3'-C-branched-chain-substituted nucleosides and nucleotides as potent inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase
| Autor: | Veerle Vanheusden, Serge Van Calenbergh, Roger Busson, Sylvie Pochet, Arne Heyerick, Hélène Munier-Lehmann, Denis De Keukeleire, Laurence Dugué, Piet Herdewijn, Matheus Froeyen |
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| Přispěvatelé: | Laboratory for Medicinal Chemistry-FWW, Universiteit Gent = Ghent University [Belgium] (UGENT), Chimie Structurale des Macromolécules (CSM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratory of Medicinal Chemistry, Rega Institute-Catholic University of Leuven, Chimie Organique, Universiteit Gent = Ghent University (UGENT), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Models
Molecular MESH: Mycobacterium tuberculosis AZT ACTIVATION Antitubercular Agents GENETIC ALGORITHM 01 natural sciences chemistry.chemical_compound MESH: Structure-Activity Relationship Drug Discovery Nucleotide Enzyme Inhibitors MESH: Thymidine Monophosphate Antibacterial agent HUMAN THYMIDYLATE KINASE chemistry.chemical_classification 0303 health sciences Thymidine monophosphate Nucleoside-phosphate kinase biology MESH: Kinetics Nucleotides Nucleosides 3. Good health Chemistry Enzyme inhibitor MESH: Enzyme Inhibitors Molecular Medicine MESH: Models Molecular Azides Stereochemistry 03 medical and health sciences Structure-Activity Relationship Thymidine Monophosphate Structure–activity relationship Humans MESH: Nucleosides 030304 developmental biology MESH: Humans ANALOGS PURIFICATION 010405 organic chemistry Mycobacterium tuberculosis MESH: Antitubercular Agents MESH: Azides 0104 chemical sciences MESH: Nucleotides Kinetics chemistry RESOLUTION Dideoxynucleotide Thymidine kinase biology.protein Nucleoside-Phosphate Kinase MESH: Nucleoside-Phosphate Kinase |
| Zdroj: | JOURNAL OF MEDICINAL CHEMISTRY Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2003, 46 (18), pp.3811-21. ⟨10.1021/jm021108n⟩ Journal of Medicinal Chemistry, 2003, 46 (18), pp.3811-21. ⟨10.1021/jm021108n⟩ |
| ISSN: | 0022-2623 1520-4804 |
| Popis: | International audience; Thymidine monophosphate kinase (TMPK) of Mycobacterium tuberculosis (TMPKmt) represents an attractive target for blocking the bacterial DNA synthesis. In an attempt to find high-affinity inhibitors of TMPKmt, a cavity in the enzyme at the 3'-position was explored via the introduction of various substituents at the 3'-position of the thymidine monophosphate (dTMP) scaffold. Various 3'-C-branched chain substituted nucleotides in the 2'-deoxyribo (3-6) and ribo series (7, 8) were synthesized from one key intermediate (23). 2'-Deoxy analogues proved to be potent inhibitors of TMPKmt: 3'-CH(2)NH(2) (4), 3'-CH(2)N(3) (3), and 3'-CH(2)F (5) nucleotides exhibit the highest affinities within this series, with K(i) values of 10.5, 12, and 15 microM, respectively. These results show that TMPKmt tolerates the introduction of sterically demanding substituents at the 3'-position. Ribo analogues experience a significant affinity decrease, which is probably due to steric hindrance of Tyr103 in close vicinity of the 2'-position. Although the 5'-O-phosphorylated compounds have somewhat higher affinities for the enzyme, the parent nucleosides generally exhibit affinities for TMPKmt in the same order of magnitude and display a superior selectivity profile versus human TMPK. This series of inhibitors holds promise for the development of a new class of antituberculosis agents. |
| Databáze: | OpenAIRE |
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