title: Triazole-containing monophosphate mRNA cap analogs as effective translation inhibitors.
abstract: Synthetic analogs of the 5' end of mRNA (cap structure) are widely used in molecular studies on mechanisms of cellular processes such as translation, intracellular transport, splicing, and turnover. The best-characterized cap binding protein is translation initiation factor 4E (eIF4E). Recognition of the mRNA cap by eIF4E is a critical, rate-limiting step for efficient translation initiation and is considered a major target for anticancer therapy. Here, we report a facile methodology for the preparation of N2-triazole-containing monophosphate cap analogs and present their biological evaluation as inhibitors of protein synthesis. Five analogs possessing this unique hetero-cyclic ring spaced from the m7-guanine of the cap structure at a distance of one or three carbon atoms and/or additionally substituted by various groups containing the benzene ring were synthesized. All obtained compounds turned out to be effective translation inhibitors with IC50 similar to dinucleotide triphosphate m(7)GpppG. As these compounds possess a reduced number of phosphate groups and, thereby, a negative charge, which may support their cell penetration, this type of cap analog might be promising in terms of designing new potential therapeutic molecules. In addition, an exemplary dinucleotide from a corresponding mononucleotide containing benzyl substituted 1,2,3-triazole was prepared and examined. The superior inhibitory properties of this analog (10-fold vs. m(7)GpppG) suggest the usefulness of such compounds for the preparation of mRNA transcripts with high translational activity.
authors.affiliation: Faculty of Chemistry, University of Warsaw, 02-093, Warsaw, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Piecyk
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-089, Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lukaszewicz
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-089, Warsaw, Poland Centre of New Technologies, University of Warsaw, 02-097, Warsaw, Poland.
authors.forename: Edward
authors.initials: E
authors.lastname: Darzynkiewicz
authors.affiliation: Faculty of Chemistry, University of Warsaw, 02-093, Warsaw, Poland marzena@chem.uw.edu.pl.
authors.forename: Marzena
authors.initials: M
authors.lastname: Jankowska-Anyszka
mesh_terms: D000818:Animals; D010710:Phosphates / Q000737:chemistry*; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D012314:RNA Cap Analogs / Q000138:chemical synthesis / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics*; D011817:Rabbits; D012156:Reticulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014230:Triazoles / Q000737:chemistry*; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D010710:Phosphates; D011500:Protein Synthesis Inhibitors; D012314:RNA Cap Analogs; D012333:RNA, Messenger; D014230:Triazoles; D055544:beta-Globins
keywords: 1,2,3-triazole; cap analog; cap-dependent translation; click chemistry; mRNA; translation inhibitor