Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
In the previous section, the action of water as nucleophile in hydrolytic reactions of different organic compounds have been illustrated, here the role of other nucleophiles will be deeply analysed. For instance, the esterification of carboxylic acids with alcohols is well known, and this has allowed the formation of esters in non-selective and selective fashions. For instance, the reaction of substituted benzoic acids with alcohols and (N,N)-disubstituted amino alcohols has allowed the synthesis of interesting alkyl esters, some of them key intermediates in the synthesis of benzocaine, chloroprocaine and procaine anaesthetics (Giunta et al., 2013). The reaction with CAL-B and equimolecular amounts of a determined (amino) alcohol led to complete conversions in many cases by using cyclohexane as solvent, yielding the desired esters in quantitative yields after a simple work-up by filtration and solvent distillation (Scheme 9.19). Esterification of benzoic acids with alcohols in the presence of CAL-B.
Substrates of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
A study using human liver microsomes indicated that CYP2D6 and 3A4 are able to metabolize emetine to cephaeline (both are alkaloids from ipecac) and 9-O-demethylemetine, and CYP3A4 also participated in metabolizing emetine to 10-O-demethylemetine (Asano et al. 2001). The CYP2D6 enzyme also has high affinity for toxic plant alkaloids such as lasiocarpine and monocrotaline, both pyrrolizidine alkaloids (Wolff et al. 1985, 1987). Pyrrolizidine alkaloids are found in plants growing in most environments and all parts of the world. They have long been known to be a health hazard for livestock, wildlife, and humans (Stegelmeier et al. 1999). Plants known or suspected to contain toxic alkaloids are widely used for medicinal purposes as home remedies all over the world, without systematic testing for safety (Roeder 2000). Most pyrrolizidine alkaloids are hepatotoxic (Liddell 2001). The following are the major metabolic pathways of unsaturated pyrrolizidine alkaloids such as lasiocarpine in animals (Figures 3.112 and 3.113) (Cheeke 1988; Fu et al. 2004; Liddell 2001): (a) hydrolysis of the ester groups, (b) N-oxidation, and (c) dehydrogenation of the pyrrolizidine nucleus to dehydro-alkaloids (pyrrolic derivatives). Routes a and b are believed to be detoxification mechanisms, while route c leads to toxic metabolites capable of binding DNA and proteins and appears to be the major activation mechanism (Fu et al. 2004; Zhou et al. 2007). Both lasiocarpine and monocrotaline are procar-cinogens that are bioactivated by P450s to carcinogens (Xia et al. 2006).
Functional Study of Lysosomal Nutrient Transporters
Bruno Gasnier, Michael X. Zhu in Ion and Molecule Transport in Lysosomes, 2020
As with subcellular fractions, each amino acid ester should be individually tested in a dose-response curve, starting with the simple methyl ester and extending to other alcohol derivatives if necessary. An additional complexity with live cells compared with cell fractions arises from the competition between ester cleavage in the cytoplasm and ester entry in intact form into lysosomes. High ester concentrations favour the latter process. The distribution of TFEB is a good readout to perform these preliminary experiments. TFEB distribution can be assessed either by expressing a tagged recombinant construct or by analyzing the endogenous protein with an antibody. Ester treatments inducing ~30% nuclear translocation provide a good starting point to detect with good sensitivity both decreases and increases in lysosomal overload upon transporter expression. Optimal working concentrations for 11 amino acid esters applied for 2 h to HeLa cells are provided in our study of the transporter SNAT7 (Verdon et al., 2017).
The influence of physicochemical properties on the reactivity and stability of acyl glucuronides†
Published in Xenobiotica, 2018
Patrick Camilleri, Akshay Buch, Brandi Soldo, Andrew J. Hutt
The presence of a carboxylic acid functionality in a molecule, whether a xenobiotic or an endogenous compound, gives rise to the formation of reactive acyl glucuronide metabolites formed via conjugation mediated by the multiple glucuronosyl transferases (UGTs). The reaction involves the transfer of the glucuronic acid moiety of uridine diphosphate glucuronic acid (UDPGA) to the carboxylic functionality to yield the 1-O-acyl-β-d-glucuronide. In effect this is an enzymatically driven esterification reaction. An alternative metabolic pathway available to the carboxyl moiety, which may give rise to chemically or biochemically reactive intermediates, involves the formation of coenzyme-A thioesters which are significant in the metabolism of both xenobiotic acids and in intermediary metabolism. Coenzyme A formation is the initial step in the formation of amino acid conjugates, and also involved in carbon chain elongation, conjugation with steroids and formation of hybrid triglycerides (Darnell & Weidolf, 2013; Hutt & Caldwell, 1990; Knights et al., 2007; Lassila et al., 2015; Steventon & Hutt, 2002).
Liver-targeted delivery of asiatic acid nanostructured lipid carrier for the treatment of liver fibrosis
Published in Drug Delivery, 2021
Ya-Wen Zhang, Ling-Lan Tu, Yi Zhang, Jie-Chao Pan, Gao-Li Zheng, Li-Na Yin
Figure 1(B) shows the spectra of the structures of intermediate and final products verified by 1H NMR. The signals at δ 4.54–4.64 ppm in Figure 1(B) (a) were attributed to the hydrogen attached to the acetoxy group of UA. No signal peaks were observed between δ 3.87 and 4.45 (the two hydroxyl groups of UA) (Zhang et al., 2019), demonstrating the acetylation of the carboxyl group on UA. The carboxyl active hydrogen of acetyl ursodeoxycholic acid (Figure 1(B) (a)) was δ 11.96 ppm; however, the peak disappeared (Figure 1(B) (b)), indicating complete esterification of the carboxyl group on UA. Additionally, two strong hydrogen signal peaks occurred at δ 3.51 and 1.23 ppm (hydrogen of polyethylene glycol and stearic acid, respectively (Figure 1(B) (b)); however, no other active hydrogen signals were reported, which demonstrate successful esterification of the target product UA-PEG-SA.
Discovery of 3,6-disubstituted pyridazines as a novel class of anticancer agents targeting cyclin-dependent kinase 2: synthesis, biological evaluation and in silico insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Ahmed Sabt, Wagdy M. Eldehna, Tarfah Al-Warhi, Ohoud J. Alotaibi, Mahmoud M. Elaasser, Howayda Suliman, Hatem A. Abdel-Aziz
The target 5-(trifluoromethyl)pyridazine-3-carboxamide derivatives (11a–r) were prepared through several synthetic steps (Schemes 1–3) starting from the commercially available ethyl 3,3,3-trifluoropyruvate. With respect to Scheme 1, ethyl trifluoropyruvate (1) reacted with acetone in the existence of L-proline and DMF following a reported method31 to yield ethyl 2-hydroxy-4-oxo-2-(trifluoromethyl)pentanoate (2), the later compound was converted into 6-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (3) upon reaction with hydrazine hydrate in the existence of acetic acid32. Compound (3) was then subjected to oxidation process using potassium chromate and sulphuric acid at room temperature to give 6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-3-carboxylic acid (4). Fischer esterification was then carried out for compound (4) through reflux with ethanol in the presence of sulphuric acid (catalytic amount) in order to afford the corresponding ester derivative (5), Scheme 1.
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