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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
Another synthesis was based on the asymmetric dihydroxylation of α,β-unsaturated acid t-butyl ester. This procedure presents a direct access to optically pure 3-acyloxy fatty acids occurring in many natural lipid As (18).
Environmental Toxins and Chronic Illness
Published in Aruna Bakhru, Nutrition and Integrative Medicine, 2018
Additional ways that gut microflora can affect detoxification were discussed by Swanson (2015). Gut microbiota can affect expression of phase I and II enzymes in ways that either metabolically activate or inactivate drugs through processes that involve reduction, hydrolysis, dihydroxylation, acetylation, deacetylation, proteolysis, deconjugation, and deglycosylation. An example of this has been seen with sulfalzine, which is used to treat gut inflammation. Microbial enzymes in the gut will convert it to its pharmacologically active form, 5-amino 5-salicyclic acid. Concerning xenobiotics, the organism Desulfovibrio desulfuricans has been reported to participate in the metabolism of arsenic by producing hydrogen sulfide (H2S) that converts monomethylarsonic acid to monomethyl monothioarsonate, a more toxic form of arsenic. Finally, another xenobiotic example is hydrazine, which has been used, along with its derivatives, as a rocket propellant and as a constituent of several industrial processes and agricultural chemicals. Gut microflora can significantly reduce the toxicity of this substance.
Biocatalysts: The Different Classes and Applications for Synthesis of APIs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
An overview of chemoenzymatic routes to oseltamivir was given by Werner et al. (2011), who rely in part on using cyclohexadiene-cis-diol, derived enzymatically from benzene derivatives, using a toluene dioxygenase (Sullivan et al., 2009; see also Semak et al., 2012). The total synthesis requires 10 steps involving apart from the toluene DO-mediated dihydroxylation, a hetero-Diels–Alder cycloaddition, and the generation of C4 acetamido functionality. Oseltamivir—sold under the brand name Tamiflu—is an antiviral neuraminidase inhibitor used to treat or to prevent (primary or secondary prophylaxis) influenza A and influenza B. The benefit of this drug, however, is controversial; due to a Cochrane review (Jefferson et al., 2014), oseltamivir in the treatment of adults reduced the time to first alleviation of symptoms from 7 days to just 6.3 days compared with the control group and there was no difference in rates of admission to hospital. Vomiting, diarrhea and headache are common side effects. Similar results have been obtained for Zanamivir (Heneghan et al., 2014). According to a meta-analysis published in The Lancet (Dobson et al., 2015) with data from 4328 patients, the time to alleviation of all symptoms for oseltamivir versus placebo recipients is reduced from 122·7 to 97.5 h, and fewer lower respiratory tract complications requiring antibiotics were noted. A recent summary of the debate concerning the use of Oseltamivir for treating seasonal and pandemic influenza has been provided by Hurt and Kelly (2016).
Comparative metabolism of THCA and THCV using UHPLC-Q-Exactive Orbitrap-MS
Published in Xenobiotica, 2023
Qianru Rao, Ting Zhang, Qian-Lun Pu, Bin Li, Qi Zhao, Dong-Mei Yan, Zhanxuan E. Wu, Fei Li
The chemical formulas of metabolites A2–A6 were C22H30O5 according to the observed [M + H]+ at m/z 375.2148+ to 375.2163+. A2–A6 were the isomers and were eluted successively from 5.91 to 8.76 min. The diagnostic product ion at m/z 357 was detected by the loss of 18 Da, suggesting that a molecule of H2O was lost from a protonated molecular ion. The possible positions of the oxidation reaction for five metabolites (A2–A6) may occur at 4′, 2′, 5′, 11, and an unidentified position, respectively. Similarly, metabolites V3 and V4 were observed in the extracted chromatogram from m/z 303.1956+ and 303.1950+, which were 18 Da (1 H2O) higher than that of THCV, indicating that these metabolites were the hydroxylated products of THCV. The formation of A7–A8 and V3–V4 indicated that they were produced in the metabolism of THCA and THCV, respectively. Those metabolites were 32 Da (two oxygen atoms) higher than the parent structure (Supplemental Figures 3 and 4), which implied that the positions of dihydroxylation might happen to alkyl side chain or C-11.
Metabolism and disposition of 2-hydroxy-4-methoxybenzophenone, a sunscreen ingredient, in Harlan Sprague Dawley rats and B6C3F1/N mice; a species and route comparison
Published in Xenobiotica, 2020
Esra Mutlu, C. Edwin Garner, Christopher J. Wegerski, Jacob D. McDonald, Barry S. McIntyre, Melanie Doyle-Eisele, Suramya Waidyanatha
While the presence of 2,5-DHMB was reported following incubation of HMB with rat and liver microsomes (Kamikyouden et al., 2013), to the best of our knowledge, this is the first investigation reporting the detection of ring dihydroxylated metabolites of HMB (2,3-, 2,5- and 2,6-DHMB) in rodents. These metabolites, present as glucuronides and sulfate conjugates, were not readily detected in radiochromatograms but were detected by MS. Following deconjugation of rodent urine via acid hydrolysis or with β-glucuronidase or β-glucuronidase/sulfatase preparations, three DHMB isomer peaks observed. While one of the three peaks determined to be 2,5-DHMB, the other two peaks were tentatively assigned as 2,3- and 2,6-DHMB. Presence of 2,2′-DHMB, where dihydroxylation is in opposite rings, has been reported previously (Jeon et al., 2008; Okereke et al., 1993; Okereke & Abdel-Rhaman, 1994) although we did not find this metabolite in urine from HMB-exposed animals.
Metabolic map of osthole and its effect on lipids
Published in Xenobiotica, 2018
Qi Zhao, Xin-Mei Li, Hong-Ning Liu, Frank J. Gonzalez, Fei Li
Neutral losses of 72 (C4H8O or H2O + C4H6) or 60 (H2O + C3H6) suggested the existence of a hydroxylated 3-methyl-2-butenyl group in metabolites M4, M8, M9, M9′, M10, M11, and M13. Metabolite M4 was calculated as C15H16O4 based on the accurate mass of m/z 261.1131+, and higher by 16 Da (O) than osthole, indicating that it was the carbon chain hydroxylation product of osthole based on the MS/MS fragmentations (Table S1). Metabolite M13 was deduced as C14H16O4 based on the accurate mass measurement m/z 249.1137+, indicating that it was the 7-demethylation and hydrogenation product of M4 based on the MS/MS fragmentations in Table S1. Metabolites M8, M9, M9′, M10, and M11 were deduced as C15H16O5, and higher by 32 Da (O2) than osthole, indicating they were the dihydroxylation product of osthole. The other MS/MS fragmental ions of M8, M9, M9′, M10, and M11 were interpreted in Table S1.