Medications and substances of abuse
James W. Albers, Stanley Berent in Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives, 2005
There is an abundant literature describing the adverse neurologic effects of n-hexane. Recognition of n-hexane as a neurotoxicant began with the initial description of neuropathy among Japanese workers exposed to n-hexane fumes, followed by case reports of a similar syndrome in workers in the USA and Europe. The neurotoxic potential was supported by experimental studies that identified accumulation of neurofilaments in nerves of n-hexane-intoxicated animals (Cavanagh, 1985). n-Hexane is a hexacarbon, one of many six-member carbon chain rings with different substitution groups. n-Hexane, the unsubstituted molecule, exists in industrial and household glues and is known to produce peripheral neuropathy, usually after volitional inhalation (huffing) (Korobkin, Asbury, Sumner, & Nielsen, 1975). Methyl n-butyl ketone (MBK) is a common substituted hexacarbon. Both n-hexane and MBK undergo oxidative metabolism in the liver, forming 2,5-hexanedione, the purported neurotoxic component (Allen, Mendell, Billmaier, Fontaine, & O’Neill, 1975; Governa et al., 1987; Couri & Milks, 1985).
Drug Targeting to the Lung: Chemical and Biochemical Considerations
Anthony J. Hickey, Sandro R.P. da Rocha in Pharmaceutical Inhalation Aerosol Technology, 2019
In a structure-activity correlation study, a number of N-substituted derivatives of rolipram (52) were prepared and evaluated (Tanaka et al. 1995). A carbamate ester of rolipram was found to be approximately 10-fold more potent than rolipram itself at inhibiting human PDE IV. A methyl ketone derivative of rolipram showed more potent inhibition of PDE IV compared to rolipram or its carbamate ester. Based on proton NMR spectroscopy and computer modeling studies, a pharmacophore model of the methyl ketone derivative was proposed (Stafford et al. 1995). This model showed that the ketone carbonyl oxygen atom is involved in an important interaction within the PDE IV active site. Sodium orthovanadate, a phosphotyrosine phosphate inhibitor, exhibits dose- and time-dependent suppression of Lewis lung carcinoma A11 cell spreading. Protein tyrosine phosphorylation levels in A11 cells were elevated after treatment with ortho vanadate; this increase was partially diminished by the tyrosine kinase inhibitor ST 638, concomitantly with restoration of the suppressed cell spreading, as well as invasive and metastatic ability (Takenaga 1996). These results suggest tyrosine phosphorylation influences adhesion of cancer cells to lung surface endothelia, and that a valid approach in treating cancer is inhibition of phosphotyrosine phosphatase.
Antioxidant properties and application information
Roger L. McMullen in Antioxidants and the Skin, 2018
Ubiquinone-10, also referred to as coenzyme Q, is a lipid-soluble antioxidant that is naturally found in the body and is also available from commercial sources. In vivo it is found in lipid membranes, most prominently in the inner membrane of the mitochondrion where it carries out the function of electron transport carrier. This process, known as oxidative phosphorylation, is the principal energy producing (in the form of ATP) event in the cell. Structurally, ubiquinone-10 consists of 10 isoprenoid units that provide it with a long aliphatic tail to anchor into lipid membranes. The quinone portion of the molecule contributes to its antioxidant properties. The structural form shown earlier is fully oxidized—with two ketone groups. There is also a semiquinone (ubisemiquinone) and fully reduced structure (ubiquinol), in which there are one or two hydroxy groups, respectively, at the location of the ketone groups. Coenzyme Q’s unique behavior—electron transfer agent and antioxidant—is a result of these molecular forms, in which case the quinone structure is involved with electron transport and ubiquinol with antioxidation.
Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: molecular docking study
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Magda A.-A. El-Sayed, Walaa M. El-Husseiny, Naglaa I. Abdel-Aziz, Adel S. El-Azab, Hatem A. Abuelizz, Alaa A.-M. Abdel-Aziz
Generation of the acid chlorides 5a,b from their corresponding carboxylic acids 3a,b was achieved through heating under reflux with thionyl chloride (Scheme 2). These acid chlorides 5a,b were subjected to reaction with 4-hydroxybenzaldehyde and phenylhydrazine in dimethylformamide containing potassium carbonate to yield 4-formylphenyl 2-(4-(dimethylamino)styryl)-6-substituted quinoline-4-carboxylates 6a,b and 2-(4-(dimethylamino)styryl)-6-substituted N′-phenylquinoline-4-carbohydrazides 7a,b, respectively (Scheme 2). The IR spectra of compounds 6a,b and 7a,b showed absorption bands at 1644–1657 cm−1 and 3362–3365 cm−1 attributed to formyl and amino groups, respectively. In addition, 1 H NMR spectra of compounds 6a,b showed signals in the range of 9.07–9.13, characteristic of the formyl moieties. The acid chlorides 5a,b were further condensed with either ethyl cyanoacetate or acetyl acetone, to afford compounds 8a,b and 9a,b (Scheme 2). 1 H NMR spectra of compounds 8a,b showed characteristic triplet and quartet signals for the ethyl ester groups at 1.22–1.24 ppm and 4.18–4.20 ppm, respectively. Furthermore, compounds 9a,b showed singlet signals for the methyl ketone groups (O = C–CH3) at approximately 3.34–3.37 ppm in addition to a singlet peak at 4.60–4.64 ppm characteristic of the –CH– groups (–CH–CO–CH3).
HDAC inhibitors: a 2013–2017 patent survey
Published in Expert Opinion on Therapeutic Patents, 2018
Micaela Faria Freitas, Muriel Cuendet, Philippe Bertrand
The activities of compounds 45–52, which are mainly HDAC4 inhibitors, are reported in Table 3. The group of Dominguez et al. investigated several scaffolds to design HDAC inhibitors, focusing on hydroxamic acids linked to a hindered carbon (tertiary, quaternary). Diarylhydroxyacetamides 45 (Scheme 3(g)) [38] were synthesized in a straightforward manner, with modulation of the biaryl part. Aryl substituted cyclopropyl hydroxamates 46–49 were also proposed (Scheme 3(h)) [39]. Compounds with a quaternary carbon bearing two rings and the hydroxamic acid function were investigated and are illustrated by compound 50 (Scheme 3(i)) [40]. An enantiomeric resolution of the intermediate ketone is described. An analogous series was proposed with a quaternary carbon included in a cyclopentene ring [41]. The chemistry used the same ketone intermediate to obtain compounds such as 51 or 52 (Scheme 3(i)).
Ketogenic diet: overview, types, and possible anti-seizure mechanisms
Published in Nutritional Neuroscience, 2021
Mohammad Barzegar, Mohammadreza Afghan, Vahid Tarmahi, Meysam Behtari, Soroor Rahimi Khamaneh, Sina Raeisi
During KD treatment, the metabolic efficiency of the tricarboxylic acid (TCA) cycle is reduced and body energy is generally derived from fatty acid oxidation in mitochondria that results in the generation of a large amount of acetyl-CoA. Acetyl-CoA accumulation leads to the synthesis of the two primary ketone bodies, β-hydroxybutyrate and acetoacetate, mainly in the liver that can then spill into the blood circulation. Acetone, the other major ketone, is a metabolite of acetoacetate. The ketone bodies can be used as an alternative source of energy instead of glucose in the brain. Fatty acids are not utilized due to their inability to pass through the blood–brain barrier (BBB) [12]. There are some specific monocarboxylate transporters in BBB and some mitochondrial enzymes in the brain which make the ketone bodies possible to be extracted and used by the brain [46]. It has been shown that KD by upregulating of these specific proteins can induce the using of ketone bodies by the brain [46]. After the entering to the brain, ketone bodies can be converted to acetyl-CoA and then enter the TCA cycle within brain mitochondria leading eventually to the production of adenosine triphosphate (ATP) [12]. Several hypotheses have been focused on the ketone bodies as the key mediators involved in the anticonvulsant effect of the KD. Based on the several studies [46–54], the potential mechanisms are generally center around the roles of brain energy metabolism, neurotransmitters, ion channels, and oxidative stress which are briefly discussed below.
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