PMID: 9443944Jan 28, 1998Paper

Intracellular metabolism of the N7-substituted acyclic nucleoside analog 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine, a potent inhibitor of herpesvirus replication

Molecular Pharmacology
J NeytsE De Clercq

Abstract

We investigated the intracellular metabolism of S2242 (2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine), the only known antivirally active acyclic nucleoside analogue with the side chain substituted at the N7 position of the purine ring. Uptake of S2242 by CEM cells increased linearly with increasing extracellular concentrations of the compound and was blocked by inhibitors of nucleoside transport. S2242 was phosphorylated in a time- and concentration-dependent manner to its monophosphates, diphosphates, and triphosphates. Intracellular half-life of the diphosphates and triphosphates in CEM cells was approximately 3-6 hr. A strong correlation was found between the cytostatic action of the compound and its phosphorylation in different cell lines. In accord with the findings that (1) the cytostatic potential of S2242 is reversed by deoxycytidine (dCyd) and (2) the growth of deoxycytidine kinase-deficient (dCK-) cells is refractory to the inhibitory effect of S2242, the amount of metabolites formed from S2242 in the dCK- cell line was approximately one hundredth of that in the wild-type cells. The observation that purified dCK phosphorylates S2242 to its monophosphate further corroborates these results. The activity of S2242 again...Continue Reading

References

Jul 1, 1991·Antiviral Research·G PalúE De Clercq
May 1, 1980·The Journal of Infectious Diseases·E De ClercqD Shugar
Apr 15, 1994·Pharmacy World & Science : PWS·V W Ruiz van Haperen, G J Peters
Jul 9, 1996·Proceedings of the National Academy of Sciences of the United States of America·M Johansson, A Karlsson
Jan 7, 1998·Antimicrobial Agents and Chemotherapy·J Neyts, E De Clercq

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Citations

Jul 26, 2008·Reviews in Medical Virology·Liesbeth LenaertsLieve Naesens
Jan 6, 1999·Antiviral Chemistry & Chemotherapy·A MeerbachJ Neyts
Dec 18, 2001·Reviews in Medical Virology·E De ClercqJ Neyts
Nov 26, 2014·Viruses·Natacha CoenGraciela Andrei
Feb 25, 2005·Antimicrobial Agents and Chemotherapy·L NaesensErik De Clercq
Sep 1, 2007·Expert Opinion on Drug Discovery·Kamel El Omari, David K Stammers
Sep 13, 2005·Journal of Combinatorial Chemistry·Han Fu, Yulin Lam

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