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High-Performance Liquid Chromatography
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Joel J. Kirschbaum, Adorjan Aszalos
Moxalactam epimers were quantified in body tissues using an octadecylsilane column and a mobile phase of 0.1 M sodium phosphate-methanol (84:16) at pH 3.2 flowing at 2 ml/min into a 254 nm detector. Responses were linear from 0 to 100 μg/ml, with recoveries averaging 98%. The R epimer may have a greater affinity for tissue [275].
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.
On Biocatalysis as Resourceful Methodology for Complex Syntheses: Selective Catalysis, Cascades and Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Andreas Sebastian Klein, Thomas Classen, Jörg Pietruszka
The principle is illustrated on a cascade including three enzymes to produce tetrahydroisoquinolines (20) from inexpensive compounds (see Fig. 21.5). Besides their excellent stereoselectivity, the chemoselectivity of the enzymes is exploited. The enzymes can act within one medium because they are acting on their specific substrate. For instance, the transaminase catalyzes the reductive amination of ketone 16 but does not convert aldehyde 15 despite having the higher carbonyl activity, or the Pictet-Spenglerase uses benzyl aldehyde (19) but not meta-hydroxy benzaldehyde (15). Furthermore, the authors could show that the very last step—the Pictet-Spengler-reaction—could be carried-out using the phosphate buffer rather than the enzyme, which leads to the epimer of the newly formed stereogenic centre. This is a nice example illustrating that the combination of chemical steps and biocatalytical steps is a fruitful expansion of the synthetic methodology.
Frankincense diterpenes as a bio-source for drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Hidayat Hussain, Luay Rashan, Uzma Hassan, Muzaffar Abbas, Faruck L. Hakkim, Ivan R. Green
A prenylaromadendrane-type diterpene core skeleton ‘B’ is the combination of an aromadendrane sesquiterpene (Figure 6; red color) with an attached prenyl group (Figure 6; blue color) via C-15. A prenylaromadendrane-type diterpene named olibanumol D (67) was produce by B. carterii and illustrated inhibitory effects of 35.8% on NO production [85]. In another report, B. carterii also produced another seven prenylaromadendrane-type diterpenes, boscartols A − C (68–70), E (71), F (72), H (73), and I (74). Of note, compound 72 bearing an aldehyde group at the C-20 position, was the most potent and illustrated hepatoprotective activity with a percentage inhibition: 69.6%, which effect was 1.6 times higher than the standard bicyclol (percentage inhibition: 42.5%). In addition, the hepatoprotective activity of compound 71 which has three additional hydroxyl groups (compared to compound 72), was less active than 72 but did demonstrate significant inhibition effects of 36.3% followed by compound 74 with 33.6%. However, these effects were lower than the standard bicyclol (Figure 6). Notably, the position of the double bond at C-17/C-18 slightly decreased activity because diterpene 69 (33.6%) illustrated better effects than compound 68 (26.1%). Additionally, stereochemistry at C-16 plays a role in biological activity because compounds 73 (24.3%) and 74 (33.6%) are epimers [86].
Intra-site differential inhibition of multi-specific enzymes
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mario Cappiello, Francesco Balestri, Roberta Moschini, Umberto Mura, Antonella Del-Corso
Although a “complete” intra-site differential inhibitor as defined above has not as yet been envisaged for AKR1B1, molecules able to differentially inhibit aldoses reduction and/or GSHNE reduction versus HNE reduction have been proposed. The typical basic conditions to illustrate in vitro the differential inhibition of AKR1B1 mimic those occurring in a hyperglycaemic status, with the aldose substrates kept at the mM level, and the toxic aldehydes (i.e., HNE) or their glutathionyl-derivatives (i.e., GSHNE) kept at the µM level. D,L-glyceraldehyde, the most common substrate used in AKR1B1 inhibition studies, was also utilised as a substrate in differential inhibition studies. However, the evidence of incomplete inhibitory action exerted on the enzyme activity by aldose hemiacetals51,52, which cannot take place with a triose, suggested the use of an aldohexose as the substrate. Thus, L-idose, an epimer of D-glucose at C5, with a free aldehyde form approximately 80 times higher than what was observed for glucose, was chosen as elective substrate for inhibition studies53. Finally, the problem of poor solubility of molecules often encountered in inhibition studies of AKR1B1 was overcome by using a proper aqueous cocktail of either methanol or dimethyl sulfoxide, after evaluating the limits of their suitability for the enzyme assay20. In these conditions, supported by kinetic analysis of the inhibitory action towards the different substrates, a number of molecules, coming both from organic synthesis and from natural sources, were identified as having differential inhibitory abilities.
Stereoselective in vitro metabolism of rhynchophylline and isorhynchophylline epimers of Uncaria rhynchophylla in rat liver microsomes
Published in Xenobiotica, 2018
Xin Wang, Zhou Qiao, Jia Liu, Mei Zheng, Wenyuan Liu, Chunyong Wu
RIN and IRN possess the same structural skeleton with four chiral centers at C-3, C-7, C-15 and C-20 positions in the molecules (Figure 1). They are a pair of epimers, differing from each other only in the spatial configuration at C-7. It is well known that the stereochemistry of chiral drugs may result in different pharmacokinetic, pharmacological and toxicological features. Hence, it is important to understand in vivo disposition of each epimeric compound. However, there is hardly any report about stereoselective pharmacokinetics and metabolic processes of TOMAs in UR to date. For IRN, several metabolic studies have been reported (Chen et al. 2014; Wang et al. 2016; Wang et al. 2010b). Wang et al (Wang et al. 2016) systematically identified metabolites of IRN in vivo and in vitro using UPLC/LTQ-Orbitrap-MS. Results revealed that the major metabolic sites of IRN were the positions at C-5 of C-ring and C-15 side chain, and the main metabolic pathways were oxidation, hydroxylation, hydrolysis and dehydrogenation. On the contrary, for RIN, there was a lack of systematic identification of metabolites, and only hydroxylation and glucuronide conjunction at C-10 or C-11 of A-ring were reported (Wang et al. 2010a). In our previous study, we found that after oral administration of individual epimer at equal dosage to rats, the plasma exposure of RIN was significantly higher than that of IRN, indicating that 7 R/7 S epimeric TMOAs may exhibit dissimilar pharmacokinetic behaviors due to the stereo-structures at C-7, and this different in vivo disposition were possibly due to the stereoselective hepatic metabolism (Wang et al. 2017). Collectively, it is well worthy to explore whether the spatial configuration of C-7 would affect hepatic metabolism of TMOAs at adjacent A- and C-ring.