We compared the anti-HIV activity of 13 phenyl phosphate derivatives of stavudine (2′,3′-didehydro-2′,3′-dideoxythymidine/d4T) by examining their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells. Our results show that the introduction of electron-withdrawing substituents enhances the activity of these phosphoramidate derivatives. The rate of chemical hydrolysis under alkaline conditions (but not the lipophilicity) predicted the potency of the compounds.
BalzariniJHeredewijnPDe ClercqE (1989). Differential patterns of intracellular metabolism of 2′,3′-didhydro-2′,3′-dideoxythymidine and 3′-azido-2′,3′-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. Journal of Biological Chemistry264: 6127–6133.
2.
GreeneWC (1991). The molecular biology of human immunodeficiency virus Type-1 infections. New England Journal of Medicine324: 308–317.
3.
McInteeEJRemmelRPSchinaziRFAbrahamTW & WagnerCR (1997). Probing the mechanism of action and decomposition of aminoacid phosphomonoester amidates of antiviral necleoside prodrugs. Journal of Medicinal Chemistry40: 3323–3331.
4.
SepkowitzKA (2001). AIDS the first 20 years. New England Journal of Medicine344: 1764–1772.
5.
SiddiquiAQMcGuiganCBallatoreCZuccottoFGilbertIHDe ClercqE & BalzariniJ (1999). Journal of Medicinal Chemistry42: 4122–4128.
6.
UckunFMChelstromLMTuel-AhlgrenLDibirdikIIrvinJDChandan-LanglieM & MyersDE. (1998). TXU(Anti-CD7)-Pokeweed Antiviral Protein as a Potent Inhibitor of Human Immunodeficiency Virus. Antimicrobial Agents and Chemotherapy42: 383–388.
7.
UckunFM & VigR (2000) Aryl phosphate derivatives of D4T having anti-HIV activity. US Patent Number 6,030,957. Issue date: 2-29-2000. US Patent Number 6,350,736. Issue date: 2-26-2002.
8.
UckunFMQaziSPendergrassSVenkatachalamTKMaoCRichmanD (2002) Stampidine is a potent inhibitor of NRTI-resistant primary clinical HIV-1 isolates with B- and non-B subtypes. Antimicrobial Agents and Chemotherapy (in press).
9.
UckunFMChenCLLisowskiEMitcheltreeGCVenkatachalamTKErbeckDChenH & Waurzyniak (2002) Toxicity and pharmacokinetics of stampidine in mice and rats. Arzneimittelforschung Drug Research (in press).
10.
VenkatachalamTKTaiHLVigRChenCLJanS & UckunF (1998). Enhanced effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of D4T-phenyl methoxyalaninyl phosphate derivatives. Biorganic Medicinal Chemistry Letters8: 3121.
11.
VigRVenkatachalamT K & UckunFM (1998). D4T-5′-[p-bromophenyl methoxyalaninyl phosphate] as a potent and non-toxic anti-human immunodeficiency virus agent. Antiviral chemistry and Chemotherapy9: 445.