The Modification of Methionine
Roger L. Lundblad in Chemical Reagents for Protein Modification, 2020
The site-specific modification of methionine (Figure 1) in proteins and peptides is somewhat difficult to achieve under relatively mild conditions. Methionine contains a thioether functional group connected to the peptide chain backbone via a relatively hydrophobic two-carbon segment. The sulfur which is present in a thioether linkage is a relatively weak nucleophile and is unprotonated over a wide pH range. As a reflection of the hydrophobic character of methionine, it is generally a “buried” residue as opposed to a “surface” residue. Since the dissociation of a proton from the sulfur nucleophile is unnecessary, relatively specific derivatization by alkylating agents can be accomplished at acidic pH. Indeed, it has been suggested that the selective modification of methionine via alkylation in proteins is possible at low pH as other potential nucleophiles in a protein are unreactive.1
Special Problems with Biological Fluids
Joseph Chamberlain in The Analysis of Drugs in Biological Fluids, 2018
Aromatic amines are hydroxylated to the corresponding hydroxylamino compounds; sulfanilamide is hydroxylated at the N4-amino group to give p-hydroxylaminobenzenesulfonamide (Figure 2.5).166 Tertiary amines may be oxidized to the N-oxide, the main route of metabolism of the benzodiazepine, loprazolam (Figure 2.6).167 Secondary amines are dealkylated to primary amines and the corresponding aldehyde (Figure 2.7). Thioethers are converted by oxidation to sulfoxides, an example being the metabolism of the phenothiazine, quinuclidinyl-3-methyl-10-phenothiazine (Figure 2.8).168,169 Thiones may be oxidized to the corresponding oxo compound as in the metabolism of thiobarbital to barbital (Figure 2.9).170 Metabolism is sometimes reversible as for example in the interconversion of 4-amino-5-chloro-2-[(methylsulfinyl)ethoxy]-N[2-(diethylamino)ethyl]benzamide and its sulfide and sulfone metabolites in rats.171
Use of Biomarkers in Occupational Safety and Health
Anthony P. DeCaprio in Toxicologic Biomarkers, 2006
PAH absorption and uptake has been monitored by several different biomarkers, including urinary metabolites, protein adducts, and DNA adducts. Urinary mutagenicity and urinary thioethers have also been used in studies of workers but, because they are nonspecific indicators of PAH exposure and subject to confounding exposures, they are not suitable for routine biomonitoring (47). The most widely used biomarker of human exposure to PAH is the measurement of urinary 1-hydroxypyrene (1-OHP), a metabolite of pyrene (49). Pyrene is relatively abundant in PAH mixtures and metabolized and excreted as a glucuronide in urine. Half-lives for urinary formation of 1-OHP are relatively long, ranging from 6 to 48 hours, allowing for the collection of spot urine samples at the end of a work shift and end of a work week (47). Other data suggest that a sampling strategy where urine is collected over a 24-hour period gives a better estimate of the relationship between PAH dose and 1-OHP metabolite levels (50,51). In general, published occupational health studies using the urinary 1-OHP marker have used the spot sample protocol and include workers in asphalt paving (52), aluminum smelting (53), coke oven refineries (54), coal tar painting (55), and steel manufacturing (56). In each of these studies, urinary 1-OHP was demonstrated as a useful measure of recent PAH exposure, which had occurred by multiple routes. These studies also demonstrate, however, that cigarette smoking, diet, nonoccupational environmental exposures, and genetic polymorphisms of cytochrome P450 1A1 and glutathione transferases can all affect urinary concentration of 1-OHP.
Bioresponsive albumin-conjugated paclitaxel prodrugs for cancer therapy
Published in Drug Delivery, 2018
Jincheng Yang, Qingzhi Lv, Wei Wei, Zhengtao Yang, Jiajun Dong, Ruoshi Zhang, Qiming Kan, Zhonggui He, Youjun Xu
Cancer is one of the most common life-threatening diseases in the world. Chemotherapy is the first choice for the treatment of most cancers but has some limitations, such as poor bioavailability, rapid blood clearance, non-selectivity, and high toxicity to normal cells and tissues. Drug delivery systems (DDS; Jahangirian et al., 2017; Ramasamy et al., 2017) are designed for improving the therapeutic efficiencies of anticancer drugs. Chemotherapeutic drugs are loaded or covalently conjugated to the delivery systems and expected to release only at specific tumor sites. In DDS, chemotherapeutic agents can be triggered by a unique tumor microenvironment (TME), a low pH value, a high concentration of reactive oxygen species (ROS), or glutathione (GSH), etc. The overproduced GSH creates a strongly reductive environment in tumor cells, for which prodrug, DDS, and disulfide bond strategies have been developed to facilitate an efficient intracellular release of anticancer drugs. The intramolecular disulfide bond is most likely mediated by thiol-disulfide exchange reactions with GSH. Moreover, most cancer cells simultaneously exhibit elevated amounts of ROS and various ROS-responsive DDS have been developed and investigated for therapeutic purposes. The monosulfide/thioether functional groups impart the intracellular ROS-responsiveness. A thioether group can be oxidized to a sulfone to induce ester bond hydrolysis.
Paclitaxel-loaded ROS-responsive nanoparticles for head and neck cancer therapy
Published in Drug Delivery, 2023
Yaqin Tu, Wei Zhang, Guorun Fan, Chenming Zou, Jie Zhang, Nan Wu, Jiahui Ding, Wen Qing Zou, Hongjun Xiao, Songwei Tan
Given the pathological ROS levels in cancer cells, researchers have been increasingly interested in the application of ROS-responsive drug delivery systems for tumor therapy (Saravanakumar et al., 2017; Li et al., 2020; Liang et al., 2021; Mollazadeh et al., 2021). Various ROS-responsive functional groups, such as prodrugs or carriers that have been utilized in the application of smart drug delivery systems, including structures that contain thioketal, thioether, monoselenide/diselenide, telluride, arylboronic ester, aminoacrylate, oligoproline, and peroxalate ester, have been employed in the development of ROS-responsive drug delivery systems (Saravanakumar et al., 2017; Tao & He, 2018). Among them, thioether is a widely used ROS-responsive functional group with broad ROS species responsivity. Its oxidation products are sulfoxide or sulfone; these are much more hydrophobic than the original thioether, inducing a hydrophobic-hydrophobic phase transition of thioether-containing polymers. Moreover, the formation of sulfone promotes the hydrolysis of the proximal ester bond (Luo et al., 2016; Tan et al., 2022). Thus, a ROS-accelerated drug release will be achieved with thioether-based polymers or prodrugs.
Bioactive cyclic molecules and drug design
Published in Expert Opinion on Drug Discovery, 2018
Cysteine residues are rather common in the ribosomal ‘core’ peptide(s) and post-translational modifications that involve Cys residues occur especially frequently in RiPPs. With these, sulfur chemistry converts the thiols of cysteines to disulfides. Examples occur in the ‘final versions’ of conopeptides (multiple Cys-Cys bridges), cyclotides, cyanobactins, lanthipeptides, lasso peptides, sactipeptides, and glycocins. Conversion to a thioether can be seen in the lanthipeptides, sactipeptides, phalloidins, and in some thiopeptides. Conversion to thiazoles and thiazolines can be observed in thiopeptides, cyanobactins, and the unusual bottromycins. The oxidative modification to sulfoxides can be seen in lantipeptides and the amatoxins. Other common features, some mentioned above, are macrocycle formation which can increase metabolic stability and at the same time, decrease the number of conformations that can be assumed. In addition, by substitution at the N and C termini, these modified peptides are significantly less susceptible to protease digestion.
Related Knowledge Centers
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