Oligonucleotides containing 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-adenine and -guanine: Synthesis, hybridization and antisense properties

Synthesis of 9-(2-deoxy-2-fluoro-beta -D-arabinofuranosyl)-adenine (7, ara- A(2'F)) and -guanine (12, ara-G(2'F)) was accomplished via the condensation of 2,6-dichloropurine (1) with 2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-alpha -D-arabinofuranose (2) as a key chemical step. Condensation of silylated N- 6-benzoyladenine (6) with 2 gave, after deblocking and chromatographic sepa ration, ara-A(2'F) (7) (14%), it's alpha -anomer 8 (14%) and N-7-alpha -iso mer 9 (25%). The PSEUROT analysis of N-9-beta -D-arabinosides 7 and 12 mani fested slight preference for the S rotamer (64%) for the former, and an equ al population of the N and S rotamers for the latter. The arabinosides 7 an d 12 were used for the preparation of the respective phosphoamidite buildin g blocks 13 and 14 for automated oligonucleotide synthesis. Four 15-mer oli gonucleotides (ONs) complementary to the initiation codon region of firefly luciferase mRNA were prepared: unmodified 2'-deoxy-ON (AS1) and containing (i) ara-A(2'F) instead of the only A (AS2), (ii) ara-G(2'F) vs. 3-G from t he 5'-terminus (AS3), and (iii) both arabinosides at the same positions (AS 4). All these ONs display practically the same (i) affinity to both complem entary DNA and RNA, and (ii) ability to inhibit a luciferase gene expressio n in a cell-free transcription-translation system.