SYNTHESIS AND PROPERTIES OF PHOSPHODIESTER AND TRIESTER DERIVATIVES OF AZT WITH TETHERED POTENTIAL RIBONUCLEASES

The synthesis of phosphate ester derivatives of AZT with tethered N,N, N'trimethylethylenediamine, N-methylpiperazine and 2,6-diacetyl pyridi ne as prodrugs of AZT with potential ribonuclease activity was describ ed. The metal complexes of these compounds should combine a reverse tr anscriptase inhibition and the ability to hydrolyze the RNA of HIV. Di fferent phosphorus chemistries have been used to synthetize phosphodie sters. The synthesis of phosphotriesters was achieved by a nucleophili c displacement of the halogeno moieties by an activated phosphodiester in one or two chemical steps. The copper complexes of N,N,N'trimethyl ethylenediamine derivatives were fully characterized and their ribonuc lease activity toward 25-mer and 28-mer oligoribonucleotides was demon strated by capillary electrophoresis. The in vitro anti HIV preliminar y assays revealed no synergistic effect with copper chelate on the act ivity of the prodrugs.