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The Modification of Cystine — Cleavage of Disulfide Bonds
Published in Roger L. Lundblad, Chemical Reagents for Protein Modification, 2020
In most proteins, the free sulfhydryl groups (cysteine) derived from the reduction of cystine will, at alkaline pH, fairly rapidly undergo reoxidation to form the original disulfide bonds. This process can be accelerated by the sulfhydryl-disulfide interchange enzyme6,7 or sulfhydryl oxidase.8 Thus, it is necessary to “block” the new sulfhydryl groups by alkylation, arylation or reaction with dithionite (see Chapter 6).
Biochemical Methods of Studying Hepatotoxicity
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Prasada Rao S. Kodavanti, Harihara M. Mehendale
There are several excellent reviews regarding the formation and detoxification of reactive metabolites and their interaction with hepatic constituents (Mitchell and Jollow, 1975; Mazel and Pessayre, 1976; Gillette, 1977; Mitchell and Boyd, 1978; Sipes and Gandolfi, 1982; Mitchell et al., 1984; Cheesman et al., 1985). However, a detailed discussion will be beyond the scope of this chapter. One important aspect is that hepatotoxicity need not be correlated with pharmacokinetics of the parent substance or even its major metabolites, but may be correlated with the formation of quantitatively minor, highly reactive intermediates (Mitchell and Boyd, 1978). However, there are several factors such as glutathione, epoxide hydrolase, and glutathione-s-transferase that play a significant role in preventing covalent binding of reactive intermediates to some extent. When low doses of acetaminophen (Mitchell et al., 1976) or bromobenzene (Jollow et al., 1974) are administered, the toxic metabolite combines with glutathione, thereby preventing arylation of macromolecules and necrosis. As the dose is increased, availability of glutathione is decreased and a sharp increase in covalent binding occurs at a threshold dose, eventually leading to cell necrosis.
Total Synthesis of Some Important Natural Products from Brazilian Flora
Published in Luzia Valentina Modolo, Mary Ann Foglio, Brazilian Medicinal Plants, 2019
Leonardo da Silva Neto, Breno Germano de Freitas Oliveira, Wellington Alves de Barros, Rosemeire Brondi Alves, Adão Aparecido Sabino, Ângelo de Fátima
Robustic acid (3; Figure 12.2) is a pyranocoumarin that was first isolated from Derris robusta (Fabaceae), an Indian tree, by Harper (1942), and only after approximately 20 years was its chemical structure elucidated by Johnson and Pelter (1964). In 2001, researchers also isolated this coumarin from petrol and dichloromethane extracts of Deguelia hatschbachii (Fabaceae), roots, a Brazilian native species (Magalhães et al., 2001). Donnelly et al. (1995) reported a total synthesis of robustic acid from methyl 2,4,6-trihydroxyphenyl ketone in nine steps and an 18% overall yield (Figure 12.2). In this study, the authors employed the Claisen reaction followed by an intramolecular transesterification to construct the pyrone-phenyl system of compound 5. A regioselective arylation reaction was employed using an appropriate aryl lead triacetate, in part inspired from earlier work (Barton et al., 1989; Donnelly et al., 1993). Using this methodology in the final step, Donnelly et al. were able to prepare robustic acid, a 3-aryl-pyranocoumarin derivative.
Transition metal-catalysed A-ring C–H activations and C(sp2)–C(sp2) couplings in the 13α-oestrone series and in vitro evaluation of antiproliferative properties
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Péter Traj, Ali Hazhmat Abdolkhaliq, Anett Németh, Sámuel Trisztán Dajcs, Ferenc Tömösi, Tea Lanisnik-Rizner, István Zupkó, Erzsébet Mernyák
Phenylations of natural or 13α-oestrone derivatives at C-2 were earlier carried out via Pd-catalysed cross-coupling reactions of steroidal aryl halides with boronic acid reagents17,34,35. However, this strategy requires multiple steps and prefunctionalisation of the reagents. An alternative methodology, based on C–H activation, might circumvent the inconveniences of cross-coupling reactions, such as halogenation of the substrates and the use of organometallic nucleophilic coupling partners. Regioselective C–H bond arylation of 3-carbamoylestrone with aryl iodides was described by Bedford et al.36 In this transformation, Pd(OAc)2 was used as a catalyst, AgOAc as a base in TFA solvent, and the mixture was stirred at 60 °C for 18 h. Arylation occurred at the C-2 ortho-position owing to the directing ability of the carbamate group. The removal of the DG was achieved in a subsequent step, by treatment with LiAlH4 followed by acidic hydrolysis. Note that not only 3-carbamoylestrone, but its 3-pivaloyl derivative also proved to be suitable for the regioselective arylation via C–H activation. Palladium-catalysed transformation of oestrone pivalate with the appropriate hypervalent iodonium salt gave the 2-tolyl derivative37. The reaction mixture was stirred at room temperature for 24 h.
Metabolomic analysis of acetaminophen induced subclinical liver injury
Published in Clinical Toxicology, 2020
Michael Ganetsky, Anders H. Berg, Joshua J. Solano, Steven D. Salhanick
Mitochondrial dysfunction secondary to injury has been well described as crucial in the initiation of APAP induced liver injury. The likely mechanism for early mitochondrial injury is direct arylation of mitochondrial proteins leading to inhibition of respiration [24]. Drug-induced liver injury, including acetaminophen induced liver injury, is associated with disturbances in mitochondrial fatty acid β-oxidation [25]. Inhibition of fatty acid β-oxidation by APAP has been shown in animal models of APAP toxicity. In mice given toxic APAP doses, there is an early rise in acylcarnitine levels, followed by a delayed decrease below baseline levels, that correlates with ALT elevation [26]. In CYP2E1-null mice, there is reversible inhibition of β-oxidation but irreversible inhibition in wild type mice [27]. Inhibition may be due to direct mitochondrial damage or may be due to suppression of peroxise proliferator-activated receptor α (PPARα) regulated pathways. PPARα controls the expression of genes encoding peroxisomal and mitochondrial fatty acid β-oxidation enzymes; PPARα-humanized mice are protected from APAP toxicity felt to be from induction of a gene encoding mitochondrial uncoupling protein 2 (UCP2) which protects against reactive oxygen species generated during drug-induced hepatotoxicity [28].
An overview of late-stage functionalization in today’s drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Michael Moir, Jonathan J. Danon, Tristan A. Reekie, Michael Kassiou
Biaryl motifs are ubiquitous in pharmaceutically relevant compounds. Traditional cross-coupling methods have made the synthesis of biaryl units viable; however a more attractive approach would be C–H arylation. Generally however, such C–H functionalization methods do not tolerate the polar and reactive functionalities that tend to decorate pharmaceuticals. Simonetti and coworkers have developed a cyclometallated ruthenium catalyst which enables the arylation of densely functionalized molecules (Figure 4(b)) [45]. A mechanistic investigation revealed the Ru(II) catalyzed C–H arylation of directing-group containing arenes and aryl halides relied on the formation of bis-cycloruthenated species as the key intermediate required for oxidative addition. The authors demonstrate the utility of the reaction on a range of (hetero)aromatic compounds with an sp2 nitrogen (such as sulfaphenazole) suitable for cyclometallation and for (hetero)aromatic (pseudo)halides with biological activity.