title: 5'-Trityl-substituted thymidine derivatives as a novel class of antileishmanial agents: Leishmania infantum EndoG as a potential target.
abstract: Two series of 5'-triphenylmethyl (trityl)-substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes and amastigotes. Several of these compounds show significant antileishmanial activity, with IC50 values in the low micromolar range. Among these, 3'-O-(isoleucylisoleucyl)-5'-O-(3,3,3-triphenylpropanoyl)thymidine displays particularly good activity against intracellular amastigotes. Assays performed to characterize the nature of parasite cell death in the presence of the tritylthymidines indicated significant alterations in mitochondrial transmembrane potential, an increase in superoxide concentrations, and also significant decreases in DNA degradation during the cell death process. Results point to the mitochondrial nuclease LiEndoG as a target for the action of this family of compounds.
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Casanova
authors.forename: David
authors.initials: D
authors.lastname: Moreno
authors.forename: Alba
authors.initials: A
authors.lastname: Gigante
authors.forename: Eva
authors.initials: E
authors.lastname: Rico
authors.forename: Carlos Mario
authors.initials: CM
authors.lastname: Genes
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliva
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.forename: Antonio
authors.initials: A
authors.lastname: Jiménez-Ruiz
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Pérez-Pérez
mesh_terms: D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004706:Endodeoxyribonucleases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D018314:Leishmania infantum / Q000187:drug effects* / Q000201:enzymology*; D008928:Mitochondria / Q000201:enzymology; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D013936:Thymidine