title: Synthesis and evaluation of 6-aza-2'-deoxyuridine monophosphate analogs as inhibitors of thymidylate synthases, and as substrates or inhibitors of thymidine monophosphate kinase in Mycobacterium tuberculosis.
abstract: A series of 5-substituted analogs of 6-aza-2'-deoxyuridine 5'-monophosphate, 6-aza-dUMP, has been synthesized and evaluated as potential inhibitors of the two mycobacterial thymidylate synthases (i.e., a flavin-dependent thymidylate synthase, ThyX, and a classical thymidylate synthase, ThyA). Replacement of C(6) of the natural substrate dUMP by a N-atom in 6-aza-dUMP 1a led to a derivative with weak ThyX inhibitory activity (33% inhibition at 50 μM). Introduction of alkyl and aryl groups at C(5) of 1a resulted in complete loss of inhibitory activity, whereas the attachment of a 3-(octanamido)prop-1-ynyl side chain in derivative 3 retained the weak level of mycobacterial ThyX inhibition (40% inhibition at 50 μM). None of the synthesized derivatives displayed any significant inhibitory activity against mycobacterial ThyA. The compounds have also been evaluated as potential inhibitors of mycobacterial thymidine monophosphate kinase (TMPKmt). None of the derivatives showed any significant TMPKmt inhibition. However, replacement of C(6) of the natural substrate (dTMP) by a N-atom furnished 6-aza-dTMP (1b), which still was recognized as a substrate by TMPKmt.
authors.affiliation: Katholieke Universiteit Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Minderbroedersstraat 10, B-3000 Leuven.
authors.forename: Martin
authors.initials: M
authors.lastname: Kögler
authors.forename: Roger
authors.initials: R
authors.lastname: Busson
authors.forename: Steven
authors.initials: S
authors.lastname: De Jonghe
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.forename: Kristien
authors.initials: K
authors.lastname: Van Belle
authors.forename: Thierry
authors.initials: T
authors.lastname: Louat
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003903:Deuterium / Q000737:chemistry; D041961:Deuterium Exchange Measurement; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C519341:6-aza-2'-deoxyuridine; D003903:Deuterium; D013940:Thymidylate Synthase; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D003857:Deoxyuridine