NEIGHBORING GROUP CATALYSIS IN THE DESIGN OF NUCLEOTIDE PRODRUGS

An approach is described for potential application to the delivery of polar nucleosides and nucleotides across lipophilic membranes, namely, nucleotide prodrugs based on salicyl phosphate. 3'-Azido-3'-deoxythym idine (AZT) and 3'-deoxythymidine (ddT) were chosen as models. For the synthesis of prototype compounds 1 and 2, the approach was first to r eact either methyl salicylate (for 1) or phenyl salicylate (for 2) wit h phosphorus oxychloride in dry methylene chloride at 0 degrees C with the addition of triethylamine as acid scavenger. The resulting interm ediate phosphorodichloridate was reacted immediately with excess nucle oside under the same conditions. The control model compound 3 was prep ared by reaction of phenyl phosphorodichloridate and excess nucleoside in pyridine/methylene chloride at 0 degrees C to give 3 in 82% yield. The synthesis of triester 7 involved reaction of alpha-(chloroacetyl) salicyl chloride with 2,3,4,6-tetra-O-benzyl-D-glucopyranose to give p yranosyl)oxy]carbonyl]-2-(1-chloroacetoxy)benzene (4) which was dechlo roacetylated to 5, 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl salicylate. Phosphorylation of 5 with phosphorus oxychloride provided the phospho rodichloridate which was directly converted to 6 by reaction with dide oxythymidine. Removal of benzyl groups by catalytic hydrogenation gave compound 7, bis(2',3'-dideoxythymidin-5'-yl) D-glucopyranosyl phospha te. The AZT prodrug triesters, 1 and 2, underwent much more rapid hydr olysis than the triester 3, most probably due to the formation of an a cyl phosphate complex from the attack on phosphorus of the salicylate carboxylate. The hydrolysis of the less lipophilic 7 was significantly slower than that of 1 or 2. Both pig liver esterase and rat brain cyt osol were able to effect the cleavage to dinucleotide or mononucleotid e of prodrug forms 2 and 7, much more rapidly than either 3 or 1, sugg esting that the esterase-like enzymatic activity of rat brain was simi lar to that of pig liver esterase. This study suggests the possibility of use of salicylic acid-based prodrugs for nucleotides, subject to s pecific refinements in the choice of carboxylate- and phosphoric acid ester-protecting groups.