Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV-1 activity

Abstract

Combinations of an amidoalkylphosphocholine, 8, and AZT have been found to cause an apparent synergistic action in suppressing infectious HIV-1 replication. In addition, amidoalkyl, oxyalkyl, and thioalkyl ether lipids have been chemically linked to anti-HIV-1 nucleosides (AZT and DDI) through phosphate and phosphonate linkages. These conjugates have shown promising in vitro anti-HIV-1 activity. Also, the conjugates have a 5-10-fold reduction in cell cytotoxicity compared to AZT alone. The most active compound, an amidoalkyl ether lipid-AZT conjugates, 4A, was found to have a differential selectivity of 1793 in a syncytial plaque assay. In comparison, AZT alone has a value of 1281.

Boronic Acid Derivatives Targeting HIV-1

“…Thus, the lack of activity of the latter compounds may be due either to their polar Boronic Acid Derivatives Targeting HIV-1 111 TdR for 6 hrs to measure total DNA synthesis in treated and untreated cell cultures and calculate the IC so as previously described (Kucera et al, 1990). The IC 5 0 value for AZT, the control antiviral compound, was 5.1 ± 3.0 J.IM as previously reported (Piantadosi et al, 1991).…”

Synthesis and cycloaddition reactions of [2-deoxy-3,5-bis[O-(p-toluoyl)]-α-D-ribofuranosyl]ethyne

“…However, since 5 did not undergo the Diels-Alder-reaction with one of the most reactive dienes, the Danishefsky diene, 11 we chose dimethyl [1,2,4,5]tetrazine-3,6-dicarboxylate 12 6a as one of the most activated electron-deficient heterocyclic diazadienes for [4+2]-cycloadditions with inverse electron demand. Reaction of 6a with the precursor 5 resulted in a typical cycloaddition-extrusion sequence (Scheme 2).…”

“…AZT, 3'-azido-2',3'-dideoxythymidine, 1 ddI, 2′,3′-dideoxyinosine, 2 and the anti-cancer activity of some C-glycosides such as pseudocytidine 3 ), we have now synthesized the first examples of 2-deoxy-C-glycosides which combine both structural properties. We used [4+2]-and [3+2]-cycloaddition reactions of suitable acetylenic carbohydrate derivatives.…”

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

“…It is conceivable that the antiviral activity of the dideoxynucleosides might be enhanced by using masked 5'-phosphate derivatives of the corresponding nucleosides, which release the 5'-phosphorylated ddN intracellularly. Conjugates, in which dideoxynucleosides are linked by their 5'-hydroxyl group via a natural phosphodiester linkage (Hostetler et al, 1990;Steim et sl., 1990;Piantadosi et al, 1991;Amari et al, 1992) or via diphosphates (van Wijk et al, 1992a,b) to phospholipids, should provide enzymatic release by phosphodiesterases or hydrolytic cleavage of the active dideoxynucleoside-5'-monophosphate in the cytoplasm.…”