Synthesis of a purine acyclonucleoside series having pronounced antiviral activity. The glyceropurines

Abstract

The synthesis of a series of purine analogues of the acyclonucleoside compound A* (A-Star, 1) is described. Compounds in this series have been shown to have pronounced activity against herpesviruses. These compounds have been designated "the glycerosides". The glyceropurines are described in this report. Nucleotides have been constructed containing glyceroadenine (A*, compound 1). These nucleotides are resistant to degradation by phosphodiesterases. The compound A* is both a poor substrate and a poor inhibitor of adenosine deaminase.

Solution Conformations of Some Acyclo Nucleoside and Nucleotide Analogues of Antiviral Acyclonucleosides, and Their Substrate/Inhibitor Properties in Several Enzyme Systems

“…The product, m.p. 195 -196 °C, compared to reported values of 193-195 °C [12] and 195-197 °C [14], was chromatographically homogeneous in 4 solvent systems (Table I). 2',3'-seco derivatives of nucleosides and nucleotides were prepared as previously described [9,10].…”

“…(DHPAde) was prepared according to Ogilvie et al [12] by condensation of 6-chloropurine, obtained by chlorination of hypoxanthine according to Beaman and Robins [13], with l,3-dibenzoxy-2-propanol (kindly provided by Dr. M. Draminski). The product, m.p.…”

A trihydroxy acyclonucleoside series

“…The route to compound 5 is outlined in Scheme 1. The starting material, 1,3-dibenzyloxy-2-propanol (I), is readily available (5) and is easily oxidized to the ketone 2 using N-chlorosuccinimide and dimethyl sulfide (14). Other common oxidizing agents such as pyridinium chlorochromate, pyridinium dichromate, and Jones reagent were less successful.…”

“…We have developed an analogue structure Y (2-6, the "glycerosides"), members of which have shown pronounced antiviral activity (5,(7)(8)(9)(10)(11)(12). As part of our overall program to determine the limits on structural changes to the side chain with regard to optimal biological activity, we have introduced specific changes at the 3'-position.…”

Evaluation of retinal toxicity and efficacy of the anticytomegalovirus compound 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine

“…In the synthesis of these purine nucleosides with acyclic substituents, the N-9 region selectivity of the coupling of the heterocycle with the acyclic residue was considered essential, as natural purine nucleosides are substituted at N-9. Compound 2242 (2-amino-7-[(1,3dihydroxy-2-propoxy)methyl]purine) is the first known nucleoside analog with the side chain substituted at the N-7 position of the purine ring system that is active against herpesviruses (19,20,23,26,27). Activity against ganciclovirresistant herpes simplex virus type 1 (HSV-1) and HSV-2 strains as well as against ganciclovir-resistant human CMV strains was also found, indicating a different mode of action (13,25,33).…”