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J Med Chem. 1998 Apr 9;41(8):1284-98.

Synthesis and antiviral activity of novel acyclic nucleosides: discovery of a cyclopropyl nucleoside with potent inhibitory activity against herpesviruses.

Author information

1
Central Research Laboratories, Ajinomoto Company, Inc., 1-1 Suzuki-cho, Kawasaki 210, Japan.

Abstract

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 microg/mL against HSV-1 Tomioka vs 0.81 microg/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.

PMID:
9548818
DOI:
10.1021/jm9705869
[Indexed for MEDLINE]

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