Ekaterina Viazovkina

A New Synthesis of 9-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)guanine (araF-G)

Abstract Interesting and very promising antisense properties of 2′-deoxy-2′-fluoroarabinonucleic acids ((a) Wilds, C.J.; Damha, M.J. 2′-Deoxy-2′-fluoroarabinonucleosides and oligonucleotides (2′F-ANA): synthesis and physicochemical studies. Nucl. Acids Res. 2000, 28, 3625–3635; (b) Viazovkina, E.; Mangos, M.; Elzagheid, M.I.; Damha, M.J. Current Protocols in Nucleic Acid Chemistry 2002, 4.15.1–4.15.21) (2′F-ANA) has encouraged our research group to optimize the synthetic procedures for 2′-deoxy-2′-fluoro-β-D-arabinonucleosides (araF-N). The synthesis of araF-U, araF-T, araF-A and araF-C is straightforward, (Tann, C.H.; Brodfuehrer, P.R.; Brundidge, S.P.; Sapino, C., Jr. Howell H.G. Fluorocarbohydrates in synthesis. An efficient synthesis of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouracil (β-FIAU) and 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)thymine (β-FMAU). J. Org. Chem. 1985, 50, 3644–3647; Howell, H.G.; Brodfuehrer, P.R.; Brundidge, S.P.; Benigni, D.A.; Sapino, C., Jr. Antiviral nucleosides. A stereospecific, total synthesis of 2′-fluoro-2′-deoxy-β-D-arabinofuranosyl nucleosides. J. Org. Chem. 1988, 53, 85–88; Maruyama, T.; Takamatsu, S.; Kozai, S.; Satoh, Y.; Izana, K. Synthesis of 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine bearing a selectively removable protecting group. Chem. Pharm. Bull. 1999, 47, 966–970) however, the synthesis of the guanine analogue is more complicated and affords poor to moderate yields of araF-G (4) ((a) Elzagheid, M.I.; Viazovkina, E.; Masad, M.J. Synthesis of protected 2′-deoxy-2′-fluoro-β-D-arabinonucleosides. Synthesis of 2′-fluoroarabino nucleoside phosphoramidites and their use in the synthesis of 2′F-ANA. Current Protocols in Nucleic Acid Chemistry 2002, 1.7.1–1.7.19; (b) Tennila, T.; Azhayeva, E.; Vepsalainen, J.; Laatikainen, R.; Azhayev, A.; Mikhailopulo, I. Oligonucleotides containing 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine and -guanine: synthesis, hybridization and antisense properties. Nucleosides, Nucleotides and Nucl. Acids 2000, 19, 1861–1884). Here we describe an efficient synthesis of araF-G (4) that involves coupling of 2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D- arabinofuranosyl bromide (1) with 2-chlorohypoxanthine (2) to afford 2-chloro-β-araF-I (3) in 52% yield. Nucleoside (3) was transformed into araF-G (4) by treatment with methanolic ammonia (150°C, 6 h) in 67% yield.

Synthesis and Physicochemical Properties of 2′-Deoxy- 2′,2″-difluoro-β-D-ribofuranosyl and 2′-Deoxy-2′,2″- difluoro-α-D-ribofuranosyl Oligonucleotides

Abstract We present procedures for nucleoside and oligonucleotide synthesis, binding affinity (T m) and structural analysis (CD spectra) of 2′-deoxy-2′,2″-difluoro-α-D-ribofuranosyl and 2′-deoxy-2′,2″-difluoro-β-D-ribofuranosyl oligothymidylates. Possible reasons for the thermal instability of duplexes formed between these compounds and RNA or DNA targets are discussed.

Synthesis and Properties of Oligonucleotide Chimeras Containing 5′-Amino-2′-deoxy-2′-fluoroarabinonucleosides

Abstract Oligonucleotide analogues comprised of 2′-deoxy-2′-fluoro-β-D-arabinose units joined via P3′-N5′ phosphoramidate linkages (2′F-ANA5′N) were prepared for the first time. Among the compounds prepared were a series of 2′OMe-RNA-[GAP]-2′OMe-RNA ‘chimeras’, whereby the “GAP” consisted of DNA, DNA5′N, 2′F-ANA or 2′F-ANA5′N segments. The chimeras with the 2′F-ANA and DNA gaps exhibited the highest affinity towards a complementary RNA target, followed by the 5′-amino derivatives, i.e., 2′F-ANA > DNA > 2′F-ANA5′N > DNA5′N. Importantly, hybrids between these chimeras and target RNA were all substrates of both human RNase HII and E.coli RNase HI. In terms of efficiency of the chimera in recruiting the bacterial enzyme, the following order was observed: gap DNA > 2′F-ANA > 2′F-ANA5′N > DNA5′N. The corresponding relative rates observed with the human enzyme were: gap DNA > 2′F-ANA5′N > 2′F-ANA > DNA5′N.