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Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sergio González-Granda, Vicente Gotor-Fernández
Bufuralol is a potent β-adrenergic receptor antagonist applied in the treatment of hypertension, the activity of the (S)-enantiomer being 100 times higher than its enantiomer. The resolution of racemic 2-bromo-1-(7-ethylbenzofuran-2-yl)ethanol led to the (R)-alcohol and a series of (S)-esters depending on the acyl donor used in the lipase-catalysed KR (Scheme 9.32), finding practical conditions for the acylation catalysed of 1 g of substrate (Nagy et al., 2014). CAL-B and 2 equiv. of vinyl dodecanoate in toluene after 16 h at room temperature provided an efficient access to both alcohol and ester in enantiopure form, which served for the chemoenzymatic synthesis of Bufuralol enantiomers. Starting from the chlorinated analogue the KR is also feasible (Hull et al., 2003), and interestingly the DKR was also effectively performed using PSL, 1.5 equiv. of isopropenyl acetate and chlorodicarbonyl(1,2,3,4,5-pentphenylcyclopentadienyl)ruthenium (II) at 40°C for 24 h (Johnston et al., 2010), yielding the enantiopure (R)-acetate in 96% yield (Scheme 9.33). Lipase-catalysed KR and DKR of 2-halo-1-(7-ethylbenzofuran-2-yl)ethanols for the chemoenzymatic synthesis of Bufuralol enantiomers.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Bufuralol, a β-adrenoceptor blocker, has been extensively used as a probe substrate for the in vitro study of CYP2D6 (Dayer et al. 1984; Gut et al. 1984, 1986; Minder et al. 1984). Bufuralol is metabolized to three metabolites, namely, 1′-hydroxybufuralol, 1′-oxobufuralol, and 1′2′-ethenylbufuralol (Figure 3.64) (Hiroi et al. 2002). 1′2′-Ethenylbufuralol is considered to be formed both from bufuralol by ethenylation and from 1′-hydroxybufuralol by dehydration. 1′2′-Ethenylbufuralol formation from bufuralol has been demonstrated to be mediated by CYP2D6 (Hanna et al. 2001). The level of 1′-hydroxybufuralol, a major metabolite of bufuralol, is often measured as an index of CYP2D6 activity or levels, and the amount of 1′-hydroxybufuralol formed from bufuralol is known to be small in CYP2D6-deficient metabolizers (Carcillo et al. 2003). However, bufuralol, but not sparteine and debrisoquine, is also extensively metabolized by CYP2C19 (Mankowski 1999) and, to a lesser extent, by 1A2 (Yamazaki et al. 1994), and this may affect its specificity as a prototypical substrate of CYP2D6.
Pirfenidone 5-hydroxylation is mainly catalysed by CYP1A2 and partly catalysed by CYP2C19 and CYP2D6 in the human liver
Published in Xenobiotica, 2021
Yongjie Zhang, Rei Sato, Tatsuki Fukami, Masataka Nakano, Miki Nakajima
The bufuralol 1′-hydroxylase activities of HLM from different donors were determined based on CYP2D6 marker activity. Bufuralol at 1 µM was incubated with 0.5 mg/mL HLM in 100 mM Kpi buffer (pH 7.4) containing 5 mM MgCl2. The concentration of bufuralol was determined by referring to previous reports (Yamazaki et al. 1994; Nakajima et al. 1999). After 3 min of preincubation at 37 °C, reactions were initiated by adding NRS. After 20 min, reactions were terminated by adding an equal volume of ice-cold acetonitrile. The incubation time was determined in the linear range. After centrifugation at 20,380 g for 5 min at 4 °C, the supernatants were subjected to LC-MS/MS. The conditions for LC-MS/MS analysis were the same as those described for phenacetin O-deethylation, and the m/z values were set at 278.35 and 186.05 for 1′-hydroxylbufuralol.
Development and validation of probe drug cocktails for the characterization of CYP450-mediated metabolism by human heart microsomes
Published in Xenobiotica, 2019
Jade Huguet, Fleur Gaudette, Veronique Michaud, Jacques Turgeon
The final concentration of organic solvent in each incubation was set to a maximum of 0.5% to avoid possible solvent inhibitory effects (Easterbrook et al., 2001). Ebastine, midazolam and chlorzoxazone were prepared in methanol and 2.5 µl was added to the incubation (all three substrates were prepared in the same methanol solution when used in cocktail #1). Bupropion and bufuralol were dissolved in 0.1 N HCl (10 µl was added to the incubation). Tolbutamide was prepared in 0.1 N NaOH (10 µl added to the incubation). 7-Ethoxyresorufin, repaglinide and dodecanoic acid were solubilized in DMSO (2.5 µl per incubation). Ebastine, chlorzoxazone and midazolam were prepared at concentrations of 500 µM, 200 mM and 3 mM, respectively. Bupropion, bufuralol, 7-ethoxyresorufin, repaglinide, dodecanoic acid and tolbutamide were prepared at concentrations of 38.75, 2.5, 1, 3.4, 5.0 and 62.5 mM, respectively. Serial dilutions were performed to dilute each substrate to cover a range of 0.15, 0.25, 0.5, 0.75, 1, 2, 3 and 5 times their previously reported respective Km values; ebastine = 0.5 µM, bupropion = 155 µM, repaglinide = 3.4 µM, bufuralol = 10 µM, 7-ethoxyresorufin = 1 µM, midazolam = 3 µM, tolbutamide = 105 µM, chlorzoxazone = 200 µM and dodecanoic acid = 5 µM (data not shown).