Study on the metabolic mechanism of chiral inversion of <i>S</i>‐Mandelic acid <i>in vitro</i>

Gao, Lingbo; Wang, Jinzhao; Yao, Tong-wei; Zeng, Su

doi:10.1002/chir.21031

Cited by 18 publications

(24 citation statements)

References 21 publications

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“…Flosequinan is a chiral sulfoxide approved as peripheral vasodilator. Several strains of intestinal bacteria can reduce flosequinan to the sulfide, which, when followed by hepatic oxidation, results in flosequinan formation with chirality opposite to the original enantiomer . S‐Oxidation may also contribute indirectly to chiral carbon inversion.…”

Section: Chirality Of Sulfoxidesmentioning

confidence: 99%

Interconnection of sulfides and sulfoxides in medicinal chemistry

Surur

Schulig

Link

2018

Arch. Pharm. Chem. Life Sci.

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Aromatic heterocycles with basic nitrogen atoms as well as carboxylic acid derivatives are the dominating chemical space in the universe of drug-like molecules. These established and exceedingly evaluated structural motifs have to be combined with elements of diversity in order to chart less well-explored galaxies of chemical space and to be able to tackle seemingly undruggable targets. Flat scaffolds should be replaced by shapely molecular cores. In this context, it has been unheeded that phenyl rings in diaryl sulfides are less co-planar than in ethers and that the metabolic interconnection of sulfides and sulfoxides offers advantages that are unalike from the chemistry of amines and N-oxides in the CHN-O world. Moreover, σ-hole potentials increase with the polarizability of the atom N < P < O < S and do not only play a role in long-time overlooked halogen bonds. Examples for λ 2 , λ 4 , and λ 6 S-based functionalities related to improved solubility, reduced drug resistance, linkers in drug conjugates, drugtargeting to parasites, and as basis for drug monitoring in sports are given and discussed. K E Y W O R D Santituberculosis activity, inhibitors, oxidation kinetics, rational drug design, sulfides, sulfoxides Arch Pharm Chem Life Sci. 2019;352:e1800248.wileyonlinelibrary.com/journal/ardp

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Section: Chirality Of Sulfoxidesmentioning

confidence: 99%

Interconnection of sulfides and sulfoxides in medicinal chemistry

Surur

Schulig

Link

2018

Arch. Pharm. Chem. Life Sci.

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“…Animals were euthanized and their kidneys and livers were removed to prepare tissue homogenates. The rat liver homogenate, S9 (containing both cytosolic and microsomal enzymes) was prepared according to the previously published methods (32,33). Briefly, the fresh rat liver was weighed and washed with icecold 0.9% sodium chloride solution.…”

Section: Rat Tissue Preparationmentioning

confidence: 99%

Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs

Moradi

Varamini

Tóth

2015

AAPS J

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Abstract. The enzymatic stability, antitumor activity, and gonadotropin stimulatory effects of glycosylated luteinizing hormone-releasing hormone (LHRH) analogs were investigated in this study. Conjugation of carbohydrate units, including lactose (Lac), glucose (GS), and galactose (Gal) to LHRH peptide protected the peptide from proteolytic degradation and increased the peptides' half-lives in human plasma, rat kidney membrane enzymes, and liver homogenate markedly. Among all seven modified analogs, compound 1 (]LHRH) and compound 6 (GS 4 -[w 6 ]LHRH) were stable in human plasma during 4 h of experiment. The half-lives of compounds 1 and 6 improved significantly in kidney membrane enzymes (from 3 min for LHRH to 68 and 103 min, respectively). The major cleavage sites for most of the glycosylated compounds were found to be at Trp ]LHRH) stimulated the release of follicle-stimulating hormone (FSH) at 5 nM concentration in dispersed rat pituitary cells (p<0.05). In our studies, compound 1-bearing lactose and D-Trp was the most stable and active and is a promising candidate for future preclinical investigations in terms of in vitro biological activity and metabolic stability.

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“…5 Because chiral drugs exist in racemic reaction in vitro and in vivo, homochiral drugs are being used in clinical treatment. A lot of research has focused on exploiting effective methods to distinguish chiral isomers . The development of the stereoisomer separation method has made a great contribution to the routine detection of pure enantiomers, intermediates in the process of preparation, and metabolites in humans.…”

Section: Introductionmentioning

confidence: 99%

Chiral detection of entecavir stereoisomeric impurities through coordination with R‐besivance and Zn^II using mass spectrometry

Wang

Chen

et al. 2018

J Mass Spectrom

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In this study, a mass spectrometry (MS)-based kinetic method (KM) is shown to be successful at analyzing a multichiral center drug stereoisomer, entecavir (ETV), both qualitatively and quantitatively. On the basis of the KM, the bivalent complex ion [M (A)(ref*) ] (M = divalent metal ion, A = analyte, and ref* = chiral reference) was set as precursor ion in MS/MS. The experiment results suggest strong chiral selectivity between ETV and its isomers when using Zn coordinated with the chiral reference R-besivance (R-B). The logarithm of the fragment ion abundance ratio and the enantiomeric percentage (%) exhibits a strong linear relation because of the competitive loss of the reference and analyte. The product ion pair [Zn (R-B)A-H] (m/z 733) and [Zn (R-B) -H] (m/z 849), together with [R-B + H] (m/z 394) and [A + H] (m/z 278), can realize the identification of ETV and all of its chiral isomers. Theoretical calculation were also performed using the B3LYP functional with the 6-31G* and LanL2DZ basis set to clarify the mechanism of structural difference of these bivalent complex ions. The results reveal that MS-KM can be used to detect optical impurities without a chiral chromatographic column and fussy sample pretreatment. The established method has been used to determine stereoisomeric impurities of less than 0.1% in ETV crude drug, a demonstration of its simple and effective nature for rapid detection of stereoisomeric impurities.

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Study on the metabolic mechanism of chiral inversion of S‐Mandelic acid in vitro

Cited by 18 publications

References 21 publications

Interconnection of sulfides and sulfoxides in medicinal chemistry

Interconnection of sulfides and sulfoxides in medicinal chemistry

Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs

Chiral detection of entecavir stereoisomeric impurities through coordination with R‐besivance and Zn^II using mass spectrometry

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Study on the metabolic mechanism of chiral inversion of S‐Mandelic acid in vitro

Cited by 18 publications

References 21 publications

Interconnection of sulfides and sulfoxides in medicinal chemistry

Interconnection of sulfides and sulfoxides in medicinal chemistry

Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs

Chiral detection of entecavir stereoisomeric impurities through coordination with R‐besivance and ZnII using mass spectrometry

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Chiral detection of entecavir stereoisomeric impurities through coordination with R‐besivance and Zn^II using mass spectrometry