Biocatalysts: The Different Classes and Applications for Synthesis of APIs
Peter Grunwald in 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).
The Chemical Synthesis of Lipid A
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
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).
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.
Comprehensive metabolism study of swertiamarin in rats using ultra high-performance liquid chromatography coupled with Quadrupole-Exactive Orbitrap mass spectrometry
Published in Xenobiotica, 2021
Beibei Ma, Tianyu Lou, Tingting Wang, Ruiji Li, Jinhui Liu, Shangyue Yu, Yudong Guo, Zhibin Wang, Jing Wang
The retention time of metabolites M14, M16, and M23 was 4.29 min, 4.58 min, and 4.93 min, respectively, which were 16 Da higher than that of gentianine. They showed the same molecular ion at m/z 192.06558 (C10H10O3N, error≤ ±2.50 ppm) and exhibited the NLF of 18 Da (m/z 162 → m/z 144) in their ESI-MS2 spectra, which meant the existence of hydroxyl group. Therefore, M14, M16, and M23 could be reasonably inferred as hydroxylated products of gentianine and were positional isomers. Similar to the above statement, metabolites M6, M8, and M13 were eluted at 3.09 min, 3.42 min, and 4.29 min, respectively, and the same [M–H]– ion was produced at m/z 206.04473 (C10H8O4N, error≤ ±2.00 ppm) in the negative ion mode, which was 32 Da higher than gentianine. Moreover, the formation of characteristic ions such as m/z 206, m/z 162, m/z 134, and m/z 118 argued that the three metabolites were dihydroxylation products of gentianine. With reference to the identification process of M13 and M14, M2 and M4, which brought out the identical [M–H]– ion at m/z 222.03963 (C10H8O5N, error≤ ±2.00 ppm), were diagnosed as the trihydroxylation products of gentianine.
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.
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