Synthesis and evaluation of some masked phosphate esters of the anti-herpesvirus drug 882C (netivudine) as potential antiviral agents.
A number of symmetric and asymmetric 5'-phosphate esters of the potent anti-varicella-zoster virus (VZV) agent 1-(beta-D-arabinofuranosyl)-5-prop-1-ynyluracil (882C; netivudine) were prepared as potential lipophilic, membrane-soluble prodrugs of the bio-active phosphate forms. The compounds were prepared by the base-catalysed coupling of various phosphorochloridates with the free nucleoside analogue. Compounds were fully characterized by a range of spectroscopic and analytical methods and were studied for their inhibition of several viruses in tissue culture. All of the phosphate esters were inactive against human cytomegalovirus, herpes simplex virus type 2, VZV, human immunodeficiency virus type 1 and influenza A virus (EC50 > 100 microM) except the 5'-(4-nitrophenyl phenyl) phosphate, which inhibited influenza A virus. The relative rate of esterase-mediated hydrolysis of one of the lead target structures was measured in order to rationalize the poor antiviral action, and data were collected on possible metabolites in support of this analysis. Cell-specific esterases are implicated as key determinants of the antiviral potency of prodrugs of this type.
McGuigan
C
C
Welsh School of Pharmacy, University of Wales Cardiff, UK.
Perry
A
A
Yarnold
C J
CJ
Sutton
P W
PW
Lowe
D
D
Miller
W
W
Rahim
S G
SG
Slater
M J
MJ
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D004950:Esterases / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D010710:Phosphates / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D013552:Swine
D000998:Antiviral Agents; D010710:Phosphates; D011355:Prodrugs; D001086:Arabinofuranosyluracil; D004950:Esterases; C067854:5-propynylarabinofuranosyluracil