title: Solid-phase combinatorial synthesis of a lysyl-tRNA synthetase (LysRS) inhibitory library.
abstract: The solid-phase combinatorial synthesis of a new library with potential inhibitory activity against the cytoplasmic lysyl-tRNA synthetase (LysRS) isoform of Trypanosoma brucei is described. The library has been specifically designed to mimic the lysyl adenylate complex. The design was carried out by dividing the complex into four modular parts. Proline derivatives (cis-gamma-amino-L-proline or trans-gamma-hydroxy-L-proline) were chosen as central scaffolds. After primary screening, three compounds of the library caused in vitro inhibition of the tRNA aminoacylation reaction in the low micromolar range.
authors.affiliation: Institute for Research in Biomedicine and Combinatorial Chemistry Unit, Barcelona Science Park, University of Barcelona, Josep Samitier 1, 08028-Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Farrera-Sinfreu
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Español
authors.forename: Renaud
authors.initials: R
authors.lastname: Geslain
authors.forename: Tanit
authors.initials: T
authors.lastname: Guitart
authors.forename: Fernando
authors.initials: F
authors.lastname: Albericio
authors.forename: Lluís
authors.initials: L
authors.lastname: Ribas de Pouplana
authors.forename: Miriam
authors.initials: M
authors.lastname: Royo
mesh_terms: D049148:Aminoacylation / Q000187:drug effects; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D008250:Lysine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D008968:Molecular Conformation; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D014346:Trypanosoma brucei brucei / Q000201:enzymology
chemical_list: D000981:Antiprotozoal Agents; D011392:Proline; D008250:Lysine-tRNA Ligase