A Dihydroisoquinoline Targetor-Based Acid Resistant Chemical Delivery System of Azidothymidine (AZT)

Abstract

A 1,2-dihydroisoquinoline targetor-based brain-specific chemical delivery system (CDS) (6) was prepared for 3'-deoxyazidothymidine (AZT). The synthesis involved acylation of the 5'-OH group of the AZT by the anhydride of isoquinoline-4-carboxylic acid, followed by N-methylation with methyl iodide of the resulting ester and subsequent sodium borohydride reduction of the quaternary salt. Lipophilicity and stability studies in buffers and biological tissues were performed for 6 in comparison with a similar 1,4-dihydropyridine targetor-based CDS of AZT (7). The dihydroisoquinoline derivative 6 proved to be more lipophilic than 7 and quite stable to acidic conditions, including in pH 1.2 simulated gastric fluid, while the dihydropyridine analog rapidly degraded under these conditions as a result of an irreversible water addition reaction. The oxidation of the isoquinoline CDS in brain tissue was some-what slow compared to the dihydropyridine derivative. The study indicated that the isoquinoline-based CDS, 6, generally possesses the properties required for oral administration.