9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo.
A new class of compounds, 9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] [(RS)-FPMP] derivatives of purines, is described that has selective activity against a broad spectrum of retroviruses [including human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)] but not other RNA or DNA viruses. This activity spectrum is completely different from that of the parental compounds, 9-[(2S)-3-hydroxy-2-phosphonylmethoxypropyl] [(S)-HPMP] derivatives of purines, which are active against a broad range of DNA viruses. The racemic (RS)-FPMP derivatives of adenine and 2,6-diaminopurine, termed (RS)-FPMPA and (RS)-FPMPDAP, respectively, are markedly more selective as in vitro antiretroviral agents than their 9-(2-phosphonylmethoxyethyl) (PME) counterparts, PMEA and PMEDAP. Also, (RS)-FPMPA and (RS)-FPMPDAP have a substantially higher therapeutic index in mice in inhibiting Moloney murine sarcoma virus-induced tumor formation and associated death and are markedly less inhibitory to human bone marrow cells than PMEA and PMEDAP. The diphosphate derivative of (RS)-FPMPA [(RS)-FPMPApp] is a potent and selective inhibitor of HIV-1 reverse transcriptase but not of HSV-1 DNA polymerase or DNA polymerase alpha. (RS)-FPMPApp, akin to PMEA diphosphate (PMEApp), acts as a DNA chain terminator. The DNA chain-terminating properties of PMEApp and (RS)-FPMPApp seem to be a prerequisite for acyclic nucleoside phosphonates to exhibit antiretrovirus (i.e., anti-HIV) activity.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Holy
A
A
Jindrich
J
J
Dvorakova
H
H
Hao
Z
Z
Snoeck
R
R
Herdewijn
P
P
Johns
D G
DG
De Clercq
E
E
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D009189:Avian Myeloblastosis Virus / Q000201:enzymology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D006678:HIV / Q000201:enzymology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D051379:Mice; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology*; D012190:Retroviridae / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011687:Purines; D018894:Reverse Transcriptase Inhibitors; C069328:9-(3-fluoro-2-phosphonylmethoxypropyl)adenine; D054303:HIV Reverse Transcriptase; D000225:Adenine