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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Whereas DNA and RNA have deoxyribose and ribose sugar backbones, respectively, the PNA backbone is comprised of repeating N-(2-aminoethyl)-glycine units linked by peptide bonds (Figure 5.95). The various purine and pyrimidine bases are linked to the backbone by a methylene bridge and a carbonyl group. PNAs are analogous to peptides, with the N-terminus at the first (left) position and the C-terminus at the last (right) position. Since the backbone of PNA contains no charged phosphate groups, the binding between PNA/DNA strands is stronger than between DNA/DNA strands due to the lack of electrostatic repulsion. Early experiments with homopyrimidine strands showed that the melting temperature (Tm) of a 6-base thymine PNA/adenine DNA double helix was 31°C in comparison to an equivalent 6-base DNA/DNA duplex that denatured at less than 10°C. Interestingly, the affinity between two PNA/PNA oligomers is greater than that between equivalent lengths of PNA/DNA oligomers.
Metabolism of Terpenoids in Animal Models and Humans
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
3-Carene is found in various Pinaceae essential oils: (+)-3-Carene is a major compound of Pinus palustris essential, and (−)-3-carene of Pinus sylvestris. It is used as raw material in perfumery (Bornscheuer et al., 2014). In rabbits, 3-carene is metabolized into 3-caren-9-ol and presumably via 3-caren-10-ol, and further oxidized into carboxylic and dicarboxylic acid products (Ishida et al., 1981, 2005). Another metabolic pathway takes place via opening of the methylene bridge to m-mentha-4,6-dien-8-ol with subsequent dehydrogenation of the cyclohexene ring to m-cymen-8-ol (Ishida, 2005). In vitro experiments with human liver microsomes revealed 3-caren-10-ol and 3-carene epoxide as metabolites (Figure 10.4). Hydroxylation was catalyzed by CYP2B6, CYP2C19, and CYP2D6, whereas epoxidation could be attributed to CYP1A2 (Duisken et al., 2005). Interestingly, neither of these two metabolites, nor the supposed hydrolysis product of the epoxide, 3-carene-3,4-diol, could be detected in rabbit or human urine, yet (Ishida, 2005; Schmidt et al., 2013, 2015). A recent study (Schmidt et al., 2015) identified chaminic acid as a new metabolite in human urine after oral intake of 3-carene (Figure 10.4). Moreover, Schmidt et al. suggested that dihydrochaminic acid and carene-3,4,9-triol are additional metabolites of 3-carene in humans (Schmidt et al., 2015).
Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Nonsmoking adults do not have normally more than 1% carboxyhemoglobin of the total circulating heme pigments in their blood, but heavy smokers may have much higher values up to 5 to 10% saturation. Combustion of fossil fuels and motor vehicle exhaust contain 4 to 7% carbon monoxide. The basic carboxyhemoglobin level in the blood is not caused by environmental exposure to carbon monoxide. It is generated endogenously mainly from the catabolism of hemoglobin. The breakdown of cytochromes and catalase provide small amounts of carbon monoxide. The methylene bridge of the heme molecules is metabolized to carbon monoxide in equivalent amounts with bilirubin. In hemolytic disease, carbon monoxide production is enhanced due to increased heme catabolism.
Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
János Garai, Marcell Krekó, László Őrfi, Péter Balázs Jakus, Zoltán Rumbus, Patrik Kéringer, András Garami, Eszter Vámos, Dominika Kovács, Viola Bagóné Vántus, Balázs Radnai, Tamás Lóránd
Docking experiments revealed two possible types of binding mode (Figure 2). In Type I complexes, the A and B rings occupy the binding pocket. The ketone oxygen forms a hydrogen bond with the peptide NH of Ile64A. The aromatic ring interacts with Tyr95C through π–π stacking. The catalytic Pro1A and Lys32A are in the proximity of the methylene bridge. The aryl or heteroaryl group bonds with Lys32A, Tyr36A and Phe113A through hydrophobic and π-interactions. Such binding mode can be observed in the PDB entry 3L5R of a 3-phenylchromen-4-one compound64. In type II binding mode, where the ligand is horizontally flipped, the C-ring interacts with Tyr95C, the ketone oxygen with Ile64A and Lys32A, and the A ring with Tyr36A. A similar binding mode of a structurally related covalent inhibitor can be observed in the PDB entry 4Z1U65. After visual analysis and consideration of docking scores, we propose Type I binding mode to be more favourable.
Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Alessandro Deplano, Mariateresa Cipriano, Federica Moraca, Ettore Novellino, Bruno Catalanotti, Christopher J. Fowler, Valentina Onnis
As further modification, a methylene bridge was inserted between the piperazine and the aromatic ring. The amides 30–34 were prepared by condensation of ibuprofen (1) with N-BOC-piperazine (29), using the same EDC method described above. After BOC-deprotection, a benzyl group was added by reductive alkylation, treating the intermediate 6 with the suitable substituted arylaldehyde in presence of NaHCO3, NaBHAc3 in CH2Cl2 solution (Scheme 3). Unfortunately, this modification afforded the poor active analogues 30–34 (Table 3). This loss of activity could be attributed to the protonation of the nitrogen atom of the piperazine ring that is unfavourable in the hydrophobic environment of the FAAH channels. The induced fit docking of 30 and 32 confirmed this hypothesis, yielding binding modes characterised by the loss of interactions with Ser241, and by a closed conformation (Supplementary Figure S3), due largely to an intramolecular cation-π interaction, thus explaining the loss in the inhibition activity.
The development and application of a novel reagent for fixing red blood cells with glutaraldehyde and paraformaldehyde
Published in Hematology, 2023
Xinyang Li, Miyang Li, Yuhong Wang, Shengbao Duan, Hongmei Wang, Yong Li, Zhonghe Cai, Ruiyao Wang, Shuang Gao, Yan Qu, Tianxia Wang, Fei Cheng, Tiemei Liu
The primary factors affecting RBC storage were repeated freezing and thawing cycles, pH, RBC storage solution, NO, and chemical modification [8,16]. Two fixatives, GA and PFA, were used in our laboratory to modify RBCs, extending their storage time from 2 to 3 months to 6–7 months. Fixatives are classified into two types: cross-linking and denaturation [20,21]. In the laboratory, we treated RBCs using cross-linking fixatives [22,23]. Combining GA and PFA to fix RBCs compensates for the shortcomings of a single application and achieves perfect fixation [24]. GA is a linear 5-carbon dialdehyde that can react with the amino group of proteins in normal saline solution [25] and maintain the protein's stable structure; however, it is slow and takes a long time to fix [26]. Although PFA rapidly crosslinks with surrounding proteins via aldehyde groups to form a methylene bridge complex that preserves the structure of the protein, this process is insufficient to prevent protein redistribution and slight destruction of the cell membrane structure [27]. Combining GA and PFA compensates for their shortcomings [28,29]. In addition, when GA and PFA interact with red blood cell reagents, the volume of red blood cells increases, and their deformability decreases [30], making it difficult for GA/PFA treated red blood cell reagents to pass through the pores of the microcolumn gel cards. The purpose of this study is to develop a novel reverse typing red blood cell reagent that can be stored for 6 months and has high accuracy, and then apply it to the reverse typing test of clinical patients prior to blood transfusion to ensure the safety and efficacy of blood transfusion.