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The Modification of Methionine
Published in Roger L. Lundblad, 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
Hepatotoxic and Hepatocarcinogenic Effects of Chlorinated Ethylenes*
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Jeffrey L. Larson, Richard J. Bull
A minor pathway of metabolism of the chlorinated ethylenes is via direct conjugation of glutathione with the chlorinated ethylene (Dekant et al., 1986a; Dekant et al., 1986b). This glutathione-substituted ethylene is further metabolized to the cysteine-ethylene conjugate by the enzymes of mercapturic acid biosynthesis in the renal tubules, yielding the cysteine-ethylene conjugate (Dekant et al., 1987). This metabolite is postulated fb be responsible for the necrosis and induction of tumors in the kidney by TCE and PCE (Dekant et al., 1986a; Dekant et al., 1986b). The cysteine thioether may be acetylated to the mercapturic acid and excreted in the urine in a nontoxic pathway, but it is also a substrate for B-lyase which cleaves the thioether to pyruvate, ammonia, and a reactive, mutagenic fragment (Dekant et al., 1986c). The cysteine conjugate has been demonstrated to be toxic and mutagenic only upon further metabolism of the conjugates by renal B-lyase. Elfarra et al. (1986) and Dekant et al. (1986c) both demonstrated that the toxicity of the cysteine-ethylene conjugates could be prevented by either inhibitors of gamma glutamyl transpeptidase, the renal organic ion transport system or cysteine-conjugate B-lyase. The investigators conclude that the potential for damage is limited to the kidney due to the localization of the enzymes necessary to convert the conjugate to the toxic form.
Reactivities of Amino Acids and Proteins with Iodine
Published in Erwin Regoeczi, Iodine-Labeled Plasma Proteins, 2019
Compounds in which two carbon atoms are connected to a single oxygen are ethers. Their sulfur analogues, containing a sulfur atom in place of the oxygen, are known as organic sulfides or thioethers. This structure occurs in one of the essential amino acids, methionine α-amino-γ-methylmercaptobutyric acid):
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.
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.
How do we address neglected sulfur pharmacophores in drug discovery?
Published in Expert Opinion on Drug Discovery, 2021
Michael J. Tilby, Michael C. Willis
Given the prevalence of sulfonamides in known medicines, as well as their ease of preparation, it is not surprising that many drug discovery programmes are still drawn to this functional group [3]. Nonetheless, several other sulfur functional groups are also straightforward to prepare, and have been integrated into numerous drug molecules. In particular, the role of thioethers (B) and sulfoxides (C; see Omeprazole 3) as pharmacophores has been examined in detail [4]. In contrast, there are fewer synthetic routes to sulfamates (D) [5], and sulfamides (E) [6]. However, these groups still feature in blockbuster drugs such as topiramate (4) and macitentan (5).