title: Anti-mycobacterial activity of thymine derivatives bearing boron clusters.
abstract: A series of novel thymine derivatives bearing lipophilic, electron-neutral 1,2-dicarba-closo-dodecaborane, 1,12-dicarba-closo-dodecaborane or hydrophilic 7,8-dicarba-nido-undecaborate anions were synthesized. Synthesis was performed via copper(I)-catalysed Huisgen-Meldal-Sharpless 1,3-dipolar cycloaddition of N(1)-propargylthymine or N(1),N(3)-bispropargylthymine to 1-(3-azidopropyl)-1,2-dicarba-closo-dodecaborane. The obtained compounds were tested in vitro against Mycobacterium tuberculosis thymidylate kinase (TMPKmt) and as inhibitors of mycobacteria growth in culture using both saprophytic Mycobacterium smegmatis (M. smegmatis) and pathogenic Mycobacterium tuberculosis (M. tuberculosis) strains. The most potent TMPKmt inhibitor in the series contained two negatively charged 7,8-dicarba-nido-undecaborate modifications at positions 1 and 3 of thymine (9) and exhibited a Ki value of 1.5 μM. The most potent inhibitors of mycobacteria growth was compound 5 with one electron-neutral 1,2-dicarba-closo-dodecaborane modification at position 1 of thymine, and compound 8 with two modifications, at position 1 and 3. Both compounds completely inhibited M. smegmatis proliferation at a concentration of 100 μg/mL (0.25 mM and 0.15 mM, respectively).
authors.affiliation: Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology PAS, 106 Lodowa St, 93-232 Lodz, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Adamska
authors.affiliation: Laboratory of Mycobacterium Genetics and Physiology, Institute of Medical Biology PAS, 106 Lodowa St, 93-232 Lodz, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rumijowska-Galewicz
authors.affiliation: Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 101 Żwirki and Wigury St, 02-089 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Ruszczynska
authors.affiliation: Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology PAS, 106 Lodowa St, 93-232 Lodz, Poland.
authors.forename: Mirosława
authors.initials: M
authors.lastname: Studzińska
authors.affiliation: Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology PAS, 106 Lodowa St, 93-232 Lodz, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jabłońska
authors.affiliation: Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology PAS, 106 Lodowa St, 93-232 Lodz, Poland.
authors.forename: Edyta
authors.initials: E
authors.lastname: Paradowska
authors.affiliation: Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 101 Żwirki and Wigury St, 02-089 Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Bulska
authors.affiliation: Institut Pasteur, Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, 28 Rue du Dr Roux, F-75724 Paris cedex 15, France; CNRS UM53523, F-75015 Paris, France.
authors.forename: Hélene
authors.initials: H
authors.lastname: Munier-Lehmann
authors.affiliation: Laboratory of Mycobacterium Genetics and Physiology, Institute of Medical Biology PAS, 106 Lodowa St, 93-232 Lodz, Poland.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Dziadek
authors.affiliation: Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology PAS, 106 Lodowa St, 93-232 Lodz, Poland.
authors.forename: Zbigniew J
authors.initials: ZJ
authors.lastname: Leśnikowski
authors.affiliation: Screening Laboratory, Institute of Medical Biology PAS, 106 Lodowa St, 93-232 Lodz, Poland. Electronic address: aolejniczak@cbm.pan.pl.
authors.forename: Agnieszka B
authors.initials: AB
authors.lastname: Olejniczak
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001881:Borates / Q000494:pharmacology; D001896:Boron Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D009161:Mycobacterium / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives*
chemical_list: C535189:7,8-dicarba-nido-undekaborate; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001881:Borates; D001896:Boron Compounds; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013941:Thymine
keywords: Anti-mycobacterial activity; Boron cluster; Nucleobase; Nucleoside