Design and synthesis of vidarabine prodrugs as antiviral agents

Abstract

5'-O-D- and L-amino acid derivatives and 5'-O-(D- and L-amino acid methyl ester phosphoramidate) derivatives of vidarabine (ara-A) were synthesized as vidarabine prodrugs. Some compounds were equi- or more potent in vitro than vidarabine against two pox viruses and their uptake by cultured cells was improved compared to the parent drug.

Figure 1

Deamination of vidarabine and its prodrugs by adenosine deaminase1. Top: Concentration (μM) profiles of the disappearance of vidarabine and the appearance of Ara-H in the presence of adenosine deaminase. Bottom: Percent vidarabine or prodrug remaining following incubation with adenosine deaminase1 for 90 min.

Scheme 1

Reagents and condition: (a) TBSCl and Im./DMAP DMF; (b) levulinic acid, DCC, DMAP in ethyl acetate; and (c) TBAF/acetic acid (1:2 mole ratio) in tetrahydrofuran.

Scheme 2

Reagents and condition: (a) alpha N-Boc D- and L-amino acid, DCC, DMAP DMF; (b) 1 ml of 2 M hydrazine hydrate in pyridine–acetic acid buffer; and (c) removal of protection group from amino acid moieties.

Scheme 3

Reagents and condition: (a) one milliliter of 2 M hydrazine hydrate in pyridine–acetic acid buffer.