9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo.

• DOI: 10.1073/pnas.88.11.4961
• Publication Date: 2006-05-31T11:40:24Z
• Authors: J Balzarini; A Holy; J Jindrich; H Dvorakova; Z Hao; R Snoeck; P Herdewijn; D G Johns; E De Clercq
• Keywords: DNA Replication; 0301 basic medicine; Avian Myeloblastosis Virus; 0303 health sciences; Adenine; Organophosphonates; HIV; Antiviral Agents; HIV Reverse Transcriptase; Cell Line; 3. Good health; Mice; Structure-Activity Relationship; 03 medical and health sciences; Cell Transformation, Neoplastic; Organophosphorus Compounds; Retroviridae; Purines; HIV-2; HIV-1; Animals; Humans; Reverse Transcriptase Inhibitors; Simian Immunodeficiency Virus

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.