title: 3'-C-branched-chain-substituted nucleosides and nucleotides as potent inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase.
abstract: 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.
authors.affiliation: Laboratory for Medicinal Chemistry (FFW), Ghent University, Harelbekestraat 72, 9000 Gent, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Vanheusden
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Matheus
authors.initials: M
authors.lastname: Froeyen
authors.forename: Laurence
authors.initials: L
authors.lastname: Dugué
authors.forename: Arne
authors.initials: A
authors.lastname: Heyerick
authors.forename: Denis
authors.initials: D
authors.lastname: De Keukeleire
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pochet
authors.forename: Roger
authors.initials: R
authors.lastname: Busson
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D009711:Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C477193:1-(2,3-dideoxy-3-(fluoromethyl)-5-O-phosphorylpentofuranosyl)thymine; C477192:1-(3-(aminomethyl)-2,3-dideoxy-5-O-phosphorylpentofuranosyl)thymine; C477191:1-(3-(azidomethyl)-2,3-dideoxy-5-O-phosphorylpentofuranoyl)thymine; D000995:Antitubercular Agents; D001386:Azides; D004791:Enzyme Inhibitors; D009705:Nucleosides; D009711:Nucleotides; D013938:Thymidine Monophosphate; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase