Deoxythreosyl Phosphonate Nucleosides as Selective Anti-HIV Agents

Abstract

Out of a series of eight new phosphonate nucleosides with an l-threose and an l-2-deoxythreose sugar moiety, two new compounds were identified (PMDTA and PMDTT) that showed potent anti-HIV-1 (HIV-2) activity [EC50 = 2.53 microM (PMDTA) and 6.59 microM (PMDTT)], while no cytoxicity was observed at the highest concentration tested [CC50 > 316 microM (PMDTA) and > 343 microM (PMDTT)]. The kinetics of incorporation of PMDTA into DNA (using the diphosphate of PMDTA as substrate and HIV-1 reverse transcriptase as catalyst) was similar to the kinetics observed for dATP, while the diphosphate of PMDTA was a very poor substrate for DNA polymerase alpha. The incorporated PMDTA fits very well in the active site pocket of HIV-1 reverse transcriptase.

Role of Hydroxymethyl Group as a New Hydrophilic 4'-Pocket in 5'-Norcarbocyclic Nucleoside Analogues

“…7 The phosphonate has certain advantages over its phosphate counterpart as it is metabolically stable because its phosphoruscarbon bond is not susceptible to hydrolytic cleavage. 8 The spacial location of the oxygen atom, namely the β-position from the phosphorus atom in the nucleoside analogue, plays a critical role in the antiviral activity. This increased antiviral activity with this oxygen atom may be attributed to the increased binding capacity of the phosphonate analogues to target enzymes.…”

“…The hydroxyl functional group of (5) was subjected to protection reaction by benzyl bromide (BnBr, NaH, DMF) to furnish the acetonide (6), which was subjected to hydrolysis to provide diol derivative (7). The selective protection of primary hydroxyl group of (7) was successfully accomplished under mild silylation conditions (TBDMSCl, imidazole) to give the secondary alcohol (8). 11 The secondary hydroxyl group of (8) was oxidized to the ketone (9) using Corey and Kim's oxidation conditions (NCS, DMS).…”

Dideoxyapiose nucleosides revisited: syntheses and protide derivatives

“…Recently, Herdewijn and coworkers showed that the related L-2-deoxythreose nucleoside phosphonates (I; Figure 1) selectively inhibit HIV without affecting human DNA synthesis. 2 A serious problem associated with phosphonates, however, is their low bioavailability. Inspired by the cellular activity of I, we decided to reinvestigate the synthesis of the ddANs.…”

Synthesis and Anti-HCV Activity of 3',5'-cyclic SATE Phosphonodiester Nucleoside as a Novel Prodrug

“…However, a phosphonate has certain advantages over its phosphate counterpart as it is metabolically stable because its phosphorus-carbon bond is not susceptible to hydrolytic cleavage. 11 Moreover, a phosphonate nucleoside can skip the requisite first phosphorylation, which is a crucial step for the activation of nucleosides. Though triphosphates of several of these nucleoside analogues exhibit excellent RdRp inhibitory potency, only a few nucleoside derivatives have exhibited biological activity in cell culture assays.…”