Synthesis of a 1'-aminomethylthymidine and oligodeoxyribonucleotides with 1'-acylamidomethylthymidine residues.
Reported here is a 10-step synthesis of a phosphoramidite building block of 1'-aminomethylthymidine that starts from 2-deoxyribose. The framework of the branched aminonucleoside was elaborated from a known 1-cyano-1-bromo glycosyl donor, whose reaction with the silylated nucleobase furnished the 1'-cyanide, which was reduced to the desired aminomethylnucleoside. The N-allyloxycarbonyl (Alloc)-protected nucleoside was converted to a phosphoramidite building block and incorporated into the oligonucleotides 5'-GCAT*TATTAC-3', and 5'-GCAT*TAT*TAC-3', where T* denotes 1'-acylamidomethylthymidine residues. Removal of the Alloc protecting group and acylation with the residue of pyrene-1-yl-butanoic acid were achieved on support, using microwave irradiation to ensure full conversion. The UV-melting point of the duplex of the singly and doubly modified decamers with their fully complementary target sequence is 0.1-6.9 degrees C higher than that of the unmodified control duplex, depending on the salt concentration. This suggests that the aminomethyl linker may allow for the placing of a functional "payload" in the minor groove of DNA duplexes without disrupting the helix. Oligonucleotides thus endowed with functional modifications may become useful for biomedical applications.
Grünefeld
Peter
P
Institute for Organic Chemistry, University of Karlsruhe (TH), D-76131 Karlsruhe, Germany.
Richert
Clemens
C
D001483:Base Sequence; D002625:Chemistry, Organic / Q000379:methods*; D004247:DNA / Q000737:chemistry; D003855:Deoxyribose / Q000737:chemistry; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013936:Thymidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry
D009838:Oligodeoxyribonucleotides; D003855:Deoxyribose; D004247:DNA; D013936:Thymidine