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Acyclic nucleoside phosphonates (ANPs) inhibit replication of both DNA viruses and retroviruses, including HIV. The major mechanism of their antiviral action is inhibition of virus-induced DNA polymerases and/or of reverse transcriptases. We investigated the effects of ANPs on proliferation of mitogen-stimulated mouse and rat splenocytes. Included in the study were compounds differing at the heterocyclic base, i.e., adenine (A) and 2,6-diaminopurine (DAP), and at the N9-side chain, i.e., 9-[2-(phosphonomethoxy)ethyl] (PME) and (R)- or (S)-enantiomers of 9-[2-(phosphonomethoxy)propyl] (PMP) moieties, and their numerous N6-substituted derivatives. The medial inhibitory concentrations (IC50) of N6-nonsubstituted compounds range from 0.13 (PMEDAP) to 354 μM ((R)-PMPA). Antiproliferative effects are more pronounced in PME than in PMP series, and they are more prominent in DAP compared to A analogs. The (S)-enantiomers of PMP series are more effective than corresponding (R)-congers. The highest cytostatic potential is exhibited by N6-allyl-PMEDAP (IC50 = 0.017 μM) and N6-cyclopropyl-PMEDAP (IC50 = 0.036 μM). The N6-substituted derivatives of (S)-PMPA are virtually devoid of cytostatic activity. No tight correlation between the cytostatic and reported antiviral effects could be detected.