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Synthesis and Antiviral Activity of Novel Acyclic Nucleosides: Discovery of a Cyclopropyl Nucleoside with Potent Inhibitory Activity against Herpesviruses

1998; American Chemical Society; Volume: 41; Issue: 8 Linguagem: Inglês

10.1021/jm9705869

1520-4804

Takaaki Sekiyama, Satoshi Hatsuya, Yasuhiro Tanaka, Mamoru Uchiyama, Nobukazu Ono, Satoshi Iwayama, Miki Oikawa, Katsuya Suzuki, Masahiko Okunishi, Takashi Tsuji,

HIV Research and Treatment

A series of acyclic nucleosides with two hydroxymethyl groups mimicking the 3'- and 5'-hydroxyl groups of the 2'-deoxyribose moiety were prepared and evaluated for their antiherpetic activity. Among those, 9-[[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine (3) showed extremely potent antiviral activity against herpes simplex virus type-1 (HSV-1) with good selectivity. Both enantiomers of 3 were synthesized starting from chiral epichlorohydrins, and only one of the enantiomers with 1'S,2'R-configuration (3a) exhibited strong antiherpetic activity (IC50 of 0.020 μg/mL against HSV-1 Tomioka vs 0.81 μg/mL for acyclovir). Enantiomer 3a was also more inhibitory than acyclovir against varicella-zoster virus (VZV) but ineffective against human immunodeficiency virus (HIV). Compound 3a is phosphorylated by HSV-1 thymidine kinase (TK) very efficiently. The relationship between conformation and antiherpetic activity in this series of compounds is discussed.