Prodrugs of 9-.beta.-D-arabinofuranosyladenine. 1. Synthesis and evaluation of some 5'-(O-acyl) derivatives

Abstract

A number of 5'-(O-acyl) derivatives of 9-beta-D-arabinofuranosyladenine (ara-A, VIRA-A) (2a-k) were prepared by direct acylation of the parent nucleoside 1 in pyridine-N,N-dimethyliformamide. These compounds, designed as prodrugs for 1, offer a range of solubilities and lipophilicities indicating for several examples improved solubility and the potential for improved membrane transport over 1. All are resistant to deactivation by adenosine deaminase. Of special interest is the 5'-(O-valeryl) derivative 2d that shows a marked increase in antiviral activity over 1.

Ring‐Open Analogues of Adenine Nucleoside. Aminoacyl Derivatives of Cyclo‐ and Acyclo‐Nucleosides

“…Consequently, many investigations have been carried out on flexible analogues of enzyme substrates, which have all the chemical features of deoxyadenosine, but which lack a rigid carbohydrate ring structure [7-151. Furthermore, a low lipophilicity of ara-A precludes its use as a topical agent for treating genital, oral, and other cutaneous herpes infections [16]. In addition, the parental administration of ara-A does suffer from a low aqueous solubility of the drug [ …”

Role of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of Purine-Related Drugs

“…Inhibition of ADA by co-administration of modified purine analogues with vidarabine, such as deoxycoformacine, can improve the therapeutic effect of vidarabine (Bryson et al, 1974(Bryson et al, , 1976. In addition, vidarabine has limited lipid solubility which the low delivery from cell membrane and very low solubility in water (about 0.47 mg/ml), therefore, the large fluid volumes is needed for intravenous administration (Baker et al, 1978;.…”

Synthesis of Carbocyclic 3-Deazaadenosine Analogs as Potential Agents Against Poxvirus

“…Since these targets had not previously been reported, we reviewed the literature for 5'-0-acylated nucleosides or analogs and found general approaches that seemed appropriate for the synthesis of our targets: 5'-0-acylation of 5 2',3'-isopropylidene undine followed by deprotection 5 ; and the direct 5'-0-acylation of 9-ß-Darabinofuranosyladenine (Ara-A). 6 " 8 The enzymatic acylation of adenosine 9 ' 10 also initially seemed like a possible approach. We chose not to pursue this approach because we could not find a convenient source for any of the reported enzymes (e.g., subtilisin, Candida antarctica lipases SP435-345A), because the possible alternative enzymes found commercially (e.g., Sigma) were generally expensive, and because we were uncertain that the successful enzymatic acylation of adenosine would also work with CADO.…”