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Uro-Angiographic Contrast Agents—The Holy Grail
Published in Christoph de Haën, X-Ray Contrast Agent Technology, 2019
There is consensus (Binz 1937a; Swick 1978) on the fact that Swick, imagining a connection between the known toxicity of methanol and his observations with selectan neutral (Figure 4.9, 2) in patients, at one time suggested to Binz that the compound may suffer from splitting off of the methyl radical as a cause of some adverse reactions in man—double vision, headache, and vomiting (Swick 1933a,d). Although this theory did not hold up, Swick’s willingness to converse with Binz in terms of medicinal chemistry must be seen as helpful in the interaction between actors with different knowledge cultures. Binz dates Swick’s suggestion to after his arrival in Berlin and describes having provided the latter with three diiodo derivatives (Figure 4.11, 4–6) (Binz 1937a). One of these (4) had been known since 1887 (Pfeiffer 1887). Since another of the compounds (Figure 4.11, 5) carried an N-methyl group, this account is puzzling, although it is likely that all along Binz had reservations with regard to Swick’s methyl group hypothesis (Binz 1937a).
Microsomal Oxidation of Hydroxyl Radical Scavenging Agents
Published in Robert A. Greenwald, CRC Handbook of Methods for Oxygen Radical Research, 2018
Arthur I. Cederbaum, Gerald Cohen
In studies with microsomes, we have used a number of substrates which have also been utilized in other systems (see the citations in References 6 to 8). Dimethylsulfoxide (DMSO) reacts with ·OH to produce methyl radicals, which have been detected by ESR spectroscopy.9 Methyl radicals can produce methane via hydrogen abstraction, can dimerize to produce ethane, or can react with oxygen to ultimately produce formaldehyde.2,10 Analogs of methionine, the most popular being methional and 2-keto-4-thiomethylbutyric acid (KTBA), react with ·OH to produce ethylene gas, which serves as a convenient, easily measured product.11 Benzoic acid can react with ·OH to form hydroxylated benzoic acid derivatives and can also yield CO2 via decarboxylation. The use of 7-14C-benzoic acid with the measurement of 14CO2 is a useful ·OH-detection system.12,13 Alcohols react with ·OH at the exposition to produce hydroxyalkyl radicals, which upon dismutation or loss of an electron, generate the aldehyde or ketone product. An alcohol which is a ·OH scavenger but does not contain an α-hydrogen is tertiary butyl alcohol. The reaction of t-butyl alcohol with ·OH produces either the α-hydroxyalkyl radical or the t-butoxy radical.14 The latter can decompose to produce acetone plus the methyl radical,15 with the ·CH3 ultimately producing formaldehyde.16Table 1 is a brief summary of these reactions.
Enzymes
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
DeWolf, Carr, Varrichio et al. (1988) reported the isolation and characterization of two modified tryptic peptides from DβH inactivated by p-cresol. Using a combination of techniques, they determined the sequence of the putative active site peptides, identified the site of attachment of p-cresol, and defined the chemical nature of the adduct formed. They presented additional data that indicated that a (4-hydroxyphenyl)methyl radical is generated during catalysis.
An update on late-stage functionalization in today’s drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Andrew P. Montgomery, Jack M. Joyce, Jonathan J. Danon, Michael Kassiou
Researchers from Merk & Co. Department of Discovery Chemistry published a case study in which a series of Bruton’s tyrosine kinase (BTK) inhibitors were functionalized to demonstrate how LSF can be used as a tool for SAR exploration (Figure 8B). A representative example from this study is the LSF of the 6-position of the pyridine in lead 72 (BTK IC50 = 0.1 nM) using Minisci chemistry to install an isopropyl (73, BTK IC50 = 278 nM) or cyclobutyl (74, BTK IC50 = 766 nM) group. These bulky alkyl modifications resulted in significant decreases in potency (2780- and 7660-fold, respectively); as such the corresponding methyl substituent was explored. For this purpose, methyl radicals were generated via the photoredox-mediated decomposition of tert-butyl peracetate. Due to the high reactivity of the methyl radical, the 3-methylated analog 75a (BTK IC50 = 12.5 nM) was obtained in addition to the desired 6-methylated analog 75b (BTK IC50 = 4.5 nM). The excellent potency of lead compound 72 was maintained for both methylated analogs [79]. This example, along with others in the case study, has illustrated how LSF can be applied to advanced lead molecules to rapidly generate SAR information.
Contribution of DNA methylation to the pathogenesis of Sjögren's syndrome: A review
Published in Autoimmunity, 2022
Juliana Ramalho Guimarães, Marina de Castro Coêlho, Naila Francis Paulo de Oliveira
Epigenetic marks are hereditary and reversible chemical modifications that regulate gene expression and may be related to the pathophysiology of SS. These marks include DNA methylation, histone modifications, and micro-RNAs [15]. DNA methylation is the most studied form of epigenetic regulation and has been associated with tumoral and oral inflammatory diseases [16–18]. This process is catalysed by a family of enzymes known as DNA methyltransferases (DNMT) and refers to the presence of methyl radicals (CH3) in CpG dinucleotides originating from 5-methylcytosines (5-mC). In fact, the formation of 5-mCs alone, as well as their association with methyl-CpG-binding proteins (MBP), may block the access of transcription factors to a gene’s promoter region, thus reducing or silencing its transcription [15,19].
Elevated plasma asymmetric dimethylarginine levels in children with beta-thalassemia major may be an early marker for endothelial dysfunction
Published in Hematology, 2018
Orhan Gursel, Serkan Tapan, Erdim Sertoglu, Emre Taşçılar, Ibrahim Eker, Talia Ileri, Zumrut Uysal, Ahmet Emin Kurekci
According to a new disease paradigm involving hemolysis-associated endothelial dysfunction, the process of hemolysis affects the arginine–nitric oxide pathway [7]. Nitric oxide (NO) is a paracrine factor that controls vascular tone (as a potential vasodilator), inhibits platelet function, prevents adhesion of leukocytes, and reduces proliferation of the intima [8]. It originates in the endothelium via the conversion of l-arginine to l-citrulline in the presence of endothelial NO synthase (eNOS), which is nicotinamide adenine dinucleotide phosphate dependent [9]. The addition of two methyl radicals to arginine, through the action of methyltransferase nuclear proteins produces asymmetric dimethylarginine (ADMA), which competes with l-arginine and promotes a reduction in nitric oxide formation in the vascular wall [10]. Elevated levels of ADMA inhibit NO synthesis and therefore impair endothelial function and thus promote atherosclerosis. Large body of evidence has demonstrated that ADMA is an early marker for endothelial dysfunction and also regarded as an independent predictor of future cardiovascular events [11,12]. In addition, endothelial adhesion molecules [soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and P-selectin] are also considered as early endothelial dysfunction markers, and there is scarce data that highlights the significance and role of these molecules in the endothelial dysfunction development in pediatric beta-thalassemia major patients [13].