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The Role of Plant-Based Natural Compounds in Inflammation
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Marcela Dvorakova, Premysl Landa, Lenka Langhansova
5-LOX inhibitory activity of ethanolic whole plant extracts of four Chinese medicinal plant herbs (Saposhnikovia divaricata (Turcz.) Schischk, Smilax glabra Roxb., Pueraria montana var. lobata (Willd) Sanjappa et Pradeep, and Carthamus tinctorius L., and their components were studied. All extracts exerted interesting 5-LOX inhibition with IC50 values of 0.08–0.66 µg/µL. From their components, the lowest—though moderate—IC50 values were demonstrated by daidzin (4.32 µM), followed by daidzein (6.65 µM), 3’-hydroxypuerarin (7.36 µM), sec-O-glucosylhamaudol (7.45 µM) and astilbin (8.45 µM). The importance of the presence of the vicinal hydroxyl groups for the activity was clearly shown in puerarin compounds, as the lack of 3’-hydroxy group on puerarin moiety led to the attenuation of the inhibitory activity (IC50 = 25.8 µM), while the methylation of 3’-hydroxy group to afford 3’-methoxypuerarin caused complete inactivity (Zhao et al., 2016).
Role of Metabolism in Chemically Induced Nephrotoxicity
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
In addition to mercapturate formation and metabolism of the cysteine S-conjugate to a reactive species, an alternative pathway by which some GSH S-conjugates cause nephrotoxicity involves nonenzymatic formation of reactive episulfonium ions (Figure 7). vicinal-1,2-Dihaloethanes are nephrotoxic and nephrocarcinogenic by this mechanism. These are β-halogen sulfur mustards that are strong alkylating agents. The electrophilicity of these compounds is attributable to the nucleophilic displacement of a good leaving group, such as a chlorine or a bromine atom, from the β-carbon to form the cyclic, episulfonium ion (Figure 8). The reactivity of these halogenated hydrocarbons has been demonstrated by isolation of covalent adducts between metabolites of 1,2-dibromoethane and protein (Hill et al., 1978) and between metabolites of 1,2-dibromoethane or 1,2-dibromo-3-chloropropane and DNA (Foureman and Reed, 1987; Inskeep and Guengerich, 1984; Pearson et al., 1990; Ozawa and Guengerich, 1983). Ozawa and Guengerich (1983) and Foureman and Reed (1987) identified the adduct between DNA and either 5-(2-bromoethyl)glutathione or S-(2-chloroethyl)glutathione as S-[2-(N7-guanyl)ethyl]glutathione.
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Although GSH conjugation is in general a detoxification pathway for xenobiotic biotransformation, an increasing number of xenobiotics are known to be bioactivated by this pathway [reviewed by Anders et al. (1988) and Lock (1988)]. γ-Glutamyltransferase (EC 2.3.2.2.) and dipeptidases (EC 3.4.13.6., 3.4.11.2.), respectively, catalyze the removal of the glutamyl and glycine moieties of the glutathione S-conjugates to yield the corresponding cysteine S-conjugates. Cysteine S-conjugates are the penultimate toxic metabolites of nephrotoxic halogenated alkenes. These conjugates may form electrophiles nonenzymatically, be detoxified by acetylation to a mercapturic acid by cysteine S-conjugate N-acetyltransferase (EC 2.3.1.80.), or be biotransformed by cysteine conjugate β-lyase (EC 2.6.1.64.) to toxic and/or nontoxic thiols. Some of the thiols formed by cysteine S-conjugate β-lyase can be further biotransformed to toxic and/or nontoxic methylthio derivatives by S-methyltransferases (see below). The selectivity for kidney toxicity is due to the active transport of the S-cysteine conjugates by the renal anion transport system, urinary excretion of the conjugates, and kidney localization of cysteine S-conjugate β-lyase. For hepatotoxicity, GSH conjugation plays a role in the bioactivation of vicinal dihaloethanes, such as 1,2-dibromoethane. The gluthione-S-conjugate mustards of these compounds nonenzymatically form electrophilic episulfonium ions.
Applications of fluorine to the construction of bioisosteric elements for the purposes of novel drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Influencing conformational preferences in aliphatic chains without introducing significant levels of steric bulk presents a subtle approach to fine-tuning the physicochemical properties of small-molecule drug candidates. In such acyclic systems, fluorine can profoundly impact this when situated vicinal to an electron deficient motif (X = F, N, O, S) as the interplay between stereoelectronic (σC-H → σC-F*) and electrostatic (R+……Fδ-) interactions ensures that the syn-clinal conformers are significantly populated. The so-called gauche effect presents dihedral angles approaching 60 to ensure maximal orbital overlap, and in the case of the 1,2-difluoroethylene moiety leads to a large dipole moment that directly influences a compounds physicochemical and pharmacological properties [183–192]. The vicinal 1,2-difluroethylene has recently emerged as a bioisostere of the trifluoromethyl and ethyl groups (BITE) with the further possibility based on its chirality to allow evaluation of the enantiomers of a series of bioactive molecules [193].
Study of stability and interference for catecholamines and metanephrines, 3-methoxytyramine: key point of an accurate diagnosis for pheochromocytoma and paraganglioma
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2021
Kaijuan Wang, Xiaojing Gao, Wei Zhang, Nian Sun, Lan Xie, Hongying Cong, Yutong Guo, Xiaocui Shi, Zhou Zhou
Chemically, catecholamines are monoamines linked to a benzene ring with two vicinal hydroxyl groups. The ring structure makes the compounds sensitive to light and easily oxidized, the stability of catecholamines and their metabolites in plasma has attracted much attention. However, there are some controversies, D'Alesandro [5] and Pettersson J [6] declared that EPI and NE are stable at 24 °C/20 °C for 24 h/22 h regardless of whether glutathione or sodium metabisulphite is added to the sample. However, Boomsma F [7] mentioned in his paper, blood is generally collected into tubes containing an anticoagulant and antioxidant (glutathione, sodium metabisulfite, or ascorbic acid), both Boomsma F and Carruthers M [8] believed that a delay in centrifugation of blood led to an immediate decay in measured plasma catecholamines, these studies are getting aged. In recent years, there are also studies on sample storage and transport, most of them focus on metanephrine (MN) and normetanephrine (NMN) [9,10], a few studies focus on EPI and NE. Although there is compelling evidence that plasma free metanephrines (MNs: MN and NMN) are superior to catecholamines for diagnosis of PPGLs, the determination of plasma EPI, NE, DA continues to be required by clinicians, in addition, since DA and 3-methoxytyramine (3-MT) may be markers of dopamine-producing tumors, storage and transport conditions of them should also be evaluated.
Selective COX-2 inhibitors as anticancer agents: a patent review (2014-2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Sayyed Mohammad Ismail Mahboubi Rabbani, Afshin Zarghi
A brief description of the structure-activity relationship of COX-2 inhibitors was presented above. Principally, selective COX-2 inhibitors have a central cyclic/acyclic core and two vicinal groups which are usually aromatic cycles [14]. On one of these two vicinal groups, there is an anchoring pharmacophore group which is responsible for the selective action of these compounds against COX-2 isoform [14]. There are various moieties that could play the role of the anchoring group. All of these groups are placed in a side pocket formed by Valine 523 amino acid in the active site of COX-2 enzyme [14]. This side pocket is not present in the structure of COX-1 (Figure 3). There is also a hydrophilic amino acid moiety (Arg 513) in the active site which binds to the hydrophilic anchoring groups in the drug structure by an ion-dipole bond [14,49]. Thus, the incorporation of such a group in the drug’s structure may elevate the binding potency.