Discovery, 2022
Sebastian C. Cosgrove, Gavin J. Miller
Interestingly, the final isolated yields of the α-d-ribo and α-d-2-deoxyribo 1-phosphates were highest (25% and 27% respectively) when 200 mM nucleoside substrate concentrations were used (with constant 500 mM phosphate) but the observed enzymatic conversion was lower than when using 50 mM substrate concentrations. The ability to effectively perform phosphorolytic anomeric cleavage was strongly dependent on the 2-position ring substituent. After a reaction time of 6 h, α-d-ribose 1-phosphate had formed in 43% yield whilst α-d-2-deoxy-2-fluoro and α-d-2-fluoroarabino 1-phopshates were only observed in 8% and 6% yields, respectively. This indicates that the electron withdrawing capability of fluorine at C2 within such analogues reduces the rate of cleavage, presumably by disfavoring potential buildup of positive charge at the anomeric carbon during phosphorolysis.
Pharmacokinetics, metabolism and off-target effects in the rat of 8-[(1H- benzotriazol-1-yl)amino]octanoic acid, a selective inhibitor of human cytochrome P450 4Z1: β-oxidation as a potential augmenting pathway for inhibition
Published in Xenobiotica, 2021
John P. Kowalski, Robert D. Pelletier, Matthew G. McDonald, Edward J. Kelly, Allan E. Rettie
Analysis of pooled plasma in ESI- mode revealed many of the same metabolites as seen in ESI+ and again, M3 and M9 were majorly represented. As expected, the metabolite profile was increased and totalled 25 between the two modes of ionization, with glucuronide conjugates being newly revealed. M20 at 7.8 min, and M22, denoting the cluster of peaks from 8.3 to 8.6 min, showed fragmentation indicative of acyl-glucuronides. These likely represent a mixture of the 1-β anomer as well as the 2-, 3- and 4-α/β acyl-glucuronide anomers akin to that seen in mouse metabolism of diclofenac (Sarda et al.2012). Furthermore, M21 and M23 were identified as ions with fragmentation indicating that they were acyl-glucuronide structures that had lost their ABT moiety. These metabolites had overlapping retention times with the presumed acyl-glucuronide cluster and therefore may be artifactually generated via in-source fragmentation of M22 or sample work-up. Regardless, acyl-glucuronidation was identified as an additional biotransformation pathway for 8-BOA.
The sialoglycan-Siglec glyco-immune checkpoint – a target for improving innate and adaptive anti-cancer immunity
Published in Expert Opinion on Therapeutic Targets, 2019
Carbohydrates belong to the basic macromolecules of living organisms. While other macromolecules such as DNA and proteins are well characterized due to a broad general availability of analytical methods, carbohydrates and carbohydrate-conjugates (glycans) are much less studied. Glycans are chains of carbohydrates that are attached to proteins or lipids or they can be secreted into the extracellular matrix as long chains of glycosaminoglycans [1,2]. They are diverse structures that are discriminated by the composition, anomeric form, linkage, branching and substitution of their monosaccharides. Attachment of glycans to proteins occurs at the nitrogen of asparagine (N-glycans) or at the oxygen of serine or threonine (O-glycans). Glycans can be used to store energy, as structural basis (glycocalyx) and to store information (glycocode) [3]. Glycans can thereby significantly influence cell–cell interactions by engagement of carbohydrate-binding proteins or lectins. In this review, we summarize the current knowledge of interactions mediated by sialic acid (Sia)-containing glycans (sialoglycans) with a receptor system binding to these sialoglycans, i.e. the Sia-binding immunoglobulin-like lectin (Siglec) family of receptors. We focus on the role of this interaction in anti-cancer immunity and ways how to exploit this interaction for cancer immunotherapy.