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.

Synthesis andin vitroAntiviral Properties of Amphiphilic Dinucleoside Phosphate Derivatives of 2′,3-dideoxycytidine (ddC)

“…Microanalysis was within usual limits for C, Hand N, for M[H 2012. The following substances were synthesized according to published methods: 2',3'-dideoxycytidine (Okabe et el., 1988), palmitic anhydride (Schott et al, 1994a), N 4-hexadecyl-5'-0-(4-monomethoxytrityl)-2'-deoxycytidine-3'-0-hydrogenphosphonate 2a and 5'-0-(4-monomethoxytrityl)-2'-deoxythymidine-3'-0-hydrogenphosphonate 2b (Schott et al, 1994b). 2',3'-Dideoxycytidine was also obtained as a gift from Dr P. Sorter, Hoffmann-La Roche, Nutley, NJ.…”

“…TLC was performed on pre-coated silica gel plates 60 F 254 (0.25mm, Merck) using chloroform/methanol mixtures as mobile phases. The nucleoside derivatives and impurities were detected as previously described (Schott et al, 1994a). Column chromatography was carried out on silica gel 60 (0.04-0.063 mm).…”

“…The signal for H8 appears at 5.86 ppm in 3a and at 7.22 ppm in 3b, whereas H9 is shifted from 8.07 to 8.35 ppm. strated that such derivatives are active in vitro against HIV-1 and in vivo in a murine Rauscher leukemia virus model (Schott et al, 1994a;Schwendener et al, 1994).…”