title: The synthesis of isopropylidene mRNA cap analogs modified with phosphorothioate moiety and their evaluation as promoters of mRNA translation.
abstract: Synthetic mRNA cap analogs are valuable tools in the preparation of modified mRNA transcripts with improved translational activity and increased cellular stability, and have recently attracted more attention because of their great potential in therapeutic applications. We have synthesized and tested isopropylidene dinucleotide cap analogs bearing a phosphorothioate group at the β position of the 5',5'-triphosphate bridge (two diastereomers of 2',3'-iPr-m(7)GppSpG), as synthetically simpler alternatives to previously obtained phosphorothioate cap analogs. To evaluate the utility of the new compounds in biological systems we determined their affinity to translation initiation factor 4E (eIF4E), and tested their translational properties in rabbit reticulocyte lysates (RRL) and in human immature dendritic cells (hiDCs). In order to explain the properties of isopropylidene analogs we performed (1)H NMR conformational analysis and correlated the absolute configuration at the β-phosphorous atom with previously synthesized m(7)GppSpG.
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Warminski
authors.forename: Joanna
authors.initials: J
authors.lastname: Kowalska
authors.forename: Janina
authors.initials: J
authors.lastname: Buck
authors.forename: Joanna
authors.initials: J
authors.lastname: Zuberek
authors.forename: Maciej
authors.initials: M
authors.lastname: Lukaszewicz
authors.forename: Corina
authors.initials: C
authors.lastname: Nicola
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Kuhn
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
authors.forename: Edward
authors.initials: E
authors.lastname: Darzynkiewicz
authors.forename: Jacek
authors.initials: J
authors.lastname: Jemielity
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D010710:Phosphates / Q000737:chemistry*; D012315:RNA Caps / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics; D011817:Rabbits; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics
chemical_list: D000475:Alkenes; D010710:Phosphates; D012315:RNA Caps; D012333:RNA, Messenger; C083120:phosphorodithioic acid; C013658:propylene