Preparation of azacrown-functionalized 2'-O-methyl oligoribonucleotides, potential artificial RNases.
An improved synthesis for 3-(3-aminopropyl)- and 3-(3-mercaptopropyl)-1,5,9-triazacyclododecane has been developed and alternative methods for their conjugation to oligonucleotides have been described. Accordingly, the 3-aminopropyl azacrown and its N-(3-aminopropanoyl)-3-aminopropyl analogue have been tethered to the 3'-terminus of a 2'-O-methyloligoribonucleotide by aminolytic cleavage of the thioester linker utilized for the chain assembly. Studies on a monomeric model compound verify that the reaction proceeds solely by the attack of the primary amino group. 5'-Conjugation has been achieved by introducing a 2-benzylthio-2-oxoethyl group to the 5'-terminus as a phosphoramidite reagent and cleaving the thioester bond with the 3-aminopropyl azacrown. For intrachain conjugation, a phosphoramidite reagent derived from 1-deoxy-1-(2-benzylthio-2-oxoethyl)-beta-d-erythro-pentofuranose has been inserted in a desired position within the chain and subjected to on-support aminolysis with the 3-aminopropyl azacrown or its N-(3-aminopropanoyl)-3-aminopropyl and N-(6-aminohexanoyl)-3-aminopropyl analogues. The 3-mercaptopropyl-derivatized azacrown has been tetherd by a disulfide bond to a 3'-(3-mercaptoalkyl)phosphate-tailed oligonucleotide. The 3'- and intrachain-tethered conjugates have been shown to cleave as their Zn(II) chelate complementary oligoribonucleotide sequences.
Niittymäki
Teija
T
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland.
Kaukinen
Ulla
U
Virta
Pasi
P
Mikkola
Satu
S
Lönnberg
Harri
H
D004220:Disulfides / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009843:Oligoribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D012260:Ribonucleases / Q000138:chemical synthesis* / Q000737:chemistry
D004220:Disulfides; D006573:Heterocyclic Compounds, 1-Ring; D007202:Indicators and Reagents; D009843:Oligoribonucleotides; D010455:Peptides; D012260:Ribonucleases