Synthesis,and Some Properties of,Amphiphilic Dinucleoside Phosphate Derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT)

Abstract

N⁴-hexadecyl-5′-0-(4-monomethoxytrityl)-2′-deoxycytidine-3′-hydrogenphosphate was reacted with 3′-azido-2′,3′-dideoxythymidine (AZT) according to the hydrogenphosphate method to yield N⁴-hexadecyl-2′-deoxycytidylyl-(3′-5)-3′-azido-2′,3′-dideoxythymidine. N⁴-palmitoyl-5′-O-(4-monomethoxytrityl)-2′-deoxycytidine-3′-(2-chlorophenyl)-phosphate was condensed to AZT using the triester method to give N⁴-palmitoyl-2′-deoxycytidylyl-(3′-5′)-3,-azido-2′,3′-dideoxythymidine. Both dinucleosidephosphates have amphiphilic properties and represent a new class of AZT derivatives in which the polar AZT-5′-monophosphate is masked with lipophilic deoxycytidine residues of variable stability. The AZT derivatives are water soluble, by forming micelles, and as a result of their amphiphilic nature, they can be incorporated into the lipid membranes of liposomes. In contrast to the micellar drug preparations, the liposomal formulations were shown to exert no lytic activity on human erythrocytes. Both AZT derivatives have anti HIV-1 activity in vitro.