Discovery of Type II (Covalent) Inactivation of S-Adenosyl-l -homocysteine Hydrolase Involving Its 'Hydrolytic Activity': Synthesis and Evaluation of Dihalohomovinyl Nucleoside Analogues Derived from Adenosine
| Autor: | Jan Balzarini, Yue Mao, Chong-Sheng Yuan, Ronald T. Borchardt, Morris J. Robins, Graciela Andrei, Stanislaw F. Wnuk, Erik De Clercq |
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| Rok vydání: | 1998 |
| Předmět: |
Ketone
Hydrolases Stereochemistry Placenta Microbial Sensitivity Tests Antiviral Agents Chemical synthesis chemistry.chemical_compound S-adenosyl-L-homocysteine hydrolase Drug Discovery Hydrolase Humans Acyl halide Enzyme Inhibitors Cell Line Transformed chemistry.chemical_classification Chemistry Adenosylhomocysteinase Hydrolysis Recombinant Proteins Drug Design Reagent Dideoxyadenosine Wittig reaction Molecular Medicine Nucleoside |
| Zdroj: | Journal of Medicinal Chemistry. 41:3078-3083 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm9801410 |
| Popis: | Treatment of the 5'-carboxaldehyde derived by Moffatt oxidation of 6-N-benzoyl-2',3'-O-isopropylideneadenosine (1) with the "(bromofluoromethylene)triphenylphosphorane" reagent and deprotection gave 9-(6-bromo-5, 6-dideoxy-6-fluoro-beta-d-ribo-hex-5-enofuranosyl)adenine (4). Parallel treatment with a "dibromomethylene Wittig reagent" and deprotection gave 9-(6,6-dibromo-5, 6-dideoxy-beta-d-ribo-hex-5-enofuranosyl)adenine (7), which also was prepared by successive bromination and dehydrobromination of the 6'-bromohomovinyl nucleoside 8. Bromination-dehydrobromination of the 5'-bromohomovinyl analogue 11 and deprotection gave (E)-9-(5, 6-dibromo-5,6-dideoxy-beta-d-ribo-hex-5-enofuranosyl)adenine (15). Compounds 4, 7, and 15 were designed as putative substrates of the "hydrolytic activity" of S-adenosyl-l-homocysteine (AdoHcy) hydrolase. Enzyme-mediated addition of water across the 5,6-double bond could generate electrophilic acyl halide or alpha-halo ketone species that could undergo nucleophilic attack by proximal groups on the enzyme. Such type II (covalent) mechanism-based inactivation is supported by protein labeling with 8-[3H]-4 and concomitant release of bromide and fluoride ions. Incubation of AdoHcy hydrolase with 7 or 15 resulted in irreversible inactivation and release of bromide ion. In contrast with type I mechanism-based inactivation, reduction of enzyme-bound NAD+ to NADH was not observed. Compounds 4, 7, and 15 were not inhibitory to a variety of viruses in cell culture, and weak cytotoxicity was observed only for CEM cells. |
| Databáze: | OpenAIRE |
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