Collect. Czech. Chem. Commun. 2006, 71, 595-624

Syntheses of Base and Side-Chain Modified Pyrimidine 1-[2-(Phosphonomethoxy)propyl] Derivatives as Potent Inhibitors of Thymidine Phosphorylase (PD-ECGF) from SD-Lymphoma

Karel Pomeisl*, Ivan Votruba, Antonín Holý and Radek Pohl

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic


In this study we synthesized a series of thymine and 5-ethyluracil acyclic nucleoside phosphonates bearing hydroxymethyl, methoxymethyl, azidomethyl, aminomethyl and (trimethylammonio)methyl group in side chain as potent inhibitors of thymidine phosphorylase. In addition, we investigated in particular the novel syntheses of fluorinated derivatives containing fluoromethyl or trifluoromethyl groups in side chain such as 5-ethyl- 1-[(S)-3-fluoro-2-(phosphonomethoxy)propyl]uracil (8) or 5-ethyl-1-[3,3,3-trifluoro-2-(phosphonomethoxy)propyl]uracil and thymine derivatives 27 and 28. Uracil acyclic nucleoside phosphonates 1-{2-[(diisopropoxyphosphoryl)methoxy]ethyl}uracil (12) and 1-{2-[(diisopropoxyphosphoryl)methoxy]-3,3,3-trifluoropropyl}uracil (19) were fluorinated to corresponding 5-fluorouracil derivatives. While the 5-fluorouracil derivatives exhibit a marginal inhibitory effect, thymine and 5-ethyluracil compound with fluorine in side chains possess considerable inhibitory potency toward thymidine phosphorylase from rat spontaneous T-cell lymphoma.

Keywords: Acyclic nucleoside phosphonates; Acyclic nucleotide analogues; Nucleotides; Thymidine phosphorylase; Fluorination; Pyrimidines; Uracil; Thymine.

References: 21 live references.