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Marine Algae in Diabetes and Its Complications
Published in Se-Kwon Kim, Marine Biochemistry, 2023
As the main component of algae, bromophenols may be responsible for the reported antidiabetic activity of many marine organisms. These compounds arise from the tendency of the phenol moiety to undergo electrophilic bromination to varying degrees. Bromophenols isolated from the red algae Rhodomela confervoides have been found to possess potent in vitro protein-tyrosine phosphatase 1B (PTP1B) inhibitory effects, with IC50 values fluctuating between 0.8 μM and 4.5 μM. This change in potencies could be attributed to the bromine content of these compounds or to their side chains (Shi, Guo et al., 2013; Shi, Li et al., 2012). Other brominated phenols isolated from the red algae Symphyocladia latiuscula also exerted positive inhibitory activity (Liu et al., 2011).
Halogen Labeled Compounds (F, Br, At, Cl) *
Published in Garimella V. S. Rayudu, Lelio G. Colombetti, Radiotracers for Medical Applications, 2019
Direct bromination with Br2 is commonly employed in the electrophilic reaction of aromatic compounds. The substrate usually contains an aromatic moiety with activating groups such as NH2 or OH. Br2 can be used directly as a brominating agent or it can be generated in situ. For example, 2,4-dibromoestrone was prepared by reaction of estrone and Br2, generated in situ by KBr, H2SO4 and MnO2.31 DOPA was found to react with Br2 when trifluoroacetic acid was used as the solvent,266 while in the reaction of Br2 with two psychotropic drugs, spiroperidol and α-ergocryptine, a mixture of carbon tetrachloride and methylene chloride was used. 11, 45, 267, 268
Principles of Radioiodination and Iodine-Labeled Tracers in Biomedical Investigation †
Published in Garimella V. S. Rayudu, Lelio G. Colombetti, Radiotracers for Medical Applications, 2019
Mrinal K. Dewanjee, Shyam A. Rao
The kinetics of radioiodination, like those of other enzyme-catalyzed reactions, is dependent on pH.87-89 Generally, a pH of 5.6 is useful for most labeling, except for fibrinogen, in which two pH optima, one at high and the other at low pH, have been observed. Because the proteins are not exposed to strong oxidizing or reducing agents, immunologic and biological properties of the original protein are maintained.86,89,90 The labeling efficiency is considerably lower (20 to 40%) than that of other iodination methods. During radioiodination, lactoperoxidase is self-iodinated, increasing the iodine loss and complicating the separation of labeled protein from labeled enzyme. This problem has been overcome by the use of lactoperoxidase covalently bound to insoluble matrix,91,92 for example, Sephadex® beads. These beads can be easily removed by centrifugation. Radioiodination involves substitution of the H atom in the tyrosine or histidine group.89 This technique also has been used for other steroids.93 Recently, glucose peroxidase and lactoperoxidase have been used simultaneously to increase labeling efficiency. A similar enzymatic technique using another enzyme, chloroperoxi-dase, has been used for bromination.
Metabolic activation of zolmitriptan mediated by CYP2D6
Published in Xenobiotica, 2021
Lingling Han, Yudi Jia, Yanjia Zhao, Chen Sun, Min Zhao, Ying Peng, Jiang Zheng
Chemical synthesis was executed to verify the structure of M1 and M2. As the initial step, we naturally attempted to oxidize ZOL to an α,β-unsaturated imine intermediate, which mimics the metabolic oxidation of ZOL. Unfortunately, we failed to obtain the α,β-unsaturated imine by the oxidation of ZOL using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Then we decided to brominate ZOL by NBS, which allows us to take the advantage of the departure of leaving group bromide. ZOL-Br was synthesized as an electrophilic synthon to generate a reactive carbocation (Scheme 1) and characterized by HPLC-MS/MS and Q-TOF. As expected, the reaction of synthetic ZOL-Br with GSH or NAC offered products showing similar retention time and identical molecular ions with that of M1 and M2 detected in microsomal incubations and bile and urine of animals given ZOL (Figures 4 and 5). Bromination of ZOL with NBS could generate multiple brominated products. Unfortunately, we were unable to gain enough amount of the brominated products for NMR characterization, although the HRMS data supported the production of ZOL-Br. The success in sequential SN1/SN2 reaction with NAC indicates that the bromination did not take place on the aromatic ring. Taken together, we propose that the bioactivation of ZOL occurs by metabolic oxidation of the indole moiety to the corresponding imine (Scheme 2).
Synthesis and evaluation of highly releasable and structurally stable antibody-SN-38-conjugates
Published in Drug Delivery, 2021
Lianqi Liu, Fei Xie, Dian Xiao, Xin Xu, Zheng Su, Yanming Wang, Shiyong Fan, Xinbo Zhou, Song Li
The synthetic routes of Linker-SN-38, including compounds 5, 6, 7, 8, and 11, are shown in Scheme 1. The key intermediate compound 4 was obtained first in the following steps. Compound 1 was converted into compound 2 through bromination reactions. Because of the steric hindrance of α-hydroxy lactone, the hydroxy group of SN-38 does not require protection when preparing compound 3, which was obtained through a phenolic ether connection (Lau et al., 2018). The key intermediate compound 4 was finally obtained after removal of the Boc protection group and then reacted with maleimides containing different lengths of polyethylene glycol (PEG) to yield target compounds 5, 6, 7, and 8. Overall ADC incorporating the pendant PEG linker may exhibit the better hydrophilic properties than that of straight PEG linker. (Lyon et al., 2015; Tedeschini et al., 2021; Xiao et al., 2021) Compound 4 reacted with activated Fmoc-Lys (PEG8)-OH to provide compound 9. Fmoc deprotection followed by maleimide incorporation yielded the desired compound 11 containing the pendant PEG moiety. Detailed synthetic procedures are shown in the Experimental Section.
Design of new disubstituted imidazo[1,2-b]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Jonathan Elie, Omid Feizbakhsh, Nathalie Desban, Béatrice Josselin, Blandine Baratte, Amandine Bescond, Julien Duez, Xavier Fant, Stéphane Bach, Dominique Marie, Matthieu Place, Sami Ben Salah, Agnes Chartier, Sabine Berteina-Raboin, Apirat Chaikuad, Stefan Knapp, Fabrice Carles, Pascal Bonnet, Frédéric Buron, Sylvain Routier, Sandrine Ruchaud
First, we developed an efficient synthesis of the CHR-6494 derivative in three steps as this compound was not commercially available at the beginning of this work. The first step consisted of a nucleophilic aromatic substitution (SNAr) in position C-6 with propylamine in N-methyl-2-pyrrolidone (NMP) under microwave irradiation which furnished compound 3 in 86% yield. Furthermore, a region-selective bromination of compound 3 in the presence of N-bromosuccinimide (NBS) led to compound 4 in quantitative yield. The displacement of this halogen was carried out by a Suzuki–Miyaura cross coupling, using 1H-indazole-5-boronic acid as partner, in presence of caesium carbonate as base in a mixture of ethanol/water as solvent under microwave irradiation to give compound 5 in the moderate yield of 28% (Scheme 1).